8^th European Immunology Conference June 29-July 01, 2017 Madrid, Spain

Biography:

 Dr. Olga S. Latinovic is an assistant professor working  at the Institute of Human Virology (IHV) led by Robert C. Gallo, M.D. at the University of Maryland, School of Medicine in Baltimore, MD, USA.  Dr. Latinovic heads the Laboratory for Imaging Studies of Pathogens and Host Cells Interactions. Her research focus is on developing novel antiviral therapy strategies using various HIV entry inhibitors, with a particular focus in understanding antiviral synergistic activity and its mechanism between CCR5 antagonists and CCR5 antibodies extensively collaborating with Dr. Robert R. Redfield, MD. Dr. Latinovic wrote the book Micromechanics and Structure of Soft and Biological Materials, and published by Verlag Dr. Muller in 2010, and   co-authored the book Handbook of Photonics for Biomedical Engineering published by Springer-Verlag in 2016.  Dr. Latinovic lectures Virus Entry course for the grad students at the Department of Microbiology and Immunology at the University of Maryland, School of Medicine

Abstract:

We have previously shown that FLSC, a chimeric protein containing HIV-1BAL gp120 and the D1 and D2

domains of human CD4, blocks the binding and entry of HIV-1 into target cells by occluding CCR5, the major HIV-1 coreceptor. In an effort to improve the antiviral potential of FLSC, we fused it with the hinge-CH2-CH3 region of human IgG1. The IgG moiety should increase both the affinity and stability in vivo of FLSC, due to the resultant bivalency and an extended serum half-life, thereby increasing its antiviral potency. We previously showed that (FLSC) IgG1 indeed had greater antiviral activity against T cell infections. Here we extend these results to macrophages, for which (FLSC) IgG1 has a more potent antiviral activity than FLSC alone, due in part to its higher binding affinity for CCR5. We also test both compounds in a relevant humanized mouse model and show that, as anticipated, the IgG1 moiety confers a greatly extended half-life. In addition, we previously reported that treatment with the CCR5 small molecule antagonist Maraviroc (MVC) increased the apparent exposure of the (FLSC) IgG1 binding sites on CCR5, leading us to wonder if the two compounds used in combination might synergize in their anti-viral activity. Here we show that this is indeed the case. We demonstrate that fusion protein (FLSC) IgG1, strongly synergizes with the CCR5 antagonist Maraviroc to successfully inhibit both MVC-sensitive and MVC-resistant R5 HIV-1. These data, taken together with previous results, suggest development of further in vivo studies, potential clinical utility for (FLSC) IgG1 and support further developmental work toward eventual clinical trials.

Biography:

Dr. Steve Zhou has served as the Director of Virology and Toxicology at Microbac Laboratories, Inc. since 2006.  He has more than 16 years of experience virology, molecular biology and toxicology studies.  He has to-date designed and directed over 500 viral inactivation studies for disinfectants and biopharmaceutical products.  He is also a qualified clinical principle investigator.  Dr. Zhou is an active publisher and a member of several scientific and trade associations and committees.  He sits on the editorial board of the ARC Journal of Hematology.  He has delivered many presentations in conferences.  In 2015, he was invited to a scientific expert panel by the U.S. Environmental Protection Agency (EPA).

Abstract:

Statement of the Problem: The Zika virus (ZIKV) outbreak has caused thousands of cases of birth defects in 2016.  The virus is transmitted primarily through mosquito bites, but other routes of transmission such as sexual contact and laboratory infection were also reported.  Additionally, ZIKV has been isolated from multiple tissues such as blood, saliva, urine, semen, and genital secretions.  It thus represents a threat not only to the public health but also to the blood supply in infected areas.  However, the survivability of ZIKV in environment and its resistance to inactivation was largely unknown.  Methodology & Theoretical Orientation: The survivability of ZIKV, and its susceptibility to several commonly used physical and chemical treatments were examined using glass carriers and a viral infectivity assay.  Two levels of organic load, 5% serum and 90% blood, were used to assess the impact of blood on viral survivability.  Both the viral infectivity and genome copies were examined.  Additionally, the susceptibility of ZIKV was compared to two other flaviviruses - West Nile virus (WNV) and Bovine Viral Diarrhea Virus (BVDV).  Findings: ZIKV in 90% blood displayed much higher stability than in 5% serum. ZIKV was susceptible to dry heat treatment (56 – 60°C) in 5% serum, but less so in 90% blood. Quats and alcohol caused complete inactivation of ZIKV regardless of the organic load. Efficacy on ZIKV by chlorine and peracetic acid was highly dependent on the organic load.  pH 4.0 or pH 10.0 seemed to be ineffective against ZIKV.  Conclusion & Significance: ZIKV displays susceptibility to commonly employed disinfectants similar to that of other flaviviruses; however, blood may impact the susceptibility significantly.  This must be considered in the design and implementation of an appropriate infection control strategy for hospitals, public facilities, and research laboratories; and during assessment of blood supply safety. 

Biography:

Dr. Laparra Llopis JM holds a PhD in Pharmacy gained during his stay at the High Research Council of the Spanish Government (CSIC). His scientific career is focused on the field of intestinal homeostasis and the cross-talk within gut-liver axis. The novelty and scientific and social impact of his studies was used by the European Food Safety Authority to establish recommendations concerning staple foods. He held a leading position on prebiotic research awarded by The Fulbright Commission to conduct postdoctoral research in the Food Science Department at Cornell University (NY, USA). After his relocation to CSIC, a continuous contact and interaction with internationally renowned enterprises and research groups constitutes a constant in Dr Laparra’s career where he took major responsibilities overseeing several precompetitive funded projects. This experience favored his incorporation to the Institute of Translational Immunology at the University Medical Center of Mainz University (GER) as independent researcher. Currently, as senior researcher at IMDEA Food (Madrid, SPN) he develops immunonutritional-based precision strategies to selectively modulate innate immune responses preventing/treating the risk for/severity of liver-related metabolic and immune diseases and hepatocellular carcinoma. Particularly, his research approaches naturally occurring food components with powerful immunostimulatory property of toll-like receptors (TLRs) for active immunotherapy against liver metabolic dysfunction and cancer promotion. Here, Dr Laparra’s research efforts are focused on the impact and functional differentiation and polarization of macrophages, as relevant prognostic biomarkers of tissue damage and tumor progression. He develops strategies to selectively modulate metabolic programming of antigen presenting cells that have important roles in the regulation of CD4+ T cells priming as well as immune checkpoint blockade. Thereby, preventing effector CD8+ T cells exhaustion that helps developing longer anti-tumoral response(s). Dr Laparra has published over 70 scientific articles and several book chapters.

Abstract:

Recent data started appearing to show that immunonutritional factors and its influence on and interaction with the gut microbiota, and finally their crosstalk with the host’s immune system are important determinants of the gut-liver axis health, metastasis-initiating cells and cancer promotion. For example, multistructural and multifunctional cell surface molecules such as CD44, also guiding leukocyte extravasation, and the fatty acid receptor CD36 to metastatic penetrance and tumor growth. Moreover, innate immune activators, particularly, agonists of Toll-like receptor (TLR)-4 have been identified as critical players in hepatocellular carcinoma promotion and even modulate the immune-mediated checkpoint blockade. These can be targeted by nutrients, immunologically active, modulating the plasticity of both innate and adaptive immune responses. Personalized nutrition and, moreover, nutrition precision could have a significant impact on health to reduce the risk of metabolic and immune diseases and, particularly those associated to cancer promotion and/or progression. To date, major research interest has been focused on the influence of pre/probiotics, although, additional immunonutritional factors are also relevant even modulating the polarization and activation of immune responses. However, there remain key unanswered questions about immunonutritional factors that overall require a concerted effort to overcome the usually fragmented and compartmentalized approach to address their impact.

Biography:

Alexandra Emelyanova graduated from M.V. Lomonosov Moscow State University, Russia, with the qualification in pharmacy. Presently she is a PhD student focusing on pharmacology and preclinical studies organization and conduction at Institute of General Pathology and Patophysiology, Russia. She has published manuscripts devoted to research in viral infections treatment in English and Russian reputed journals and participated in international conferences and congresses

Abstract:

Statement of the problem: viral respiratory infections represent one of the main threats to human health. Antibodies-based therapy is a modern trend for combating viral infections, restricted by challenging administration and manufacturing. Our entirely new approach is to use antibodies (Abs) to immune regulators in a specific technological form, capable of surmounting these drawbacks. We found that after the initial Abs substance gradual consequent concentration’ decrease a specific activity releases (released-activity – RA) which is not to directly neutralize the target, but to modify it. E.g., RA Abs to IFNg and RA Abs to CD4 stimulate non-specific and specific immunity, while RA Abs to histamine influence anti-inflammatory network. These Abs’ use demonstrated efficacy in experimental studies of major viral respiratory infections. Methodology & Theoretical Orientation: RA Abs to IFNg were evaluated sole using standard models of influenza A/H1N1pdm09 (Oseltamivir resistant and sensitive strain), MERS-HCoV and RSV/Long infections in vitro; and in complex with RA Abs to histamine and RA Abs to CD4 against influenza A/H3N2 infection – in vivo. Findings: RA Abs have shown anti-influenza effect against its seasonal and pandemic strains, 2 times increasing the survival, and 10 times lowering virus titer (p<0.05) in vivo; enhancing Oseltamivir antiviral effect (in combination with RA Abs), decreasing viral copies number (Oseltamivir-sensitive strain) >100 times vs Oseltamivir alone (p<0.05) in vitro. For the resistant strain Oseltamivir showed no effect alone, but in combination with RA Abs – a significant (>1000 times, p<0.05) virus titer decrease was found. Drugs’ antiviral effect against other severe respiratory viruses is represented at the Image (p<0.05). Conclusion & Significance: our fundamentally new approach to Abs’ therapeutic use not only offers an opportunity to safely and effectively treat a wide spectrum of infections even the most dangerous, but also to increase the existing drugs’ efficacy via their conjoin application with RA Abs.

Biography:

Marc Bigaud is a senior pharmacologist (PhD) at the Novartis Institutes for Biomedical Research, in Basel (Switzerland). He is part of the AutoImmunity, Transplantation and Inflammation-Disease Area

Abstract:

Non-obese diabetic (NOD) mice provide a preclinical model of autoimmune diseases as they spontaneously develop autoimmune diabetes sharing many similarities to type 1 diabetes (T1D) as well as sialadenitis resembling Sjögren's syndrome in humans. In the current study, we followed the natural course of the disease and evaluated the therapeutic effects of a potent and selective PI3Kδ inhibitor referred as “compound-1” (manuscript in preparation).

Drug-treatment was administered over 12 weeks, mixed with food at 0.1%, to 12-weeks old NOD mice (n=12). This treatment demonstrated in preliminary studies full target inhibition. In parallel, control NOD mice were given drug-free food (n=12).

Blood samples were collected for drug level measurements (LC-MS-MS). Anti-IgM/rIL-4-induced PI3Kδ-dependent pAkt in B cells was used as PD marker and monitored by flow cytometry. The incidence of diabetes, the cellularity of spleen and salivary glands were determined. The number of antibody-secreting cells was measured by ELISPOT. The development of ectopic germinal centers in salivary glands was followed by immunohistochemistry.

After 12 weeks of treatment, a similar diabetes incidence was observed in compound-1-treated vs control NOD mice. Drug blood levels (0.11-1.12 µM) showed an exposure-related inhibition of PI3K/pAkt pathway activation, with a mean IC50 value of approximately 0.44 µM. In the spleens, flow cytometry analysis revealed marked drug-induced reductions in marginal zone B cells (≥70%), in germinal center B cells (≥30%), plasma cells (≥60%) and Tfh cells (≥40%). In salivary glands, significant reductions in infiltrating CD3⁺ T cells and CD45R⁺ B cells (≥ 40%) were observed in drug-treated vs control NOD mice (Figure 1). In line with this observation, the incidences of IgM-secreting and IgG-secreting cells in salivary glands were significantly reduced (by 70-80%) in drug-treated vs control mice.

In conclusion, this study provides pre-clinical proof-of-concept that PI3Kδ inhibition reduces hallmarks of disease pathology that are operational in Sjögren's syndrome.

Biography:

Saeed El-Ashram is an Associate Professor of Parasitology, Faculty of Science, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt. He is the holder of several issued and pending patents in the field of Parasitology. He is also the Inventor of “Compositions and methods of enhancing immune responses to Eimeria” (United States Patent 8956849). Dr. Saeed El-Ashram scientific interests include Parasitology, Immunology, Veterinary Medicine and Next -Generation Sequencing (MiSeq and HiSeq). His recent publications include Electrical cream separator coupled with vacuum filtration for the purification of eimerian oocysts and trichostronglyid eggs, Gel Mapping to Differentiate between Sporozoites of Two Immunologically Distinct Strains of Eimeria maxima (Strains M6 and Guelph ),  Interferon-Gamma Release Assay,Exploring Early and Late Toxoplasma gondii Strain RH Infection by Two-Dimensional Immunoblots of Chicken Immunoglobulin G and M,  and Mycoplasma gallisepticum MGA_0676 is a membrane-associated cytotoxic nuclease with a staphylococcal nuclease region essential for nuclear.

Abstract:

The interactions between gastric microbiota, ovine host, and Haemonchus contortus portray the ovine stomach environment as a complex ecosystem, where all factors play a pertinent role in fine-tuning each other and in the homeostatic maintenance. We delineated the impact of early and late Haemonchus infection on abomasal and ruminal microbial community, and ovine host. Twelve parasite-naive lambs were divided into four treatments, uninfected-control groups and 7- and 50- day post-infected groups, in triplicate. Six sheep were inoculated with 5,000 of H. contortus infective larvae and followed for 7 and 50 days with their corresponding uninfected-control ones. Ovine stomach tissues were collected for histological and anatomical analyses and gastric fluids collected to measure PH values, microbial community isolated and subjected to the Illumina MiSeq platform and bioinformatic analysis. Our results showed that Haemonchus infection increased the abomasal gastric pH (P = 0.04953) and caused a substantial augmentation in anterior blind sac papillae numbers (P = 0.0463), as well as resulted in necrotizing and inflammatory changes that were more severe during acute infection. Furthermore, infection increased the abomasal bacterial load and decreased the ruminal microbiome, but abrogated Archea in both gastric compartments. A 7-day infection of sheep with H. contortus significantly altered approximately 98 % and 94 % of genera in the abomasal and ruminal bacterial profile, respectively (P = 0.0369-0.0495). However, the approximate altered genera 50 days after infection in the ovine abomasal and ruminal microbiome were about 62 % and 69 %, correspondingly(P = 0.0369-0.0495) with increase in some bacteria and decrease in others. Overall, these results indicate that Haemonchus infection plays a crucial role for shaping stomach microbial community composition, and diversity.

Biography:

Dong-Kyu Kim research work at Department of Otorhinolaryngology-Head and Neck Surgery, Chuncheon Sacred Heart Hospital and Nano-Bio Regenerative Medical Institute, Hallym University College of Medicine, Chuncheon, Republic of Korea

Abstract:

Background: Periostin is involved in Th2 inflammation and a biomarker of allergic diseases. However, its role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unclear.

Objective: To investigate the cellular origin and the role of periostin in CRSwNP.

Methods: Expressions of periostin and its receptor, integrin αV, were investigated in nasal polyps (NP) by qRT-PCR, IHC and ELISA. Immunohistochemistry and immunocytochemistry were used to determine cellular sources of periostin in NP and a human mast cell line, LAD2. LAD2 cells were stimulated with IgE, IL-4, IL-13 or TNF-α and periostin measured in the culture supernatants. Normal human bronchial epithelial cell (NHBE) were stimulated with periostin, IL-4, IL-13, TNF-α, and dsRNA alone or in combination and thymic stromal lymphopoietin (TSLP) measured in the culture supernatants.

Results: Periostin was up-regulated and positively correlated with IL-5, CCL-11 and CT scores in eosinophilic NP (E-NP), but not in non-eosinophilic NP. Tryptase-positive cells were a main source of periostin in E-NP. Periostin levels were also correlated positively with total IgE in E-NP homogenate. Furthermore, IgE stimulation enhanced the mRNA and protein levels of periostin. Confocal microscopic examination of LAD2 cells showed that periostin was localized in the granules. Overexpression of integrin αV was observed in epithelial layers of E-NP and correlated positively with the levels of periostin in E-NP. Periostin and integrin αV expressions in the epithelia were positively associated with TSLP at mRNA and protein levels in E-NP. Treatment with periostin induced more TSLP production in NHBE than those without periostin, in combination with IL-13 or IL-4 and TNF-α or dsRNA.

Conclusion: These data suggest that periostin is upregulated in E-NP and correlates with Th2 markers. Human mast cells are a major source of NP-derived periostin, which may induce TSLP production from epithelial cells

Biography:

Mohammad Afzal Khan research work at Comparative Medicine Department and Organ Transplant Centre, King Faisal Specialist Hospital and Research Centre, Riyadh

Abstract:

Microvascular loss is a major cause of chronic rejection in all solid organ transplants, and there are no ongoing immunosuppressive regimens sufficiently affect the restoration of functional microvascular flow during acute rejection [1]. Most immunotherapies for organ transplantation face the challenges of achieving enough immunosuppression to prevent organ rejection or limit autoreactivity without preserving microvasculature [2]. Tregs play a crucial role in maintaining immunological unresponsiveness to self-antigens and and secrete immunosuppressive IL-10 to suppress heightened immune responses destructive to the host tissue in organ transplant recipients [3], however, the effects of Treg mediated immunosuppression on microvascular reestablishment has been reported [4] but the molecular mechanism of Treg-mediated microvascular improvements has never been examined in rejecting allografts. To further demonstrate the role of IL-10, Balb/C→B6 allografts were treated with anti mouse IL-10 (10mg/kg, i.p. at d0 and every day thereafter), and allografts were monitored for Treg suppression, tissue oxygenation (tpO₂), blood perfusion and functional microvascular connections during allograft rejection. Our findings demonstrated that IL-10 blocking promotes induction of CD4⁺ T cells while suppress T regulatory cells, which favors accelerated microvascular loss and allograft rejection and as a consequence, tissue hypoxia, ischemia and associated airway remodeling after IL-10 blockade. Altogether, these findings suggested that targeted blocking of IL-10 trigger the induction of CD4⁺ T cells, which may confer key effector functions through inflammation and associated injuries. These findings may be useful in designing recombinant IL-10 based therapies to rescue tissue/organ rejection.

Biography:

Roswitha Gropp has over 25 years of experience in preclinical development and infl ammatory diseases. She recently took on a different view considering the infl ammatory process in UC as an uncontrolled wound healing process. This hypothesis assumes that epithelial damage induces the release of signals to evoke a Th2 characterized infl ammatory response that ultimately results in repair of the colon. Using agent based modeling fi rst disease maps were developed to describe the infl ammatory milieu and the dynamics of the infl ammatory response. This approach together with immunological profi ling of patients allows for a better understanding of underlying mechanisms ultimately leading to individualized therapies.

Abstract:

To date, no comprehensive analysis of autoantibodies in sera of patients with ulcerative colitis has been conducted. To analyse the spectrum of autoantibodies serum-IgG from UC patients and non-UC donors were screened by using a human protein microarray. Screening yielded a remarkable number of 697 diff erentially reactive antigens, most of which are expressed on immune cells suggesting a general lack of tolerance in a subgroup of UC patients. From this analysis, CD99 emerged as a biomarker to discriminate between non-UC and UC patients. In vitro, incubation with CD99 induced the frequencies of CCR4 expressing CD4+ cells (eff ector memory regulatory T cells) and TSLPR expressing CD11b+ macrophages and CD14+ monocytes in peripheral blood mononuclear cells (PBMC), indicating an anti-infl ammatory response. In vivo, challenge with CD99 aggravated disease symptoms and pathological phenotype in NOD-scid IL2Rnull (NSG) mice reconstituted with PBMC from UC donors and challenged with ethanol (NSG-UC) indicating failure to induce tolerance in this mouse model. Treatment with sirolimus, which is known to promote Treg suppressed infl ammation as indicated by decreased clinical and histological scores and IFN mRNA levels and increased frequencies of eff ector memory regulatory T-cells. In contrast, treatment with an anti-CCR4 antibody resulted in depletion of CCR4 expressing CD4+ T-cells and aggravated infl ammation. Th us, autoimmunity seems to be a driving force in the NSG-UC mouse model. Future studies have to show whether this also applies to the human disease and whether shift ing the immunological equilibrium towards tolerance might be a promising therapeutic alternative.

Biography:

Thomas Böldicke has obtained his PhD degree from Max Planck Institute of Molecular Genetics, Berlin. Since 1986, he has been working at Helmholtz Centre for Infection Research, as a Project Leader of Intracellular Antibodies

Abstract:

Polysialic acid (polySia) is a carbohydrate modifi cation of the neural cell adhesion molecule (NCAM), which is implicated in neural diff erentiation and plays an important role in tumor development and metastasis. Polysialylation of NCAM is mediated by two Golgi-resident polysialyltransferases (polyST) ST8SiaII and ST8SiaIV. Intracellular antibodies (intrabodies; IB) expressed inside the ER and retaining proteins passing the ER such as cell surface receptors or secretory proteins provide an effi cient means of protein knockdown. To inhibit the function of ST8SiaII and ST8SiaIV specifi c ER IBs were generated starting from two corresponding hybridoma clones. Both IBs αST8SiaII-IB and αST8SiaIV-IB were constructed in the scFv format and their functions characterized in vitro and in vivo. Stable expression of ST8SiaII-IB, ST8SiaIV-IB and luciferase in the rhabdomyosarcoma cell line TE671 reduced cell surface expression of polySia and delayed tumor growth if intrabody expressing tumor cells were xenograft ed into C57BL/6J RAG-2 mice. Data obtained strongly indicate that αST8SiaII-IB and αST8SiaIV-IB are promising experimental tools to analyze the individual role of the two enzymes during brain development and during migration and proliferation of tumor cells.

Biography:

Dong-Kyu Kim, MD, PhD, is working as an Assistant Professor at the Department of Otorhinolaryngology-Head and Neck Surgery and Nano-Bio Regenerative Medical Institute, Hallym University, College of Medicine, Chuncheon, Korea.

Abstract:

Background: Periostin is involved in Th2 inflammation and a biomarker of allergic diseases. However, its role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unclear.

Objective: To investigate the cellular origin and the role of periostin in CRSwNP.

Methods: Expressions of periostin and its receptor, integrin αV, were investigated in nasal polyps (NP) by qRT-PCR, IHC and ELISA. Immunohistochemistry and immunocytochemistry were used to determine cellular sources of periostin in NP and a human mast cell line, LAD2. LAD2 cells were stimulated with IgE, IL-4, IL-13 or TNF-α and periostin measured in the culture supernatants. Normal human bronchial epithelial cell (NHBE) were stimulated with periostin, IL-4, IL-13, TNF-α, and dsRNA alone or in combination and thymic stromal lymphopoietin (TSLP) measured in the culture supernatants.

Results: Periostin was up-regulated and positively correlated with IL-5, CCL-11 and CT scores in eosinophilic NP (E-NP), but not in non-eosinophilic NP. Tryptase-positive cells were a main source of periostin in E-NP. Periostin levels were also correlated positively with total IgE in E-NP homogenate. Furthermore, IgE stimulation enhanced the mRNA and protein levels of periostin. Confocal microscopic examination of LAD2 cells showed that periostin was localized in the granules. Overexpression of integrin αV was observed in epithelial layers of E-NP and correlated positively with the levels of periostin in E-NP. Periostin and integrin αV expressions in the epithelia were positively associated with TSLP at mRNA and protein levels in E-NP. Treatment with periostin induced more TSLP production in NHBE than those without periostin, in combination with IL-13 or IL-4 and TNF-α or dsRNA.

Conclusion: These data suggest that periostin is upregulated in E-NP and correlates with Th2 markers. Human mast cells are a major source of NP-derived periostin, which may induce TSLP production from epithelial cells. 

Biography:

Emelyanova A G graduated from M V Lomonosov Moscow State University, Russia, with qualification in Pharmacy. She is currently pursuing her PhD on Pharmacology and Preclinical Studies Organization and Conduction at Institute of General Pathology and Pathophysiology, Russia. She has published manuscripts devoted to research in viral infections treatment in English and Russian reputed journals and participated in international conferences and congresses.

Abstract:

Statement of the Problem: Viral respiratory infections represent one of the main threats to human health. Antibodies-based therapy is a modern trend for combating viral infections, restricted by challenging administration and manufacturing. Our entirely new approach is to use antibodies (Abs) to immune regulators in a specific technological form, capable of surmounting these drawbacks. We found that after the initial Abs substance gradual consequent concentration’ decrease a specific activity releases (released-activity-RA) which is not to directly neutralize the target, but to modify it, e.g., RA Abs to IFNg and RA Abs to CD4 stimulate non-specific and specific immunity, while RA Abs to histamine influence anti-inflammatory network. These Abs’ use demonstrated efficacy in experimental studies of major viral respiratory infections.

Methodology & Theoretical Orientation: RA Abs to IFNg were evaluated by using standard models of influenza A/H1N1pdm09 (Oseltamivir resistant and sensitive strain), MERS-HCoV and RSV/Long infections in vitro; and in complex with RA Abs to histamine and RA Abs to CD4 against influenza A/H3N2 infection in vivo.

Findings: RA Abs have shown anti-influenza effect against its seasonal and pandemic strains, 2 times increasing the survival, and 10 times lowering virus titer (p<0.05) in vivo; enhancing Oseltamivir antiviral effect (in combination with RA Abs), decreasing viral copies number (Oseltamivir-sensitive strain) >100 times vs. Oseltamivir alone (p<0.05) in vitro. For the resistant strain Oseltamivir showed no effect alone, but in combination with RA Abs-a significant (>1000 times, p<0.05) virus titer decrease was found.

Conclusion & Significance: our fundamentally new approach to Abs’ therapeutic use not only offers an opportunity to safely and effectively treat a wide spectrum of infections even the most dangerous, but also to increase the existing drugs’ efficacy via their conjoin application with RA Abs.

Biography:

Yanina Arana has been involved in the study of several infectious diseases that are considered public health problems in many Latin American countries. By her interest in science, she has participated in different research projects showing compromise, autonomy and valuable analytical skills that allowed to her to lead a research group in Cysticercosis in collaboration with other national and international professionals in this disease. Her expertise in several methodologies, leadership, objectivity and criticism has been reflected in her publications. Currently, she develops her doctoral thesis project at the BNITM focusing in the evaluation of regulatory pathways during the Trypanosoma cruzi infection. This experience, allow her to obtain valuable theoretical knowledge and practical skills that will be of benefit for the continuity of her research in her institution in Peru as a member of a group that have the aim to form researchers that contribute to the solution of health problems that affect this country.

Abstract:

Statement of the Problem: The protozoa parasite Trypanosoma cruzi is the etiological agent of Chagas disease or American trypanosomiasis.   Nearly 18 million people in Latin America and 90 million worldwide are at risk of infection. To establish life-long infections which are often asymptomatic or with digestive or cardiac alterations that can lead to host death, T. cruzi must subvert the host immune system employing several strategies that involve effectors and regulatory mechanisms. Preliminary studies have shown that during chronic parasite infections, Ag-specific T cells become dysfunctional, upregulate the expression of inhibitory receptors, involving these regulatory pathways in the control of the infection. Recent studies have shown that T. cruzi modulates the expression of these receptors on lymphocytes after the infection however, there are a variety of natural strains of T. cruzi and it appears that their immune modulatory effects are strain-dependent, a feature that may influence parasite-host interaction. The aim of this study is to evaluate the role of two inhibitory pathways: BTLA:HVEM and PD-1:PD-L1 during the experimental infection by T. cruzi Tulahuen strain in a murine model, focusing on the effects of a blockade of these pathways as a potential strategy to design future therapeutic approaches for Chagas disease.  Methodology & Theoretical Orientation: Knockout mice for these inhibitory molecules were employed in a previously established infection model. The immune response was evaluated by flow cytometry and cytokine analysis by cytometric bead assays. Findings: BTLA and PD-1-deficiency was not associated with a reduced parasitemia neither improved resistance to infection. No difference in the frequency of activated T cells or other immune cells populations were observed in both groups of infected knockout mice in comparison to control groups, however reduced levels of cytokines (IL-2, IL-6 and IL-9) were observed in both infected knockout mice. Strikingly, upon PD-1:PD-L1 blockade, upregulation of another inhibitory receptor (Tim-3) were observed on activated T cells.  Conclusion & Significance: In vivo assays demonstrated that these inhibitory pathways might play an important role in the control of parasite during infection. The interruption of these pathways could not improve the resistance to the infection but favored a pronounced exhaustion stage of immune cells suggesting a compensatory mechanism, specifically upon PD-1:PD-L1 blockade that induced the upregulation of another inhibitory receptor (Tim-3) during the infection, mechanism that have been reported to be involved in the anti PD-1 therapy resistance in several cancers.

Biography:

Audrey Margery-Muir is a PhD student at Curtin University (Perth, Western Australia) in the school of Biomedical Sciences. She has been researching the immune pathways involved in the pathology of SLE and has had 3 successful papers accepted/ published in well renowned papers. She is enjoying her research and hope to continue forward after the completion of her doctorate degree.

Abstract:

Systemic lupus erythematosus (SLE) is an inflammatory disorder in which autoantibodies contribute to impaired apoptosis and clearance of cell debris.  Anti dsDNA and anti C1q antibodies have been implicated, as well as complement protein C1q itself.   IgG autoantibodies reacting with the collagen-like region of C1q protein (aC1q ab) were quantitated in serum of 56 patients diagnosed with SLE and undergoing treatment for variable periods, together with 33 age/sex-matched controls.  Analysis of the results showed optimal sensitivity and specificity of 57% and 91% respectively at a cut-off concentration for positivity of 20 U/ml.  The assay is a potentially useful confirmatory test for SLE, but is not suitable as a screening test for SLE with the probability of a positive test and SLE in an individual within a random population of only ≤1%.  aC1q ab concentrations were detectable in all samples tested with concentrations manifesting no correlation with age and serum C1q levels in SLE patients and a negative correlation with age in controls.  The aC1q ab detected by this assay do not react therefore with native C1q. In SLE patients, aC1q ab concentrations correlated with the concentrations of dsDNA antibodies, (p = 0.0001) and C-reactive protein and inversely with complement component C4 (C4) concentrations (p = 0.041).  aC1q ab concentrations were not associated with individual therapeutic regimens, but were higher in those patients receiving a combination of three drug therapies and with the presence of renal disease.     The diagnostic relevance of this complex autoantibody will require further definition of its antigenic specificities.

Biography:

Abstract:

Biography:

Abstract:

Biography:

Abstract:

Biography:

Noëlle Mathieu has a thesis in Immunology from the Marseille-Luminy Immunology Center, France. She joined the Institute of Radioprotection and Nuclear Safety near Paris. Her project consists in studying late side effects of pelvic radiotherapy and developing therapeutic strategies. She used pre-clinical animal models of localized irradiation to the colorectum and developed endoscopy technique and surgery in rats. She used this model to understand the physiopathology of radiation proctitis and used cell therapy using mesenchymal stromal cells to reduce radio-induced damaged to the colon. Her studies contribute to the use of this treatment in compassional case of patients who had a surdose of ionizing radiation during their radiotherapy protocol. She is also involved in combined therapy to improve the actual treatment.

Abstract:

Statement of the Problem: Bowel radiation injury is an insidious disease associated with substantial morbidity and mortality. Moreover, it’s an increasing problem as more patients receive radiotherapy and survive longer after their tumor treatment. Bowel radiation injury results from the treatment of several cancers by radiotherapy in which normal colorectal tissues are present in the irradiation field. The clinical expression of bowel complications associated to radiotherapy resembles chronic bowel disease of other etiologies. However, recent studies have identified differences and specialists have proposed that complications following pelvic radiotherapy should be recognized as a “new disease” (Andreyev et al, 2010). The growing number of cases declared every year highlights the importance of understanding the mechanisms involved and of finding effective therapies. There is no unified approach for the assessment and treatment of this disease partly due to insufficient knowledge about the mechanism involved in the development of bowel radiation injury. However, unresolved inflammation is hypothesized to have an important role in late side effects. We used an experimental model of radiation proctitis developed in rats that reproduces severe colonic mucosal damages and fibrosis similar to those observed in patients treated by radiotherapy.

Findings: Our studies demonstrated the involvement of inflammation and immunity in colorectal damages induced after localized irradiation. We also evaluated the benefit of immunomodulatory mesenchymal stromal cells isolated from adipose tissue (Ad-MSC) to reduce late side effects. We demonstrated a therapeutic benefit on different crucial functions of the colon and determined pleiotropic action mechanisms of the cell therapy treatment.

Conclusion & Significance: Our studies provide evidence for the potential of Ad-MSC to limit radiation effects on the colon and could open new perspectives in the treatment of other inflammatory bowel diseases.

Biography:

S Steve Zhou has served as the Director of Virology and Toxicology at Microbac Laboratories, Inc. since 2006. He has more than 16 years of experience in Virology, Molecular Biology and Toxicology Studies. He has to-date designed and directed over 500 viral inactivation studies for disinfectants and biopharmaceutical products. He is also a qualified Clinical Principle Investigator. He is an active publisher and a member of several scientific and trade associations and committees. He sits on the Editorial Board of the ARC Journal of Hematology. He has delivered many presentations in conferences. In 2015, he was invited to a scientific expert panel by the US Environmental Protection Agency (EPA). He holds a PhD from Johns Hopkins University School of Medicine. Prior to joining Microbac, he served as a Laboratory Director of Viral Clearance at BioReliance Corporation and worked at Merck on Antiviral Drug Development.

Abstract:

Statement of the Problem: The Zika virus (ZIKV) outbreak has caused thousands of birth defect cases in 2016. The virus is transmitted primarily through mosquito bites, but other routes of transmission such as sexual contact and laboratory infection were also reported. Additionally, ZIKV has been isolated from multiple tissues such as blood, saliva, urine, semen and genital secretions. It thus represents a threat not only to the public health but also to the blood supply in infected areas. However, the survivability of ZIKV in environment and its resistance to inactivation was largely unknown.

Methodology & Theoretical Orientation: The survivability of ZIKV, and its susceptibility to several commonly used physical and chemical treatments were examined using glass carriers and a viral infectivity assay. Two levels of organic load, 5% serum and 90% blood, were used to assess the impact of blood on viral survivability. Both the viral infectivity and genome copies were examined. Additionally, the susceptibility of ZIKV was compared to two other flaviviruses -West Nile Virus (WNV) and Bovine Viral Diarrhea Virus (BVDV).

Findings: ZIKV in 90% blood displayed much higher stability than in 5% serum. ZIKV was susceptible to dry heat treatment (56-60°C) in 5% serum, but so less in 90% blood. Quats and alcohol caused complete inactivation of ZIKV regardless of the organic load. Efficacy on ZIKV by chlorine and peracetic acid was highly dependent on the organic load. pH 4.0 or pH 10.0 seemed to be ineffective against ZIKV.

Conclusion & Significance: ZIKV displays susceptibility to commonly employed disinfectants similar to that of other flaviviruses; however, blood may impact the susceptibility significantly. This must be considered in the design and implementation of an appropriate infection control strategy for hospitals, public facilities, and research laboratories; and during assessment of blood supply safety.

Biography:

Katarzyna Swist-Szulik is working as a consultant in paediatric intensive care and has her passion in research on the role of mitochondria in inflammatory signalling. She is pursuing her PhD on the role of mitochondrial dysfunction in intercellular crosstalk between myeloid and non-myeloid cells. There are building evidence that mitochondria-inflammatory interactions are relevant to many disease processes such as inflammatory myopathies, neurodegenerative diseases, autoimmune diseases as well as multi-organ failure and drug induced sterile inflammation. Katarzyna is working on developing the translation research investigating mitochondria-inflammatory relationship. Outside work Katarzyna is a mother of two wonderful children, an adventurer, ultramarathon runner and finisher of Marathon des Sables in 2015.

Abstract:

Introduction: Mitochondria are double-membrane-bound organelles and primary source of cellular energy adenosine triphosphate (ATP). Mitochondria are also involved in innate responses and are necessary for NLRP3 inflammasome activation and maturation of IL-1β in immune cells. Research project investigates the role of mitochondrial dysfunction in cell to cell cytokine crosstalk ((1-6) .   Aims: To characterise the nature of cytokine crosstalk between fibroblasts and myoblasts with induced mitochondrial dysfunction and inflammatory cells such as monocytes and THP1 cells.  Methods: Stimulation with LPS (lipopolysaccharide) and benzylated ATP were used to cleavage NLRP3 inflammasome and release IL-1β in monocytes and THP1 cells. Supernatants containing IL-1β from treated for inflammasomes THP1 cells  as well as recombinant IL-1β were applied on fibroblasts and myoblasts with induced  by Rotenone ( Complex I inhibitor) mitochondrial dysfunction. Blocking experiment using anti-IL-1β, anti-IL-1α antibodies as well as IL-1 receptor antagonist characterized the interactions between IL-1β and Il-6 cytokines. ELISA tests were used to measure the content of IL-1β and IL-6 in supernatants. Seahorse was used to assess the changes in bioenergetics profile of the treated cells.  Results: Fibroblasts and myoblasts release IL-6 in the presence of supernatants containing IL-1β from THP1 cells and monocytes in the dose dependent manner. Cells with induced mitochondrial dysfunction produce high levels of IL-6 level in close correlation with the degree of mitochondrial dysfunction and dose of recombinant IL-1β. IL-6 released by fibroblasts is in 90% inhibited by adding IL-1 receptor antagonist (IL-Ra) and anti-IL-1β antibodies what would suggest single cytokine crosstalk between IL-1β and IL-6. Conclusions: The data indicate the presence of crosstalk between monocytes and fibroblasts or myoblasts on the cytokine level characterized by IL-1β and IL-6 relationship. Ability to produce high levels of IL-6 by fibroblasts or myoblasts is amplified by degree of mitochondrial dysfunction and presence of IL-1β in dose dependent manner.

Biography:

Dr. Laparra Llopis JM holds a PhD in Pharmacy gained during his stay at the High Research Council of the Spanish Government (CSIC). His scientific career is focused on the field of intestinal homeostasis and the cross-talk within gut-liver axis. The novelty and scientific and social impact of his studies was used by the European Food Safety Authority to establish recommendations concerning staple foods. He held a leading position on prebiotic research awarded by The Fulbright Commission to conduct postdoctoral research in the Food Science Department at Cornell University (NY, USA). After his relocation to CSIC, a continuous contact and interaction with internationally renowned enterprises and research groups constitutes a constant in Dr Laparra’s career where he took major responsibilities overseeing several precompetitive funded projects. This experience favored his incorporation to the Institute of Translational Immunology at the University Medical Center of Mainz University (GER) as independent researcher. Currently, as senior researcher at IMDEA Food (Madrid, SPN) he develops immunonutritional-based precision strategies to selectively modulate innate immune responses preventing/treating the risk for/severity of liver-related metabolic and immune diseases and hepatocellular carcinoma. Particularly, his research approaches naturally occurring food components with powerful immunostimulatory property of toll-like receptors (TLRs) for active immunotherapy against liver metabolic dysfunction and cancer promotion. Here, Dr Laparra’s research efforts are focused on the impact and functional differentiation and polarization of macrophages, as relevant prognostic biomarkers of tissue damage and tumor progression. He develops strategies to selectively modulate metabolic programming of antigen presenting cells that have important roles in the regulation of CD4+ T cells priming as well as immune checkpoint blockade. Thereby, preventing effector CD8+ T cells exhaustion that helps developing longer anti-tumoral response(s). Dr Laparra has published over 70 scientific articles and several book chapters.

Abstract:

Recent data started appearing to show that immuno-nutritional factors and its influence on and interaction with the gut microbiota, and finally their crosstalk with the host’s immune system are the important determinants of gut-liver axis health, metastasis-initiating cells and cancer promotion. For example, multi-structural and multifunctional cell surface molecules such as CD44, also guiding leukocyte extravasation, and the fatty acid receptor CD36 to metastatic penetrance and tumor growth. Moreover, innate immune activators, particularly, agonists of Toll-like receptor (TLR)-4 have been identified as critical players in hepatocellular carcinoma promotion and even modulate the immune-mediated checkpoint blockade. These can be targeted by nutrients, immunologically active, modulating the plasticity of both innate and adaptive immune responses. Personalized nutrition and, moreover, nutrition precision could have a significant impact on health to reduce the risk of metabolic and immune diseases and, particularly those associated to cancer promotion and/or progression. To date, major research interest has been focused on the influence of pre/probiotics, although, additional immunonutritional factors are also relevant even modulating the polarization and activation of immune responses. However, there remain key unanswered questions about immunonutritional factors that overall require a concerted effort to overcome the usually fragmented and compartmentalized approach to address their impact.

Biography:

Wen Qiu is currently working as an Associate Professor at Department of Immunology, Nanjing Medical University. He is exploring the role of complement especially C5b-9 in the induction of Glomerular Mesangial Cell (GMC) apoptosis, inflammation and proliferation in rat Thy-1 nephritis as a widely used model of human mesangial proliferative glomerulonephritis (MsPGN) and its mechanisms. These include signal transduction, microRNA regulation, transcriptional factor regulation. He is also exploring the effects of post-transcriptional regulation such as ubiquitination and acetylation on the activation of signaling molecules, transcription factors and histones.

Abstract:

Inflammatory response has been reported to contribute to the renal lesions in rat Thy-1 nephritis (Thy-1N) as an animal model of human mesangioproliferative glomerulonephritis (MsPGN). Besides C5b-9 complex, C5a is also a potent pro-inflammatory mediator and correlated to severity of various nephritic diseases. However, the role of C5a in mediating pro-inflammatory cytokine production in rats with Thy-1N is poorly defined. In the present studies, the levels of C5a, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were first determined in the renal tissues of rats with Thy-1N. Then, the expression of IL-6 and TNF-α was detected in rat glomerular mesangial cells (GMC) stimulated with our recombinant rat C5a in vitro. Subsequently, the activation of mitogen-activated protein kinase (MAPK) signaling pathways (p38 MAPK, ERK1/2 and JNK) and their roles in the regulation of IL-6 and TNF-α production were examined in the GMC induced by C5a. The results showed that the levels of C5a, IL-6 and TNF-α were markedly increased in the renal tissues of Thy-1N rats. Rat C5a stimulation in vitro could up-regulate the expression of IL-6 and TNF-α in rat GMC, and the activation of MAPK signaling pathways was involved in the induction of IL-6 and TNF-α. Mechanically, p38 MAPK activation promoted IL-6 production, while either ERK1/2 or JNK activation promoted TNF-α production in the GMC with exposure to C5a. Taken together, these data implicate that C5a induces the synthesis of IL-6 and TNF-α in rat GMC through the activation of MAPK signaling pathways.

Biography:

Pierre-Yves Robillard, neonatologist and epidemiologist. Neonatal Department Centre Hospitalier Universitaire Sud Réunion, Centre d’Etudes Périnatales Océan-
Indien (Reunion island, Indian Ocean). Medical studies University of Bordeaux, fellowship in University Hospital Pointe-àPitre, Guadeloupe (French West Indies).
Post-Doctoral fellowship in perinatal Epidemiology at the Medical University of South-Carolina, Charleston, SC, USA (1991-1992), International EIS course CDC
Atlanta, GA, USA (1992). All his career in French overseas territories
- 16 years in Guadeloupe (French West Indies)
- 3 years in Tahiti (French Polynesia)
- 18 years in Réunion island (Indian Ocean)
Chief of the PICU-NICU in the Centre Hospitalier Universitaire Sud Réunion (2002-2015).
Co-Director of the Centre d’Etudes Périnatales Océan-Indien.
Organization since 1998 of the International Workshops on Reproductive Immunology, immunological Tolerance and Immunology of Preeclampsia. (10th Edition in 2016).

Abstract:

Eclampsia (together with epilepsy) being the first disease ever written down since the beginning of writings in mankind 5000 years ago, we will make a brief presentation of the different major steps in comprehension of  Pre-eclampsia. 1) 1840. Rayer, description of proteinuria in eclampsia, 2) 1897 Vaquez,  discovery of gestational hypertension (1 year after the invention of the inflatable arm band in 1896 by a young 31 year-old Italian physician Riva-Rocci) in eclamptic women, 3)  In the  1970’s, description of the “double” trophoblastic invasion existing only in humans (Brosens & Pijnenborg,), 4) between the 1970’s and the 1990’s, description of preeclampsia being a couple disease. The “paternity problem” (and therefore irruption of immunology), 5) at the end of the 1980’s, a major step forward: Preeclampsia being a global endothelial cell disease (glomeruloendotheliosis, hepatic or cerebral vascularitis, HELLP, eclampsia), inflammation  ( J.Roberts. C Redman, R Taylor), 6) End of the 1990’s: Consensus for a distinction between early onset preeclampsia EOP and late onset LOP (34 weeks gestation), EOP being rather a problem of implantation of the trophoblast (and the placenta), LOP being rather a pre-existing maternal problem (obesity, diabetes, coagulopathies etc…). LOP is predominant everywhere on this planet, but enormously predominant in developed countries (those who publish and have the means to do research): 90% of cases. This feature is very different in countries where women have their first child very young (88% of world births), where the fatal EOP (early onset) occurs in more than 30% of cases. 7) and finally, we will approach the current stage in 2017: What is the common factor which could explain the maternal global endotheliosis in EOP and LOP?. Presentation of the inositol phosphor glycans P type.

Biography:

Katarzyna Swist-Szulik is working as a consultant in paediatric intensive care and has her passion in research on the role of mitochondria in inflammatory signalling. She is pursuing her PhD on the role of mitochondrial dysfunction in intercellular crosstalk between myeloid and non-myeloid cells. There are building evidence that mitochondria-inflammatory interactions are relevant to many disease processes such as inflammatory myopathies, neurodegenerative diseases, autoimmune diseases as well as multiorgan failure and drug induced sterile inflammation. Katarzyna is working on developing the translation research investigating mitochondria-inflammatory relationship. Outside work Katarzyna is a mother of two wonderful children, an adventurer, ultramarathon runner and finisher of Marathon des Sables in 2015.

Abstract:

Introduction: Mitochondria plays a crucial role in cellular bioenergetics, immune responses, calcium homeostasis and apoptosis and thus are important to support cell homeostasis and viability. Mitochondrial diseases caused by mutations of mitochondrial DNA or of nuclear genes that encode mitochondrial proteins are leading to multisystemic and life limiting disorders (Fig.1.). Additionally, it has been recently highlighted that coexistence of mitochondrial dysfunction and inflammation is a background for many diseases with important health and social issues such as diabetes, cancer, neurodegenerative disorders and cardiac failure.
Aims: To review current knowledge and clinical aspect of mitochondria and inflammatory crosstalk from the experience of clinician working in the field of paediatric intensive care.  
Methods: As a clinician treating critically ill children I observed that some patients with cancer, post bone marrow transplant or cardiac surgery and primary mitochondrial diseases responded to additional stress such as surgery or infection with overwhelming inflammatory responses leading to multiorgan failure and death. In these situations, currently available treatments including antibiotics, ventilatory, cardiolovasculary and renal supports used in paediatric intensive care were ineffective. I collected the data from clinical observations and hypothesised that that overwhelming inflammatory responses could be triggered by changes in mitochondrial function and further intensified due to additive effect of cellular stress.
Results and Conclusions: The clinical data and some experimental studies provide evidence that mitochondrial dysfunction and abnormal inflammatory responses plays a role in acute such as sepsis and chronic such as metabolic and neurodegenerative disorders. Mitochondrial dysfunction is as well considered in pathogenesis of sepsis and multiple organ dysfunction syndrome (MODS). While it is still difficult to confirm the cause and effect mechanism it nevertheless creates a new path for translational research and therapeutic interventions focused on protection of mitochondrial function or acceleration of mitochondrial recovery.

Biography:

Reyhaneh Abgoon has received her Master’s degree in Cellular and Molecular Biology from Azad University. Her research interests include immunology, molecular immunology, especially autoimmune diseases. She is working as a supervisor in Banej Elixir molecular research institute in Tehran. She has presented several research abstracts about alopecia areata which is an autoimmune disease at various international conferences

Abstract:

Objective

Alopecia areata (AA) is an autoimmune disease characterized by patchy hair loss affecting both scalp and body hair. Although the etiology and pathogenesis of this disease is still unknown, a polymorphism within IL-12B gene have been described in few studies to be associated with AA susceptibility. Yet, these findings had so far not been independently replicated, and no data on a possible association of IL-12B mutation and AA in Iranian population were available.

Methods

This study contains 30 AA patients and 15 healthy controls. Genomic DNA was isolated using DNG-plus and PCR-RFLP analysis was performed to detect IL-12B rs3212227 polymorphism.  Several relevant information such as demographic data (age, gender, …) or clinical characteristics were analyzed for a possible effect of these factors on susceptibility to AA in patients who carry CC, AC, and AA genotypes.

Results

No association between the IL-12B rs3212227 mutation and susceptibility to AA was observed in our Iranian cohort. PCR-RFLP results showed that frequency of CC genotype (13.3% vs. 6.6%) are similar in both patient and control groups. AC genotype was detected in 46.6% and 6.6% of patients and controls, respectively. The AA genotype which is wild genotype had higher frequency in healthy individuals. Statistical analysis indicate that there no significant difference in distribution of genotypes between patients and controls (P= 0.12). Although the C allele frequency of IL-12B was higher in the patients than control subjects (36.6% vs. 10% respectively) but there is no significant difference (P= 0.12).

Conclusion  

We here demonstrate that the IL-12B rs3212227 polymorphism is not associated with the risk to develop AA in our Iranian cohort. Therefore, this study failed to confirm reported association between gene mutation and susceptibility to AA. Hence, the genetic predisposition to develop AA greatly varies among different ethnic groups.

Biography:

Jee Shum and Frederick Husher have pursed and refi ned the development of the PRS for more than a decade and they have successfully resolved many technology challenges including covalent  dhesive slide coatings supporting both tissue and proteins, non-staining label paint, bio-target printing, and bio-target fabrication. A joint  venture with the Hong Kong Productivity Council, to co-develop the production technology, will bring the PRS into commercial reality to benefi t global health.

Abstract:

The Process Record Slide (PRS) records the Immuno Histo Chemical (IHC) stain processing experience of a co-resident patient tissue section using arrays of stain reagent detection targets. Both experience all the IHC processing from tissue capture to the application of the cover slip: tissue capture, drying, deparaffi nation, antigen retrieval, primary antibody, and secondary amplifi cation processing. Because the PRS targets are comprised of known reactivity concentrations to the stain reagents, an objective measure that is unique to that slide now exists remaining forever co-resident with the tissue section. Th e result is a captured effi cacy record of the antigen recovery, stain reagents, and the processing technology. Th e PRS targets can be used with digital imaging to quantify the IHC processing upon the tissue section using the reference scales developed from the targets. Th e reference scales can be used for objective determination of antigen density in the tissue and QC reporting of the process. Additionally, utilizing the reference scales, the tissue section image presentation can be normalized to a preferred basis upon which optimal diagnostic determination can be achieved. Tele-diagnostics and second opinion are also possible since the unique processing experience is recorded. Others have attempted to produce control slides but have all failed in meeting the constraints of mass production at an aff ordable price. Th us, only with the development of a new slide coating that meets the covalent binding needs of target & tissue, target printing technology, and production automation, can the goals be satisfi ed. PRS technologies satisfi es these goals.

Biography:

Dr. Carmona is a physician-scientist focused on understanding the role of infection and chronic inflammation in the development of interstitial lung diseases (ILD). Her research to date has focused on understanding the immunomodulatory effects of fungal beta-glucans (BG) in innate immune cells. Particularly; she had characterized the role of BG on dendritic cells and their participation in T-cell polarization (Th1 and Th17). Currently, her group is interested in determining the mechanisms by which BG modulate B-lymphocyte activation and how BG-activated B-lymphocytes may drive the development of inflammation and fibrosis in a subset of patients with ILD. Her group has recently shown that BG activated B-lymphocytes release a pro-inflammatory cytokine profile that participates in neutrophil recruitment potentially contributing to lung epithelial damage. Herein, they have identified the NLRP3 inflammasome of circulating human B-lymphocytes as a key component in innate and adaptive immune response in response to fungal and bacterial antigens.

Abstract:

The NLRP3 inflammasome is activated in response to different bacterial, viral and fungal pathogens and serves as modulator of different pattern recognition receptors signaling pathways. Herein, we have investigated the role of NLRP3 in human circulating B-lymphocytes and identify that it is essential for two independent processes, pro-inflammatory cytokine and antibody regulation. Our results show that β-glucan stimulated B lymphocytes secrete IL-1β, which is important in the host defense against Pneumocystis and other fungal infections. IL-1β maturation and secretion by circulating B-lymphocytes is regulated by the NLRP3 inflammasome, which was dependent on ATP and potassium (K+) efflux. The inhibition of NLRP3 and CASP1 by specific inhibitors abolished the secretion of IL-1β. β-glucan mediated IL-1β secretion was partially mediated by Dectin-1 activation via SYK and the transcription factors NF-KB and AP-1. Furthermore, we demonstrated that B-lymphocytes activated by unmethylated CpG motifs, found in bacterial DNA, induced the production and secretion of IgM antibodies. Interestingly, this process also requires the activation of the NLRP3 inflammasome. Similar to IL-1β, B-lymphocyte stimulation by CpG resulted in NLRP3 and CASP1 activation. IgM production was inhibited by specific CASP1 and NLRP3 inhibitors and was dependent on ATP and potassium (K+) efflux. Furthermore, we identified that CPG-stimulated IgM secretion unlike IL-1β was mTOR-mediated.

Biography:

Dr. Wen Qiu is currently an associate professor at Department of Immunology of Nanjing Medical University. He is exploring the role of complement especially C5b-9 in the induction of glomerular mesangial cell (GMC) apoptosis, inflammation and proliferation in rat Thy-1 nephritis as a widely used model of human mesangial proliferative glomerulonephritis (MsPGN) and its mechanisms. These include signal transduction, microRNA regulation, transcriptional factor regulation. He is also exploring the effects of post-transcriptional regulation such as ubiquitination and acetylation on the activation of signaling molecules, transcription factors and histones.

Abstract:

Inflammatory response has been reported to contribute to the renal lesions in rat Thy-1 nephritis (Thy-1N) as an animal model of human mesangioproliferative glomerulonephritis (MsPGN). Besides C5b-9 complex, C5a is also a potent pro-inflammatory mediator and correlated to severity of various nephritic diseases. However, the role of C5a in mediating pro-inflammatory cytokine production in rats with Thy-1N is poorly defined. In the present studies, the levels of C5a, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were first determined in the renal tissues of rats with Thy-1N. Then, the expression of IL-6 and TNF-α was detected in rat glomerular mesangial cells (GMC) stimulated with our recombinant rat C5a in vitro. Subsequently, the activation of mitogen-activated protein kinase (MAPK) signaling pathways (p38 MAPK, ERK1/2 and JNK) and their roles in the regulation of IL-6 and TNF-α production were examined in the GMC induced by C5a. The results showed that the levels of C5a, IL-6 and TNF-α were markedly increased in the renal tissues of Thy-1N rats. Rat C5a stimulation in vitro could up-regulate the expression of IL-6 and TNF-α in rat GMC, and the activation of MAPK signaling pathways was involved in the induction of IL-6 and TNF-α. Mechanically, p38 MAPK activation promoted IL-6 production, while either ERK1/2 or JNK activation promoted TNF-α production in the GMC with exposure to C5a. Taken together, these data implicate that C5a induces the synthesis of IL-6 and TNF-α in rat GMC through the activation of MAPK signaling pathways.

Biography:

Anselm M and Kow, N.Y (2014). The Pathology of T Cells in Systemic Lupus Erythematosus. Hindawi Journal of Immunology Research. Volume 2014. pp: 419029-419037

Anselm M. and Tay, S.H (2014). Environmental Factors, Toxicants and Systemic Lupus Erythematosus. International Journal of Molecular Sciences. Volume 15, Number 9. 2014: pp. 16043-16056

Avery, Anthony, Creswell, Kathrin, Crowe, Sarah, Huby, Guro, Robertson, Ann and Sheikh, Aziz (2011). The Case Study Approach. BioMed Central: BMC Medical Research Methodology. Volume 11. 2011: p. 100

Bogdan, Robert, DeVault, Marjorie And Taylor, Steven (2015). Introduction to Qualitative Research Methods: A Guidebook and Resource. 2015. Retrieved from Wiley Website.

Cho, Judy H. and Gregersen, Peter K (2011). Genomics and the Multifactorial Nature of Human Autoimmune Disease. The New England Journal of Medicine. Volume 365. 2011: pp. 1612-1623

Abstract:

Medicine is a field in science that concerns itself to the improvement of an organism’s well-being by having a catena to the field of Healthcare. It is a branch of science which treats diseases and unriddles illnesses which have no available cure like autoimmune diseases, like Lupus. Lupus or Systemic Lupus Erythematosus (SLE) is a disease where the immune system attacks the body’s own cells mistaking it for a foreign aggregate of a person’s body that usually targets the female population. Due to this, many researches of this disease have focused mainly on female Lupus cases, leaving the affected male population with little knowledge about their case and about themselves. As part of the research enterprise, an introspection among the physical, mental, emotional and social aspects of a male lupus patient was done to promulgate information about the accordant aspects of a person’s self and to see any effects of the disease to the manliness of a male Lupus patient. The research was conducted through In-depth interviews and email interviews of one male lupus patient, having open-ended questions as its cornerstone being a case study. Results of the research were accomplished by sense-making, which furthered the knowledge of male lupus patients being physically deduced, mentally polished, emotionally reliant to God and family, socially selective and still relevantly male.

Biography:

Dr. Bimal is actively participating in mainstream research programmes of RMRIMS, Patna. His research focuses are immune-diagnosis, mechanism of Immuno-suppressions and Immuno-prophylactic aspects of visceral leishmaniasis. He is blessed with more than 50 peer reviewed publication in international journal of repute and guided more than 16 Ph.D students

Abstract:

In the present study the efficacy of L.donovani protein disulfide isomerase (LdPDI) as a DNA vaccine was evaluated in BALB/C mice. Mice immunized with LdPDI-DNA construct was found to be most immuno-reactive inducing higher T-cell proliferation which was associated with substantial rise in Th1 and Th17+ CD4 cell response as well as it triggered a higher proportion of CD8+ T cells for release of Interferon-gamma along with  reduced splenic parasite load on day 20 and 60 post challenge (p.c). Further, the same vaccine construct triggered an increased IFN-γ, IL-17A and IL-22 release accompanied with decreased ERK1/2 signalling and increased MAPK signalling coincided with increase in amount of nitrite and ROS in vaccinated the splenocyts. We summarise from our data that DNA-PDI construct of Leishmania donovani has potential for eliciting protective immunity through pro-inflammatory cytokines of CD8+ and CD4+(Th1 and Th17) following an intervention in downstream signalling event of ERK1/2 probably through p38MAPK signalling . Therefore, the study suggests a new control against VL in future

Biography:

Joseph M Bodi resarch work at Kinshasa University, Democratic Republic of Congo.

Abstract:

Background

Pathogenesis of acute massive intravascular hemolysis in Blackwater fever is very complex. Mostly, malaria immunity deficiency in expatriates, Quinine and Plasmodium are incriminated. The role of malaria IgG1 antibodies in BWF in older children supposed to have malaria protective immunity is not well elucidated. This study aimed to determine the profile of malaria IgG1 for malaria crude antigen in children developing blackwater fever compared to patients with uncomplicated malaria

Methodology

This is a case-control study conducted in 4 medical institutions across Kinshasa. Cases were patients with Blackwater fever (BWF) whereas controls had uncomplicated plasmodium falciparum malaria (UM). For each case, 2 controls were recruited and were matched for age, sex and the area of residence. Malaria. IgG1 were assessed by standard ELISA and absorbance measured in an automated plate reader.

Results

The level of antibodies in BWF children were very high compared to uncomplicated malaria [1.95mg/l (IC95%:1.55 – 2.44) versus [1.19 mg/l (IC95%: 0.98 – 1.43)] and p=0,002.The majority of BWF cases(81,4%) were above 5 years old while only 18,6% were under  5 years old: OR: 1.33 (0.53–3.32).Quinine was used by 95.3% of the BWF cases[OR: 50.19(10.75–234.42)] p < 0.001) versus uncomplicated malaria. There was no linear correlation between age of patients and the logarithm of antibodies.  R² is totally null (p=0,335).

Conclusion

Malaria IgG1 antibodies is high in children with BWF, and should be involved in the pathogenesis of the disease ,probably by activating complement system via classical pathway and leading to acute massive hemolysis.  No correlation was observed between increasing of antibodies and age of patients.

Biography:

Dr. Bahman Mirzaei has completed his PhD at the age of 33 years from Pasteur Institute of Iran. He is the researcher of Medical bacteriology field in Pasteur Institute of. He has published more than 7 papers in reputed journals

Abstract:

Staphylococcus epidermidis as an opportunistic pathogen and the leading cause of morbidity and premature mortality in patients with medical devices related infections, has been described as a concerning subject for hospitalized health. Developing a strategy to raise opsonic antibodies against polysaccharide intracellular adhesion (PIA) could be promising for elimination of colonization and biofilm forming Staphylococcus epidermidis. Following the purification of truncated SesC protein and mentioned polysaccharide, for the first time polysaccharide intracellular adhesion (PIA) was conjugated by using rSesC protein as a safe carrier for increasing the immunogenicity of polysaccharide and evaluated its efficacy in mice. Construction of conjugate was analyzed by using Fourier Transform Infrared spectroscopy (FTIR) and Proton Nuclear Magnetic Resonance spectroscopy (H1- NMR) methods. Subsequently, the immune response of total IgG, IgG2a, and IgG2b titers were assessed. Immunization of mice with the PIA-SesC conjugate raised the levels of opsonic antibodies, and the vaccinated mice were protected when challenged intravenously by wild type strain 1457. Further studies showed that the conjugated vaccine could eliminate S. epidermidis biofilm formation at the in vitro and in vivo assays. This study supports the proposal that immunization of mice with PIA-SesC conjugate vaccine could be safe and protective against Staphylococcus epidermidis infection.

Biography:

• MSc in Microbiology from Al-Mustansiriyah University, College of Science, Department of Biology, 2012. (Iraq). MSc thesis title: Detection of 16S rRNA Methylation Gene between Two Species of Gram Negative with High Level Resistance to Aminoglycosides.

Abstract:

 The aim of this study is to analyze the phenotypic and genotypic indicators of biofilm formation of Coagulase negative staphylococci (CONS) and Oxacillin resistance by using many different detection methods. Thirty-six CONS isolated from patients with chronic otitis media diagnosed using API Staph . PCR amplification was used to detect ica A and D gene and also to detect mec A gene, cultured strains were tested for biofilm formation ability with Congo red agar (CRA), phenotypic prediction of mecA gene positive or negative (historically referred to methicillin resistance, MR and methicillin susceptible, MS) was conducted by both Oxacillin and Cefoxitin disk diffusion tests also agar screening test both of tests on Muller Hinton agar (MHA) and mannitol salt agar (MSA) and minimum inhibition concentration (MIC) was determined by agar dilution method with MHA corporation with MIC on MHA containing 2% NaCl both of them Oxacillin concentration (0.25 to 256 μg/mL). The above tests applied to compare their MRCONS and MSCONS detection the sensi­tivity & specificity were determined to compare between the tests which is used in this study. A total of 36 CONS isolates from patients with chronic otitis media studied, the high percentage of this isolates belong­ing to staph xylosus 20 isolates (55%), of a total 36 isolates 31(86%) were found to be CRA plate test positive, ica A and D genes were found to be present in 30 isolate, the concordance between phenotypic and genotypic of biofilm formation was 90.9% (p<0.05). All isolates of study were divided in to MRCONS 29(80.5%) mecA positive and MSCONS 7(19.4%) mecA negative, all phenotypic tests used to detect MSCONS gave false resistance with high percentage (19.4%). Cefoxitin disk diffusion on MHA & MSA yielded the highest sensitivity value (100%), Oxacillin disk diffusion on MHA gave a specific­ity of 16.6%, Oxacillin screen MSA(2 μg/mL) gave the highest sensitivity value (93%), Oxacillin screening on MHA (6 μg/mL with 4% NaCl) gave the highest specificity value (100%)and MIC on MHA & MSA with 2% NaCl gave the same highest sen­sitivity value(100%), from 31 isolates positive biofilm CONS isolates 24 (77.4%) were confirmed as MRCONS while 7(23%) confirmed as MSCONS, negative biofilm CONS isolates found only between MRCONS isolates 5(14%) which means an essential role of resistance to Oxacillin referred to biofilm

Biography:

Jee Shum and Frederick Husher have pursed and refi ned the development of the PRS for more than a decade and they have successfully resolved many technology
challenges including covalent adhesive slide coatings supporting both tissue and proteins, non-staining label paint, bio-target printing, and bio-target fabrication. A joint venture with the Hong Kong Productivity Council, to co-develop the production technology, will bring the PRS into commercial reality to benefi t global health.

Abstract:

The Process Record Slide (PRS) records the Immuno Histo Chemical (IHC) stain processing experience of a co-resident patient tissue section using arrays of stain reagent detection targets. Both experience all the IHC processing from tissue capture to the application of the cover slip: tissue capture, drying, deparaffi nation, antigen retrieval, primary antibody, and secondary amplifi cation processing. Because the PRS targets are comprised of known reactivity concentrations to the stain reagents, an objective measure that is unique to that slide now exists remaining forever co-resident with the tissue section. The result is a captured effi cacy record of the antigen recovery, stain reagents, and the processing technology. Th e PRS targets can be used with digital imaging to quantify the IHC processing upon the tissue section using the reference scales developed fromthe targets. Th e reference scales can be used for objective determination of antigen density in the tissue and QC reporting of the process. Additionally, utilizing the reference scales, the tissue section image presentation can be normalized to a preferred basis upon which optimal diagnostic determination can be achieved. Tele-diagnostics and second opinion are also possible since the unique processing experience is recorded. Others have attempted to produce control slides but have all failed in meeting the constraints of mass production at an aff ordable price. Th us, only with the development of a new slide coating that meets the covalent binding needs of target & tissue, target printing technology, and production automation, can the goals be satisfi ed. PRS technologies satisfi es these goals.

Biography:

Eva M Carmona is a Physician-Scientist, whose research is focused on understanding the role of infection and chronic inflammation in the development of interstitial lung diseases (ILD). Her research to date has focused on understanding the immunomodulatory effects of fungal beta-glucans (BG) in innate immune cells. Particularly, she has characterized the role of BG on dendritic cells and their participation in T-cell polarization (Th1 and Th17). Currently, her group is interested in determining the mechanisms by which BG modulate B-lymphocyte activation and how BG-activated B-lymphocytes may drive the development of inflammation and fibrosis in a subset of patients with ILD. Her group has recently shown that BG activated B-lymphocytes release a pro-inflammatory cytokine profile that participates in neutrophil recruitment potentially contributing to lung epithelial damage. Herein, they have identified the NLRP3 inflammasome of circulating human B-lymphocytes as a key component in innate and adaptive immune response in response to fungal and bacterial antigens.

Abstract:

The NLRP3 inflammasome is activated in response to different bacterial, viral and fungal pathogens and serves as modulator of different pattern recognition receptor signalling pathways. Herein, we have investigated the role of NLRP3 in human circulating B-lymphocytes and identify that it is essential for two independent processes, pro-inflammatory cytokine and antibody regulation. Our results show that β-glucan stimulated B lymphocytes secrete IL-1β, which is important in the host defence against Pneumocystis and other fungal infections. IL-1β maturation and secretion by circulating B-lymphocytes is regulated by the NLRP3 inflammasome, which was dependent on ATP and potassium (K+) efflux. The inhibition of NLRP3 and CASP1 by specific inhibitors abolished the secretion of IL-1β. β-glucan mediated IL-1β secretion was partially mediated by Dectin-1 activation via SYK and the transcription factors NF-κB and AP-1. Furthermore, we demonstrated that B-lymphocytes activated by unmethylated CpG motifs, found in bacterial DNA, induced the production and secretion of IgM antibodies. Interestingly, this process also requires the activation of the NLRP3 inflammasome. Similar to IL-1β, B-lymphocyte stimulation by CpG resulted in NLRP3 and CASP1 activation. IgM production was inhibited by specific CASP1 and NLRP3 inhibitors and was dependent on ATP and potassium (K+) efflux. Furthermore, we identified that CPG-stimulated IgM secretion unlike IL-1β was mTOR-mediated. In conclusion, this study identifies the NLRP3 inflammasome as modulator of the innate and adaptive immune systems in response to fungal and bacterial stimuli in human circulating B-lymphocytes.

Biography:

Marc Bigaud is a senior pharmacologist (PhD) at the Novartis Institutes for Biomedical Research, in Basel (Switzerland). He is part of the AutoImmunity, Transplantation and Inflammation-Disease Area

Abstract:

Non-obese diabetic (NOD) mice provide a preclinical model of autoimmune diseases as they spontaneously develop autoimmune diabetes sharing many similarities to type 1 diabetes (T1D) as well as sialadenitis resembling Sjögren's syndrome in humans. In the current study, we followed the natural course of the disease and evaluated the therapeutic effects of a potent and selective PI3Kδ inhibitor referred as “compound-1” (manuscript in preparation).

Drug-treatment was administered over 12 weeks, mixed with food at 0.1%, to 12-weeks old NOD mice (n=12). This treatment demonstrated in preliminary studies full target inhibition. In parallel, control NOD mice were given drug-free food (n=12).

Blood samples were collected for drug level measurements (LC-MS-MS). Anti-IgM/rIL-4-induced PI3Kδ-dependent pAkt in B cells was used as PD marker and monitored by flow cytometry. The incidence of diabetes, the cellularity of spleen and salivary glands were determined. The number of antibody-secreting cells was measured by ELISPOT. The development of ectopic germinal centers in salivary glands was followed by immunohistochemistry.

After 12 weeks of treatment, a similar diabetes incidence was observed in compound-1-treated vs control NOD mice. Drug blood levels (0.11-1.12 µM) showed an exposure-related inhibition of PI3K/pAkt pathway activation, with a mean IC50 value of approximately 0.44 µM. In the spleens, flow cytometry analysis revealed marked drug-induced reductions in marginal zone B cells (≥70%), in germinal center B cells (≥30%), plasma cells (≥60%) and Tfh cells (≥40%). In salivary glands, significant reductions in infiltrating CD3⁺ T cells and CD45R⁺ B cells (≥ 40%) were observed in drug-treated vs control NOD mice (Figure 1). In line with this observation, the incidences of IgM-secreting and IgG-secreting cells in salivary glands were significantly reduced (by 70-80%) in drug-treated vs control mice.

In conclusion, this study provides pre-clinical proof-of-concept that PI3Kδ inhibition reduces hallmarks of disease pathology that are operational in Sjögren's syndrome.

Biography:

Gerald J. Prud’homme is Professor in the Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada; and Clinician-Scientist, Keenan Research Centre for Biomedical Science (St. Michael's Hospital), Toronto. He holds an M.D. degree, and is a specialist in pathology. He was a research fellow at the Charles H. Best Institute and Institute of Immunology, University of Toronto, the Scripps Research Institute (La Jolla, California), and the McGill Cancer Centre (Montreal). His research interests are in the areas of diabetes and autoimmune diseases. He is a member of the Banting and Best Diabetes Centre in Toronto

Abstract:

The inhibition of autoimmunity against pancreatic beta cells and the promotion of the proliferation/regeneration of these cells are major goals in the treatment of type 1 diabetes (T1D). Gamma aminobutyric acid (GABA) and the incretin hormone GLP-1 (currently used to treat type 2 diabetes) are candidate drugs to mediate these effects. In rodents, therapies with these agents induce beta-cell proliferation, reduce apoptosis, and increase beta-cell mass. Here, we examined the effects of these agents on human islets cells and insulinoma cell lines. We observed that GABA treatment of beta cells increases the expression of SIRT1 and Klotho, and protects against apoptosis due to glucotoxicity or inflammatory cytokines. Notably, both SIRT1 and Klotho block activation of the NF-kB inflammatory pathway. NF-kB contributes to beta cell apoptosis, and inhibiting this pathway appears to be protective. We demonstrate that a GLP-1 receptor (GLP-1R) agonist augments the activity of GABA in some (but not all) of these protective effects. Furthermore, we report that a GLP-1R agonist fails to induce human beta-cell proliferation (unlike findings in mice) but, in contrast, GABA has broader effects and induces proliferation. These results support the use of GABA as an agent to induce beta-cell regeneration. In conclusion, GABA and GLP-1, especially in combination, were effective at protecting human beta islet cells against glucotoxicity and other injuries, and GABA stimulated their proliferation. These findings suggest that GABA/GLP-1 therapy has potential application in the treatment of human T1D.

Biography:

Liwei Lu’s research is focused on studying immune dysregulations in autoimmune diseases. During last ten years, his laboratory has been exploring novel strategies for the treatment of rheumatoid arthritis. His team was among the first to successfully treat autoimmune arthritis by targeting the cytokine B-cell activating factor in a preclinical study, which has significant therapeutic implications for the effective treatment of rheumatoid arthritis. He is an internationally recognized expert in the field of Autoimmunity. He is the Councillor of Federation of Immunological Societies of Asia-Oceania and has served as the Chairman of Hong Kong Society for Immunology. He has published over 120 peer-reviewed papers in leading immunology and rheumatology journals.

Abstract:

Activation of autoreactive B cells leads to plasma cell (PC) formation and autoantibody production, contributing to the development of autoimmune diseases. Increasing evidence indicates a crucial role of leptin in immune response and autoimmune pathogenesis via enhancing CD4⁺ T cell responses, but whether and how leptin regulates B cell response in autoimmune pathogenesis remains largely unclear. Using collagen-induced arthritis (CIA) mice, we detected increased levels of leptin and anti-collagen II (CII) antibodies in the synovial fluid (SF) and sera of mice at acute and chronic stages of CIA. Higher percentage and cell number of PCs were observed in the SF of CIA mice. Leptin receptor-deficient (db/db) mice exhibited ameliorated CIA development with reduced PCs responses and CII-specific antibody production. Intra-articular injection of recombinant leptin enhanced PCs responses and CII-specific antibody production and joint damage. Importantly, intra-articular injection of a soluble leptin blocker (ObR:Fc) deceased PCs responses, CII-specific antibody production and joint damage. Mechanistic studies revealed that leptin promoted CD138⁺IFR4⁺ PC generation from GL-7⁺Fas⁺ germinal center B cells via activating Akt-mTOR-IRF4 axis. Moreover, rapamycin treatment attenuated leptin-induced IRF4 expression and PCs generation. In RA patients, leptin levels and autoantibody production were positively correlated with disease activity (DAS28 score) with increased CD38⁺CD27⁺ plasmablasts detected in the synovium of active RA patients. Together, these findings demonstrated a critical role of leptin in enhancing PCs responses and CIA progression via ObR-Akt-mTOR-IRF4 axis, indicating that leptin blockade may serve as a potential therapeutic strategy for the treatment of autoimmune arthritis.

Biography:

Dr. Ivana Stojanovic is a Research Professor and the principle investigator of the project funded by the Iacocca Family Foundation (Boston, MA, USA) that aims at developing new protocol for generation of insulin-specific T regulatory cells for the therapy of individuals with type 1 diabetes. The focus of her research has been modulation of type 1 diabetes in the animal models, as well as investigation of the pathologic processes involved in the progression of this disease. She was a principle investigator of the project funded by European Foundation for the Study of Diabetes between 2007 and 2009 and involved in numerous projects funded by the Ministry of Science, Republic of Serbia. Dr. Stojanovic is an expert in flow cytometry. She was a supervisor for 2 PhD theses and several master and diploma theses. Dr. Stojanovic published 51 research articles in peer-review journals, with 950 citations and h-index 19.

Abstract:

Immunotherapy of autoimmune diseases with CD4⁺CD25^highFoxP3⁺ T regulatory cells (Tregs) is currently in the stage of clinical trials. Tregs used for human therapy are polyclonal, but studies in animals showed that autoantigen-specific Tregs are more effective in preventing or ameliorating the pathogenesis of autoimmune diseases compared to polyclonal Tregs. Since Tregs are usually defective in individuals with an autoimmune process, the basic idea of our research was to convert insulin-specific T effector cells into insulin-specific Tregs using various in vitro manipulations. In NOD mice that develop T1D spontaneously, the occurrence of insulin-specific CD4⁺ T cells was 0,1%. In order to increase the number of insulin-specific T cells, CD4⁺ T cells were co-cultivated in vitro with autologous mature dendritic cells in the presence of insulin peptide (B9:23). The proportion of insulin-specific CD4⁺ cells after 48 h increased up to 3,4±0,1% and this level remained stable for 2 days. Insulin-specific CD4+ cells were then stained by fluorescent insulin-loaded MHC class II tetramer and sorted using flow cytometer. Obtained cells were cultured in RPMI-1640 medium supplemented with TCR stimulators (anti-CD3 and anti-CD28 antibody), recombinant IL-2 and TGF-b proteins. After 5 days, the number of CD4⁺CD25^highFoxP3⁺ Tregs reached 48%. However, further cultivation (with medium replacement every second day) did not lead to an increase in the number of Tregs, on the contrary, the Treg proportion was reduced to 14%. These results imply that it is feasible to generate antigen-specific Tregs from antigen-specific effector cells, but the protocol still requires a few modifications in order to produce sufficient number of Tregs for in vivo use.

Biography:

Stepan Dzhimak is studying the role of low deuterium concentrations in drinking water on the living systems adaptive capabilities. In the experimental clinic-laboratory of biologically active substances of animal origin he is principal investigator of the project: development of innovative natural adaptogenic stimulants of nonspecific immunity based on tissue-specific biomolecules.

Abstract:

Statement of the Problem: Immune system dysfunction is pathological processes key aspect, as result we can see protective and adaptogenic immunity reactions activation and its depletion, leads to bacterial and viral infections. Modern immunoregulating drugs, mainly synthetic origin, cause pathogens resistance increase and lead to allergic reactions. One of the possible problem solutions is to obtaining immunocorrective natural drugs with directed action based on animal origin biomolecules. Peptides and proteins complex isolated from Sus Scrofa thymus, spleen, lymph nodes (TSL) (0.9% NaCl solution) studies were conducted. Deuterium depleted water (DDW) promotes maximum biomolecules extraction. Research purpose was to investigate protein-peptide compounds fractions isolated from the organs of the immune system Sus scrofa immunological activity in vivo. Methodology & Theoretical Orientation: 58 rats (SPF) were injected with cyclophosphamide (triply, 75 mg/kg), after immunodeficiency model completed (12 days from first injection) animals were treated by: complex extract on DDW (TSL), TSL fractions less than 5 kDa (A), from 5 to 30 kDa (B), over 30 kDa (C). Findings: It has been revealed that TSL and B activate CD3 and CD4 differentiation and typing processes (CD3/CD4 shifted to larger side); increase T-lymphocytes and T-helpers content by reducing suppressors and killers; increase of cytokine factors production (Il-2, Il-4, Il-6, IgM, IgG) responsible for adaptive immune response; normalize granulocytes level, which against increased CD3 background indicates one of the immunity recovery stages. There also noted significant C1q and C4 level increase, which synergistically with a C5 and C3 level decrease indicate complementary cascade of activation reactions. Minimal therapeutic effect was noted in rats A and C. Conclusion & Significance: Biomolecules (5-30 kDa), isolated from Sus Scrofa immune tissues by DDW extraction, showed obvious immunoactivating effect. Immunosuppression model revealed complementary system cascade faster activation and protective system cellular and molecular factors maximum reactivity while biomolecules treatment.

Biography:

Dr. Yingwei Wang is currently a professor at Department of Immunology of Nanjing Medical University. She is conducting research in exploring the mechanisms of glomerular mesangial cell (GMC) apoptosis and proliferation in human mesangial proliferative glomerulonephritis (MsPGN). These include signal transduction, microRNA regulation, transcription factor regulation. She is also exploring the effects of ubiquitination and acetylation modification on the activation of signaling molecules, transcription factors and histones.

Abstract:

The apoptosis of glomerular mesangial cell (GMC) in the early phase of rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis (MsPGN), is mainly triggered by sublytic C5b-9. But the mechanism of GMC apoptosis induced by sublytic C5b-9 remains unclear. In current study, we demonstrated that the expression of TNFR1-associated death domain-containing protein (TRADD) and interferon regulatory factor-1 (IRF-1) was simultaneously up-regulated both in the renal tissue of Thy-1N rats (in vivo) and in the GMC under sublytic C5b-9 stimulation (in vitro). And in vitro, TRADD was confirmed to be a downstream gene of IRF-1 because IRF-1 could bind to TRADD gene promoter to promote its transcription, leading to caspase 8 activation and GMC apoptosis. Meanwhile, increased phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) was verified to contribute to IRF-1 and TRADD production and caspase 8 activation as well as GMC apoptosis treated by sublytic C5b-9. Furthermore, the phosphorylation of mitogen-activated protein kinase kinase kinase 2 (MEKK2) was found to mediate p38 MAPK activation. More importantly, three sites (Ser-153/164/239) of MEKK2 phosphorylation were first identified and demonstrated to be necessary for p38 MAPK activation. Besides, silence of renal MEKK2, IRF-1 and TRADD gene or inhibition of p38 MAPK activation in vivo displayed obvious inhibitory effects on GMC apoptosis, secondary proliferation and urinary protein secretion in rats with Thy-1N. Collectively, these findings indicate that the cascade axis of MEKK2-p38 MAPK-IRF-1-TRADD-caspase 8 may play an important role in GMC apoptosis following exposure to the sublytic C5b-9 in rat Thy-1N.

Biography:

Haiyan Xu has devoted herself on relative study of kidney transplantation, including rejection, opportunistic viral infection and induction of immune tolerance, since she got PHD. Taking B cell activating factor (BAFF) as the research breakthrough point, she found BAFF signaling system involve in the progression of renal allograft rejection and blockade of BAFF signaling should become the potential anti-rejection options; BAFF signaling crosstalk with HCMV/TLR9 in renal transplant recipients, which would decrease the long-term outcome of renal allograft, and mouse DC induced by liver X receptor agonist show immunosuppressive effect, which differ from natural tolerance DC.

Abstract:

Backgrounds: We previously found that BAFF and BAFF-R highly expressed on renal tubular epithelial cells (RTECs) in kidney allograft rejection tissues, but the significance of abnormal expression is still to be further investigated.

Methodology: Primary mouse RTECs (from 4-6 w C57BL/6) were isolated by enzyme digestion method, and cultured in the conditioned medium. After stimulated by 500U/mL IFN-γ for 48h, the expression of BAFF and BAFF-R on RTECs were detected by FCM. After treated with recombinant mouse BAFF and/or blockade BAFF-R-Fc fusion protein for 48h, the transport ability of fluorescein sodium and CK-18 expression of RTECs were detected, respectively; Proliferation ability and apoptosis rates of RTECs were tested by MTS and FCM method, respectively; Data were analyzed by SPSS17.0, and P < 0.05 was considered to be statistically significant. Results BAFF-R expression on RTECs in the IFN-γ treated group significantly up-regulated, compared with control group. Fluorescein sodium transport ability and CK-18 expression of BAFF stimulation group was significantly lower than that of BAFF-R-Fc+BAFF group and control group, respectively; Cell proliferation ability of 5ng/mL and 20ng/mL BAFF group were significantly higher than that of control group and BAFF-R-Fc+BAFF group; While apoptosis rate of BAFF-treated group was significantly lower than that of BAFF-R-Fc+BAFF group and control group.

Conclusion & Significance: BAFF/BAFF-R signaling could promote the proliferation ability of RTECs, but down-regulate the epithelial cell characteristics and Ionic transport ability of RTECs. And it is worth exploring whether enhancement of BAFF/BAFF-R signaling promotes the interstitial transformation of RTECs.

Biography:

Marlene Bouvier’s laboratory has been interested, for the last 20 years, in characterizing molecular and structural mechanisms involving MHC class I molecules with respect to peptide loading, selection, and processing, as well as how these events are modulated by interaction with specialized proteins of the endoplasmic reticulum

Abstract:

Statement of the Problem: The human endoplasmic reticulum aminopeptidase 1 (ERAP1) and ERAP2 are critically important in the final processing of MHC class I antigens in the endoplasmic reticulum. To date, the molecular context of peptide trimming by ERAPs, and how ERAPs shape antigen repertoires, remain open questions. Methodology: Using a cell-free system composed of ERAP1 and ERAP2 heterodimers (ERAP1/2), MHC class I molecules, and N-terminally extended model and natural peptides, we characterized the function of ERAP1/2. Findings: We provide evidence that ERAP1/2 trims MHC I-bound precursor peptides to the final lengths, albeit more slowly than the corresponding free precursors. We show that trimming of MHC I-bound precursors by ERAP1/2 increases the conformational stability of MHC I/peptide complexes. Conclusion & Significance: Our study provides new findings on ERAP1/2 as a key antigen processing complex. From our data, we propose a molecular mechanistic model of ERAP1/2 as an editor of class I antigens. Understanding class I antigen processing is significant given the role that class I antigens play in the normal recognition of virally infected and transformed cells by CD8+ T cells.

Biography:

Pasteur Institute of Iran, Iran

Abstract:

Objective: Designer T cells are T lymphocytes engineered toward specific antibody-type membrane antigens through chimeric antigen receptor (CAR) and are mainly used for adoptive cellular immunotherapy. The designer CAR T cell could be used as a valuable approach for inhibition of tumors by redirecting the T cells against markers of tumor angiogenesis. In this study, we describe the development and characterization of a novel specific designer CAR T cell against vascular endothelial growth factor receptor 2 (VEGFR2) as a tumor angiogenic marker.

Methods and Results: T-cell line was electroporated with the chimeric anti-VEGFR2 construct and was analyzed for CAR expression. The specific activation was analysed by coculturing of CAR T cell with VEGFR2-expressing cells(KDR) in vitro. T cells expressing this CAR can effectively target VEGFR2-positive cells. We show that VEGFR2-specific T cells produce the large amount of immunostimulatory cytokines such as IFN-γ(308pg/ml) and IL-2(1900pg/ml) when co-cultured with VEGFR2-positive targets and proliferate more vigorously on VEGFR2-expressing cells.

Conclusion: The anti-VEGFR2 designer T cells exhibited an antibody-type specificity that could recognize VEGFR2-expressing cells in a MHC-independent manner, resulting in T-cell activation and proliferation. This redirected T cell provides a potential method for the gene therapy of a variety of solid tumors.

Biography:

Dpartment of Immunology, Faculty of Medicine, Dezful University of Medical Sciences, Dezful, Iran

Abstract:

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin disease which may be due to the imbalance between Th1-, Th2 and Treg cell-related immune responses. Evidences suggest that appropriate stimulation with probiotics may correct the skewed immune response in children with AD. The aim was to determine the effects of the yogurt culture lactobacillus delbrueckii subsp. Bulgaricus on the secretion of Th1/Th2/Treg type cytokines by peripheral blood mononuclear cells (PBMCs) from children with AD.

METHODS: L. Bulgaricus was cultivated on MRS broth. The PBMCs from 20 children with AD were separated by Ficoll-Hypaque centrifugation and co-cultured with different concentrations of UV killed bacteria in RPMI-1640 plus 10% FCS for 48/72h. The levels of IL-10, IL-4, IL-12 and IFN-γ were measured in supernatant of PBMCs by ELISA. RNA extraction and real time RT-PCR were used to measure Foxp3 mRNA expression. RESULTS: L. Bulgaricus significantly up-regulated the secretion of IL-10, IL-12 and IFN-γ, whereas decreased the secretion of IL-4 by PBMCs compared to control (p<0.05). The secretion level of IL-10 by L. Bulgaricus-stimulated PBMCs at incubation time 72h was significantly higher than 48h. The expression of Foxp3 mRNA was changed accordingly (P<0.001 and P<0.01, respectively). CONCLUSION: These data show that L. Bulgaricus may modulate the secretion of Th1-, Th2- and Treg-related cytokines in AD patients. Therefore, the possible potential therapeutic of L. Bulgaricus for treatment of AD should be consider in further investigation.

Biography:

Professor Lu’s research has focused on studying immune dysregulations in autoimmune diseases. During last ten years, his laboratory has been exploring novel strategies for the treatment of rheumatoid arthritis. His team was among the first to successfully treat autoimmune arthritis by targeting the cytokine B-cell activating factor in a preclinical study, which has significant therapeutic implications for the effective treatment of rheumatoid arthritis. Professor Lu is an internationally recognized expert in the field of autoimmunity. He is the Councilor of Federation of Immunological Societies of Asia-Oceania and has served as Chairman of Hong Kong Society for Immunology. He has published over 120 peer-reviewed papers in leading immunology and rheumatology journals.

Abstract:

Activation of autoreactive B cells leads to plasma cell (PC) formation and autoantibody production, contributing to the development of autoimmune diseases. Increasing evidence indicates a crucial role of leptin in immune response and autoimmune pathogenesis via enhancing CD4⁺ T cell responses, but whether and how leptin regulates B cell response in autoimmune pathogenesis remain largely unclear. Using collagen-induced arthritis (CIA) mice, we detected increased levels of leptin and anti-collagen II (CII) antibodies in the synovial fluid (SF) and sera of mice at acute and chronic stages of CIA. Higher percentage and cell number of PCs were observed in the SF of CIA mice. Leptin receptor-deficient (db/db) mice exhibited ameliorated CIA development with reduced PCs responses and CII-specific antibody production. Intra-articular injection of recombinant leptin enhanced PCs responses and CII-specific antibody production and joint damage. Importantly, intra-articular injection of a soluble leptin blocker (ObR:Fc) deceased PCs responses, CII-specific antibody production and joint damage. Mechanistic studies revealed that leptin promoted CD138⁺IFR4⁺ PC generation from GL-7⁺Fas⁺ germinal center B cells via activating Akt-mTOR-IRF4 axis. Moreover, .rapamycin treatment attenuated leptin-induced IRF4 expression and PCs generation. In RA patients, leptin levels and autoantibody production were positively correlated with disease activity (DAS28 score) with increased CD38⁺CD27⁺ plasmablasts detected in the synovium of active RA patients. Together, these findings demonstrated a critical role of leptin in enhancing PCs responses and CIA progression via ObR-Akt-mTOR-IRF4 axis, indicating that leptin blockade may serve as a potential therapeutic strategy for the treatment of autoimmune arthritis.

Biography:

Dr. Ivana Stojanovic is a Research Professor and the principle investigator of the project funded by the Iacocca Family Foundation (Boston, MA, USA) that aims at developing new protocol for generation of insulin-specific T regulatory cells for the therapy of individuals with type 1 diabetes. The focus of her research has been modulation of type 1 diabetes in the animal models, as well as investigation of the pathologic processes involved in the progression of this disease. She was a principle investigator of the project funded by European Foundation for the Study of Diabetes between 2007 and 2009 and involved in numerous projects funded by the Ministry of Science, Republic of Serbia. Dr. Stojanovic is an expert in flow cytometry. She was a supervisor for 2 PhD theses and several master and diploma theses. Dr. Stojanovic published 51 research articles in peer-review journals, with 950 citations and h-index 19.

Abstract:

Immunotherapy of autoimmune diseases with CD4⁺CD25^highFoxP3⁺ T regulatory cells (Tregs) is currently in the stage of clinical trials. Tregs used for human therapy are polyclonal, but studies in animals showed that autoantigen-specific Tregs are more effective in preventing or ameliorating the pathogenesis of autoimmune diseases compared to polyclonal Tregs. Since Tregs are usually defective in individuals with an autoimmune process, the basic idea of our research was to convert insulin-specific T effector cells into insulin-specific Tregs using various in vitro manipulations. In NOD mice that develop T1D spontaneously, the occurrence of insulin-specific CD4⁺ T cells was 0,1%. In order to increase the number of insulin-specific T cells, CD4⁺ T cells were co-cultivated in vitro with autologous mature dendritic cells in the presence of insulin peptide (B9:23). The proportion of insulin-specific CD4⁺ cells after 48 h increased up to 3,4±0,1% and this level remained stable for 2 days. Insulin-specific CD4+ cells were then stained by fluorescent insulin-loaded MHC class II tetramer and sorted using flow cytometer. Obtained cells were cultured in RPMI-1640 medium supplemented with TCR stimulators (anti-CD3 and anti-CD28 antibody), recombinant IL-2 and TGF-b proteins. After 5 days, the number of CD4⁺CD25^highFoxP3⁺ Tregs reached 48%. However, further cultivation (with medium replacement every second day) did not lead to an increase in the number of Tregs, on the contrary, the Treg proportion was reduced to 14%. These results imply that it is feasible to generate antigen-specific Tregs from antigen-specific effector cells, but the protocol still requires a few modifications in order to produce sufficient number of Tregs for in vivo use.  

Biography:

Ali Ganji has her expertise in Immunology of autoimmune diseases. He works as an assistant professor of immunology at Arak University of Medical Sciences.
 

Abstract:

Background: Multiple sclerosis (MS) is an autoimmune, chronic, and inflammatory disease of the CNS, which threatens many people, annually. There has not been introduced any cure for the MS, yet. Due to the anti-inflammatory and antioxidant effects of walnut, determining the effects of the walnut oil on the MS may lead to understanding new supplements for the treatment of MS. In this study, we have investigated the therapeutic effects of walnut oil on EAE mouse model of the MS disease. Materials and Methods: EAE was induced in the inbred C57BL6 mice. The control and test groups were gavaged 100μL of walnut oil daily. The weight and clinical symptoms were monitored, daily, until the day 21st. The spleen and the brain of the mice were removed and used for ELISA and histological studies. Results: The average weight changes between all of the groups was not significant (p value > 0.05). The average maximum severity of the disease and plaque formation in the brain of walnut oil-treated group was significantly lower (p value < 0.05) than the control group. However, leukocyte infiltration and MTT assay result differences were not significant between the two groups. Cytokine measurements in spleen cell soup, stimulated with MOG protein, showed a significant decrease in INF-γ and IL-17 in the treatment group, but there were no significant differences in the levels of IL-10 and IL-5 between the two groups. Serum evaluations of these cytokines revealed a significant (p value <0.05) decrease and increase in IL-17 and IL-10 values, respectively. Conclusion: Walnut oil, significantly, has inhibited the plaque formation and has inactivated the infiltrated cells in the brain. Thus, this food can reduce the MS disease severity. More studies are required to introduce the walnut oil as a valuable supplement in the treatment of MS.

Biography:

Immune regulation has important roles in various immune diseases. The authors have studied the regulatory mechanisms and function of TIM-3 in various cells and in an in vivo tumor model. The authors revealed the involvement of MEK and c-jun in TIM-3 expression by CD4+ T cells. Additionally, they reported that the efficacy of tumor vaccine can be up-regulated by TIM-3 pathway blockade and the IL-2 production is decreased in CD4+ T cells expressing TIM-3 through NFAT dephosphorylation and AP-1 transcription.

Abstract:

T cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) is well known as one of the immune check point molecules. TIM-3 expression is increased on exhausted T cells and senescent T cells in numerous immune diseases including cancers. However, the regulatory mechanisms of TIM-3 expression in cancers have not been well studied. Using Jurkat T cells, we examined TIM-3 regulatory mechanisms in condition similar to tumor microenvironment. TIM-3 mRNA and protein levels were increased by co-culture of Jurkat T cells with tumor cell lines and by incubation of them in tumor cell conditioned media. Given that cyclic adenosine monophosphate (cAMP) can be transferred from tumor cells to T cells, we examined the effect of cAMP signaling on TIM-3 expression. It was promoted by intracellular elevation of cAMP concentration and activation of cAMP downstream pathways. Further, inhibition of cAMP downstream pathway attenuated TIM-3 expression in Jurkat T cells cultured in tumor-CM as well as in Jurkat T cells stimulated with a cAMP elevating agent. Conclusively, this study suggests that TIM-3 expression in Jurkat T cells may be induced by tumor CM through activation of cAMP pathway.

Biography:

Tie Liu Immunology and tumor research institute, the First Affiliated Hospital, Xi'an Jiaotong University Health Science Center, Xi'an, Shanxi 710061, PR China

Abstract:

We recently have detected higher levels of Foxp3 in DN cells from mice by

development a new method of Flow cytometry ¹. In this study, we examined the expression levels of cell markers in thymocytes exhibited an obvious change during different developmental stages of T cells. We found many cells expressed intracellular CD4, intracellular CD8 and intracellular CD4⁺ CD8⁺ in CD4^-CD8^- DN cells. The highest expression level of CD25 was observed in CD4^-CD8^-DN cells, followed by CD4⁺CD8^- SP, CD4⁺CD8⁺DP and CD4^-CD8⁺ SP cells. The expression level of CD44 in DP cells was much lower than that in the DN cells, and also recorded for CD4⁺CD8^- and CD4^-CD8⁺ cells. NKT cells and γδT cells were found in DN and SP cells, but not in DP cells. The highest expression level of Notch₁ and CD117 were observed in DN cells, followed by SP and DP cells. Unexpectedly, intracellular CD3 was not only expressed in SP and DP thymocytes, but also in most of DN thymocytes at various stages. Contaminated cells in DN thymocytes could be removed by the intracellular CD3 gated, replaced with specific blocking antibodies. Our results suggested that T cells classification has been completed in the DN thymocytes stage. T cells, including γδ T cells, NKT and T_reg cells may develop from DN T progenitor cells, but without the involvement of the CD4⁺CD8⁺ stage in the thymus. We present an effective, easy and accurate method that avoids interference of contaminated cells and does not require the use of blocking antibodies to remove contaminated cells.

Biography:

Dr. Yingwei Wang is currently a professor at Department of Immunology of Nanjing Medical University. She is conducting research in exploring the mechanisms of glomerular mesangial cell (GMC) apoptosis and proliferation in human mesangial proliferative glomerulonephritis (MsPGN). These include signal transduction, microRNA regulation, transcription factor regulation. She is also exploring the effects of ubiquitination and acetylation modification on the activation of signaling molecules, transcription factors and histones.

Abstract:

The apoptosis of glomerular mesangial cell (GMC) in the early phase of rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis (MsPGN), is mainly triggered by sublytic C5b-9. But the mechanism of GMC apoptosis induced by sublytic C5b-9 remains unclear. In current study, we demonstrated that the expression of TNFR1-associated death domain-containing protein (TRADD) and interferon regulatory factor-1 (IRF-1) was simultaneously up-regulated both in the renal tissue of Thy-1N rats (in vivo) and in the GMC under sublytic C5b-9 stimulation (in vitro). And in vitro, TRADD was confirmed to be a downstream gene of IRF-1 because IRF-1 could bind to TRADD gene promoter to promote its transcription, leading to caspase 8 activation and GMC apoptosis. Meanwhile, increased phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) was verified to contribute to IRF-1 and TRADD production and caspase 8 activation as well as GMC apoptosis treated by sublytic C5b-9. Furthermore, the phosphorylation of mitogen-activated protein kinase kinase kinase 2 (MEKK2) was found to mediate p38 MAPK activation. More importantly, three sites (Ser-153/164/239) of MEKK2 phosphorylation were first identified and demonstrated to be necessary for p38 MAPK activation. Besides, silence of renal MEKK2, IRF-1 and TRADD gene or inhibition of p38 MAPK activation in vivo displayed obvious inhibitory effects on GMC apoptosis, secondary proliferation and urinary protein secretion in rats with Thy-1N. Collectively, these findings indicate that the cascade axis of MEKK2-p38 MAPK-IRF-1-TRADD-caspase 8 may play an important role in GMC apoptosis following exposure to the sublytic C5b-9 in rat Thy-1N.

Biography:

Donglu Shi The Institute for Translational Nanomedicine, Shanghai East Hospital, the Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai 200092, PR China

Abstract:

Cell targeting in cancer therapy has been a great challenge due to the heterogeneities of cancer biomarkers. The key, therefore, is to develop a new targeting strategy that does not rely on biomarkers.A general hallmark of cancer cells is the much increased level of glycolysis. The loss of the highly mobile lactate from the cytoplasm inevitably removes the labile inorganic cations to form lactic salts and acids as part of the lactate cycle, creating a net negative surface charge. This net negative charge on cancer cell surfaces distinguishes them from normal cells. In this study, cancer cells are targeted by using the negative charge to advantage via a fluorescent, superparamagnetic Fe₃O₄-nanocomposite, which has a positive surface charge.  The positively charged Fe₃O₄ nanocomposite binds predominantly to cancer cells due to their negative surface charge. This simple strategy provides a new path for effective cancer cell targeting and treatment without relying on biochemical markers.

Biography:

Dr. Ziv Porat, Ph.D., serves as a Staff Scientist in the Flow Cytometry Unit at the Weizmann Institute of Science, Rehovot, Israel. He completed his B.Sc. degree with Honors on clinical nutrition at the Hebrew University of Jerusalem, and undertook M.Sc. studies at Weizmann Institute of Science in Prof. Michal Schwartz’s lab, in the field of Neuroimmunology.  He worked toward his Ph.D. degree, also at the Weizmann Institute, in Prof. Chaim Kahana’s lab, where he investigated cancer related effects of polyamines. His postdoctoral studies at the Weizmann Institute, on the effect of flow on cell physiology, with a focus on microscopy and image analysis methods, were performed in Prof. Benjamin Geiger’s lab.

Abstract:

Senescent cells are present in premalignant lesions and sites of tissue damage, and accumulate in tissues with age. In-vivo identification, quantification and characterization of senescent cells are challenging tasks that limit our understanding of the role of senescent cells in diseases and aging. Here we present a new way to precisely quantify and identify senescent cells in tissues on a single-cell basis. The method combines a senescence-associated beta-galactosidase assay with staining of molecular markers for cellular senescence and of cellular identity. By utilizing Imaging Flow Cytometry, which combines flow cytometry with high-content image analysis, we were able to quantify senescent cells in tumors, fibrotic tissues, and tissues of aged mice. Our approach also yielded the finding that senescent cells in tissues of aged mice are larger than non-senescent cells. This method provides a basis for quantitative assessment of senescent cell impact on pathologies and aging.

Biography:

Dr Fan received her PhD degree in Dalian University of Technology in 2008. After graduation, she joined in Singapore General Hospital as a research scientist.  Her research interests are to study the immunomodulatory role of mesenchymal stromal cells (MSCs) and MSCs-derived soluble factor cocktail in immunological disorders, such as graft versus host disease and autoimmune diseases.

Abstract:

Mesenchymal stromal cell (MSC) therapy has been shown to be effective in phase I/II clinical trials in the treatment of graft versus host disease (GVHD) after allogeneic hematopoietic cell transplantations. However, MSC trials still face major challenges, such as complex and time-consuming manipulation, requiring a good manufacturing practice facility, difficult and expensive to produce etc. In a screen of MSC-derived factors with serial factorial designs, we first time identified two MSC-derived factors, CXCL5 and CCL24 inhibitor (antibody), which exhibited synergistic immunomodulation effect in mixed lymphocyte reaction. This two-factor (2F) cocktail also showed excellent in vivo immunosuppressive effect in ameliorating GVHD symptoms and improving survival. A xenograft GVHD animal model was created by injecting 400×10⁶cells/kg of cryopreserved human PBMCs into NSG mice respectively. Four consecutive treatments were given on day-10, day-14, day-17 and day-21 post-transplantation. The 2F cocktail exhibited excellent immunosuppressive effect as it could improve mice 36-day survival from 19.0% with severe symptoms to 61.9% with mild symptoms (p<0.01). It was significantly better than BM-MSCs (8.3%, p<0.001) and Cyclosporine A (26.1%, p<0.05). Synergistic effect was again observed between those two factors (CXCL5, 18.2%; anti-CCL24, 9.1%; p<0.05). The 2F cocktail treatment reduced cytotoxic T lymphocytes (CTLs), T helper 1 (Th1) cells, Th17 cells, NK cells in the circulation and macrophages in the spleen, but did not affect human hematopoietic stem cells (HSCs) reconstitution in the bone marrow. Concurrently, it reduced pro-inflammatory cytokine IFN-γ, IL-1β, IL-6, IL-12, TNF-α, IL-17A, IL-8, MIP-1β and MCP-1 in the circulation. In conclusion, the efficacy of a novel identified 2F cocktail was validated in an in vivo xenograft GVHD model. It demonstrated a robust immunosuppressive effect and kept the development of GVHD under control.  The 2F cocktail could be a potential chemically defined substitute for MSCs in GVHD therapy.

Biography:

Erlinda M. Gordon, M.D. is a Diplomate of the American Board of Pediatrics, Pediatric Hematology/Oncology, Director, Biological and Immunological Therapies, Sarcoma Oncology Research Center, Santa Monica CA, Chairman, Institutional Biosafety Committee, Sarcoma Oncology Research Center, Santa Monica CA, Principal Investigator, Phase 1/2 study using Trabectedin, Ipilimumab and Nivolumab as first line therapy for soft tissue sarcoma and Co-investigator of over 20 Phase I-III clinical trials using targeted therapies. She is Co-Inventor of >200 patents/patent applications, and Founder of 2 biotech companies, Counterpoint Biomedica LLC, whose mission is to develop (1) tumor targeted bifunctional polypeptides that bond non-covalently with drugs (2) biomarkers for the identification and capture of circulating tumor cells, and (3) tumor-targeted recombinant human GM-CSF for cancer immunotherapy, and Epeius Biotechnologies Corp., whose mission is to develop targeted gene therapy vectors for cancer (Rexin-G) and cancer immunotherapy (Reximmune-C).  She was a Tenured Associate Professor, USC Keck School of Medicine.

Abstract:

Trabectedin has direct cytotoxic activity in tumor cells and has been shown to deplete pro-tumor macrophages in the tumor microenvironment. Nivolumab inhibits the immune checkpoint molecule, PD-1, which restores anti-tumor activity in tumor-infiltrating T cells.  Purpose:  To assess the safety/toxicity and efficacy of sequential administration of trabectedin and nivolumab in patients with advanced soft tissue sarcoma (STS). Methodology: Fourteen patients with metastatic STS were evaluated. Each patient received one dose of single-agent trabectedin (1.5 mg/m² continuous intravenous infusion, CIV, for 24 hours), followed by trabectedin CIV every 3 weeks, and nivolumab 3 mg/kg IV every 2 weeks. Safety/toxicity was analyzed using the NIH/NCI CTCAE v.4.03. Tumor responses were assessed by RECIST v1.1 and immune-related response criteria (irRECIST). Findings:  Histologic subtypes include undifferentiated pleomorphic sarcoma, leiomyosarcoma, synovial sarcoma, myxoid liposarcoma and chondrosarcoma. All patients had metastatic disease and a median of 4 lines of prior chemotherapy.  Safety analysis: Grade 3 treatment emergent adverse events include anemia, fatigue, decreased platelet count, decreased granulocyte count and increased creatine kinase. Efficacy analysis: Thirteen patients received at least 2 cycles of sequential chemo-/immuno-therapy, had follow-up CT scan/MRI, and were evaluated for objective response (OR), best overall response rate (BORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). There were 3 partial responses, 7 stable disease and 3 progressive disease, with BORR of 23.1%, DCR of 76.9%, median PFS  >7.8 months (range: 3.5->10.4 months), median OS  >8.4 months (3.6->10.4 months), 6 month PFS rate, 69.2%, and 6 month OS rate, 92%. Six-month OS rate for all 14 patients was 86%. In a Phase 3 study, the median PFS was 4.2 months using trabectedin alone (Demetri et al., 2015). Conclusion: Taken together, the data suggest that paired administration of trabectedin and nivolumab is safe, and that this chemo-/immuno-therapy approach has synergistic activity.

Biography:

Thomas Grundström completed his doctorate at Umeå University in 1981 and his Medical degree in 1982. Dr. Grundström was post-doc 1982-1984 in the laboratory of prof. Pierre Chambon, Strasbourg, France, where he characterised the first discovered enhancer of transcription. He is professor at the department of Molecular Biology at Umeå University since 1994. Dr. Grundström discovered the first direct Ca²⁺/calmodulin inhibition of a transcription factor (Corneliusen et al., Nature, 1994) and has characterized the Ca²⁺ regulation of many regulatory proteins with a focus on the immune system.  Dr. Grundström is presently studying regulation of production of high affinity antibodies.

Abstract:

B-lymphocytes can modify their immunoglobulin (Ig) genes to generate antibodies with a new isotype and enhanced affinity. Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates these processes. How somatic hypermutation (SH) and class switch recombination (CSR) are targeted and regulated is key to understanding how we achieve good antibodies. The trans-acting factors mediating specific targeting of AID and thereby SH and CSR have remained elusive. No direct coupling between a transcription factor and the specific targeting of AID has been demonstrated, and how AID is recruited is still a big mystery. We show that mutant E2A with defect inhibition by the Ca²⁺-sensor protein calmodulin results in reduced B cell receptor- (BCR-), IL4- plus CD40 ligand-stimulated CSR to IgE. AID is shown to be together with the transcription factors E2A, PAX5 and IRF4 in a complex on key sequences of the Igh locus in activated mouse splenic B cells. Calmodulin shows proximity with them after BCR stimulation. Direct protein-protein interactions are shown to enable formation of the complex. BCR signaling reduces binding of the proteins to some of the target sites on the Igh locus, and calmodulin resistance of E2A blocks this reduction. Thus, E2A, AID, PAX5 and IRF4 are components of a CSR and SH complex that calmodulin binding redistributes on the Igh locus. We present also regulation of a “mutasome”, the protein complex that enables repair at high error rate of the uracils made by AID on Ig genes but not on most other genes.

Biography:

Sofie Struyf obtained her PhD degree (2002) at the Laboratory of Molecular Immunology (University of Leuven) and is currently holding a position of professor at the Rega Institute. She teaches advanced immunology courses. Prof. Struyf (co-)authored 117 publications in peer-reviewed journals, which were cited more than 6000 times. Those publications deal with many aspects of chemokine biology, including gene regulation, receptor usage and signaling pathways, producer and target cells, … improving the understanding of the role of these chemotactic cytokines in inflammation, infection and tumor development.  

Abstract:

Patients suffering from Primary Ciliary Dyskinesia (PCD), an autosomal inherited disorder caused by defective motile cilia, often have to cope with recurrent infections of the upper and lower airways. We investigated the innate immune system in PCD pathology. More precisely, we verified whether the chronic inflammatory environment in PCD patients affects the activity of blood leukocytes in their defense against pathogens. We detected abnormalities in the responses of innate immune cells (neutrophils and monocytes purified from peripheral blood) from PCD patients. Both neutrophilic granulocytes and monocytes showed an altered expression pattern of chemoattractant receptors. In addition, neutrophils and monocytes from PCD patients reacted differently than those from healthy controls in terms of upregulation of adhesion molecules in response to chemotactic stimuli. But, only PCD neutrophilic granulocytes were affected in their migratory capacity. Finally, PCD patients have a higher proportion of inflammatory monocytes and those cells release higher amounts of inflammatory cytokines after stimulation with TLR ligands. We can thus conclude that innate immune cells from PCD patients act differently from those of healthy individuals and that chronic airway inflammation alters innate immune responses.

Biography:

Barbara Soares Gonçalves Undergraduate Students, Faculty of Medicine of Jundiaí, Jundiaí – SP, Brazil.

Abstract:

Several studies have shown that the inflammatory response is crucial for the control of Paracoccidioidomycosis (PCM), however, exacerbation of inflammation leads to tissue damage and imbalance of the acquired immune response. The inflammatory response initiates after the recognition of pathogens by receptors expressed by innate immune cells. Among these receptors, the NLRP3 was associated with the recognition of pathogenic fungi in experimental models. NLRP3 operates forming a multiproteic complex called inflammasome, which actives caspase-1, responsible for the production of the inflammatory cytokines IL-1beta and IL-18. In this study we aimed to investigate the involvement of NLRP3 in the inflammatory response elicited in macrophages against Paracoccidioides brasiliensis (Pb), the etiologic agent of PCM. Macrophages were differentiated from THP-1 cells by treatment with phorbol-myristate-acetate. Following differentiation, macrophages were stimulated by Pb yeast cells for 24 hours, after previous treatment with specific NLRP3 (3,4-methylenedioxy-beta-nitrostyrene) and/or caspase-1 (VX-765) inhibitors, or specific inhibitors of pathways involved in NLRP3 activation such as: Reactive Oxigen Species (ROS) production (N-Acetyl-L-cysteine), K+ efflux (Glibenclamide) or phagossome acidification (Bafilomycin). Quantification of IL-1beta and IL-18 in supernatants was performed by ELISA. Our results showed that the production of IL-1beta and IL-18 by THP-1-derived-macrophages stimulated with Pb yeast cells was dependent on NLRP3 and caspase-1 activation, once the presence of their specific inhibitors diminished the production of these cytokines. Furthermore, we found that the major pathways involved in NLRP3 activation, after Pb recognition, were dependent on ROS production and K+ efflux. In conclusion our results showed that NLRP3 participates in the recognition of Pb yeast cells by macrophages, leading to the activation of the NLRP3-inflammasome and production of IL-1beta and IL-18. Together, these cytokines can induce an inflammatory response against P. brasiliensis, essential for the establishment of the initial inflammatory response and for the development of the subsequent acquired immune response.

Biography:

Stepan Dzhimak is studying the role of low deuterium concentrations in drinking water on the living systems adaptive capabilities. In the experimental clinic-laboratory of biologically active substances of animal origin he is principal investigator of the project: development of innovative natural adaptogenic stimulants of nonspecific immunity based on tissue-specific biomolecules.

Abstract:

Statement of the Problem: Immune system dysfunction is pathological processes key aspect, as result we can see protective and adaptogenic immunity reactions activation and its depletion, leads to bacterial and viral infections. Modern immunoregulating drugs, mainly synthetic origin, cause pathogens resistance increase and lead to allergic reactions. One of the possible problem solutions is to obtaining immunocorrective natural drugs with directed action based on animal origin biomolecules. Peptides and proteins complex isolated from Sus Scrofa thymus, spleen, lymph nodes (TSL) (0.9% NaCl solution) studies were conducted. Deuterium depleted water (DDW) promotes maximum biomolecules extraction. Research purpose was to investigate protein-peptide compounds fractions isolated from the organs of the immune system Sus scrofa immunological activity in vivo. Methodology & Theoretical Orientation: 58 rats (SPF) were injected with cyclophosphamide (triply, 75 mg/kg), after immunodeficiency model completed (12 days from first injection) animals were treated by: complex extract on DDW (TSL), TSL fractions less than 5 kDa (A), from 5 to 30 kDa (B), over 30 kDa (C). Findings: It has been revealed that TSL and B activate CD3 and CD4 differentiation and typing processes (CD3/CD4 shifted to larger side); increase T-lymphocytes and T-helpers content by reducing suppressors and killers; increase of cytokine factors production (Il-2, Il-4, Il-6, IgM, IgG) responsible for adaptive immune response; normalize granulocytes level, which against increased CD3 background indicates one of the immunity recovery stages. There also noted significant C1q and C4 level increase, which synergistically with a C5 and C3 level decrease indicate complementary cascade of activation reactions. Minimal therapeutic effect was noted in rats A and C. Conclusion & Significance: Biomolecules (5-30 kDa), isolated from Sus Scrofa immune tissues by DDW extraction, showed obvious immunoactivating effect. Immunosuppression model revealed complementary system cascade faster activation and protective system cellular and molecular factors maximum reactivity while biomolecules treatment.

Biography:

Samuel Huber is an expert in the field of Gastroenterology and Immunobiology. He did his postdoctoral training at Richard A. Flavell’s lab at the Department of Immunobiology, School of Medicine, Yale University. Currently he is leading the laboratory of Molecular Gastroenterology and Immunology at the I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany. The main focus of his lab is to study mechanism controlling the homeostasis in the intestine in order to identify new therapeutic targets for the treatment of inflammatory bowel disease and colorectal cancer.

Abstract:

Statement of the Problem: The incidence and prevalence of Immune mediated inflammatory diseases (IMIDs) are steadily increasing. Unfortunately, most therapies used against these diseases have as of yet palliative character and mostly do not offer a cure. Thus, life-long treatment using immune-suppressive agents is required in the majority of cases. As a consequence, patients with IMID must live with the side effects of these treatments, such as increased risk of opportunistic infections and of relapsing flares of the disease itself. Furthermore, chronic inflammation, another possible side effect, can promote the development of certain forms of cancer. Therefore, there is major need for new therapies, which can modulate the immune response more specifically.

Theoretical Orientation: TH17 cells and their associated cytokines play an important but ambiguous role in these diseases. On the one hand they play a key role in chronic inflammatory diseases and carcinogenesis. On the other hand, however TH17 cells and their cytokine products, such as IL-22, also have beneficial properties such as promotion of wound healing and defence against pathogens. This obviously reveals that it is crucial to find out the molecular and cellular mechanisms which physiologically control TH17 cells in order to not just simply deplete them, but rather reset them to their beneficial state. We have indeed already identified several mechanisms, which explain how TH17 cells and their cytokines can be physiologically controlled (Figure 1). Of note the intestine plays a key role during this regulation.

Conclusion & Significance: Our data indicate that TH17 cells can be controlled in the intestine. Our aim is to furthermore understand the involved mechanism.

Biography:

Katarzyna Swist-Szulik is working as a consultant in paediatric intensive care and has her passion in research on the role of mitochondria in inflammatory signalling. She is pursuing her PhD on the role of mitochondrial dysfunction in intercellular crosstalk between myeloid and non-myeloid cells. There are building evidence that mitochondria-inflammatory interactions are relevant to many disease processes such as inflammatory myopathies, neurodegenerative diseases, autoimmune diseases as well as multi-organ failure and drug induced sterile inflammation. Katarzyna is working on developing the translation research investigating mitochondria-inflammatory relationship. Outside work Katarzyna is a mother of two wonderful children, an adventurer, ultramarathon runner and finisher of Marathon des Sables in 2015

Abstract:

Introduction: Mitochondria are double-membrane-bound organelles and primary source of cellular energy adenosine triphosphate (ATP). Mitochondria are also involved in innate responses and are necessary for NLRP3 inflammasome activation and maturation of IL-1β in immune cells. Research project investigates the role of mitochondrial dysfunction in cell to cell cytokine crosstalk ((1-6) .   Aims: To characterise the nature of cytokine crosstalk between fibroblasts and myoblasts with induced mitochondrial dysfunction and inflammatory cells such as monocytes and THP1 cells.  Methods: Stimulation with LPS (lipopolysaccharide) and benzylated ATP were used to cleavage NLRP3 inflammasome and release IL-1β in monocytes and THP1 cells. Supernatants containing IL-1β from treated for inflammasomes THP1 cells  as well as recombinant IL-1β were applied on fibroblasts and myoblasts with induced  by Rotenone ( Complex I inhibitor) mitochondrial dysfunction. Blocking experiment using anti-IL-1β, anti-IL-1α antibodies as well as IL-1 receptor antagonist characterized the interactions between IL-1β and Il-6 cytokines. ELISA tests were used to measure the content of IL-1β and IL-6 in supernatants. Seahorse was used to assess the changes in bioenergetics profile of the treated cells.  Results: Fibroblasts and myoblasts release IL-6 in the presence of supernatants containing IL-1β from THP1 cells and monocytes in the dose dependent manner. Cells with induced mitochondrial dysfunction produce high levels of IL-6 level in close correlation with the degree of mitochondrial dysfunction and dose of recombinant IL-1β. IL-6 released by fibroblasts is in 90% inhibited by adding IL-1 receptor antagonist (IL-Ra) and anti-IL-1β antibodies what would suggest single cytokine crosstalk between IL-1β and IL-6. Conclusions: The data indicate the presence of crosstalk between monocytes and fibroblasts or myoblasts on the cytokine level characterized by IL-1β and IL-6 relationship. Ability to produce high levels of IL-6 by fibroblasts or myoblasts is amplified by degree of mitochondrial dysfunction and presence of IL-1β in dose dependent manner.

Biography:

Professor Ping Wang is an experimental immunologist focusing on modulation of effector T cells in context with anti-tumour or autoimmunity. Based on the discovery of Egr2/3 function in effector T cells, he models an intrinsic regulatory pathway for regulating checkpoints of clonal expansion and differentiation of effector T cells differentially in response to self or pathogens. Understanding of intrinsic regulation of effector T cells may create new possibilities to modulate effector function of T cells in tumour or autoimmune conditions.

Abstract:

T cell mediated responses are controlled by checkpoints that limit over-activation of effector cells and excessive pathology. However, over control of the checkpoints will lead to weak immune responses. It is less known about the intrinsic mechanisms in effector T cells to regulate the balance of checkpoint molecules in response to different stimuli. Transcription factors early growth response gene (Egr) 2 and 3, induced in effector phenotype T cells by antigens, are intrinsic regulators served as checkpoint controllers to promote clonal expansion in adaptive immune responses, but inhibit inflammatory differentiation of effector T cells. Induction of Egr2 and 3 at early stage of anti-viral responses promote proliferation, but suppress differentiation of antigen specific T cells for optimal expansion with minimum inflammatory pathology. The expression of Egr2 and 3 are inhibited at late stage by inflammatory cytokines which is essential for activation of differentiation checkpoint of effector T cells. In homeostasis, Egr2 and 3 controls differentiation of effector phenotype T cells. CD2-specific deletion of Egr2 and 3 results in server autoimmune diseases. Egr2 and 3 regulate expression of proliferative regulators such as Myc, while inhibit inflammatory transcription factors such as T-bet and RORgt. Thus, temporal and spatial expression of Egr2 and 3, induced by antigen and inhibited by inflammatory cytokines, control checkpoints of clonal expansion and differentiation of effector T cells in both adaptive and homeostatic responses. This control is essential for both optimal adaptive immune responses and maintaining immune homeostasis.

Biography:

Maria Libera Ascierto research work in Johns Hopkins University, USA

 

Abstract:

: After Coley’s observation in 1891 of tumor regression in a patient who developed a postoperative infection, the field of cancer immunology is finally reborn. Cancer patients with active adaptive and innate arms of immunity display clinical benefit (1, 2, 3). Accordingly, avoiding immune destruction is now considered a hallmark of cancer, and the immunotherapy arena has exploded with the recent advances demonstrating an improvement in survival and a durability of response in patients with different cancer types, including melanoma (4). In this regard, monoclonal antibodies blocking programmed death 1 (PD-1):PD-1 ligand (PD-L1, B7-H1) pathway showed an unprecedented spectrum of activity versus different cancer types providing a “common denominator” for cancer therapy. Despite these very encouraging results, the majority of patients do not respond to these regimens as monotherapy leading to an urgency to identify biomarkers that accurately predict which patients will benefit from this form of therapy. At the same time, there is a critical need to identify potentially actionable mechanisms of therapeutic resistance to anti-PD-1 or anti- PD-L1 therapies in order to set successful combinatorial approaches. The expression of PD-L1 on the tumor cell surface has been previously identified as one factor associated with the clinical activity of anti–PD-1. Notably, a significant number of patients with PD-L1+ cells still do not respond to PD-1 pathway blockade, suggesting that additional factors can induce therapy resistance thus influencing treatment outcomes (5). In renal cell carcinoma, we showed with a deep molecular analysis that the intra-tumor balance between metabolic and immunologic gene expression might determine the effective response to anti-PD-1 blockade (6). In melanoma, we discovered transcriptional signatures mostly associated with epithelial to mesenchymal transition (EMT) and accumulation of neutrophils to be associated with PD-1 blockade therapy resistance (7). These studies suggested that many pathways might determine the clinical response to anti-PD-1 therapy in cancer patients and that determinants of clinical response might change based on the considered tumor type.

Biography:

Roswitha Gropp has over 25 years of experience in preclinical development and inflammatory diseases. She recently took on a different view considering the inflammatory process in UC as an uncontrolled wound healing process.  This hypothesis assumes that epithelial damage induces the release of signals to evoke a Th2 characterized inflammatory response that ultimately results in repair of the colon. Using agent based modeling first disease maps were developed to describe the inflammatory milieu and the dynamics of the inflammatory response. This approach together with immunological profiling of patients allows for a better understanding of underlying mechanisms ultimately leading to individualized therapies.

Abstract:

One reason for the lack of individualized therapies in ulcerative colitis (UC) may be that the conventional approaches are not adequate to understand the complexity of chronic inflammatory diseases. They mostly rely on the identification of certain cell types and cytokines associated with the disease phenotype, followed by verification of their roles in vitro and in vivo. This approach does not take into consideration that the observed pathologies might be the result of different causes. In addition, inflammatory responses are highly dynamic processes that require the cross talk of the immune-, epithelial-, endothelial-, muscle cells, and fibrocytes. The conventional approach further disregards the high plasticity of T-cells and monocytes, which both have the capacity to adopt their phenotype depending on the inflammatory milieu. Therefore, we took a more comprehensive approach and developed FACS, ELISA and autoantibody panels to portray individual inflammatory profiles. In addition, we developed a disease map of UC by computational modeling. Finally, we developed an animal model which enables us to proof the hypothesis generated by modeling and profiling. So far, we tested infliximab, adulizumab, sirolimus, anti CD1a antibodies, anti CCR4 antibodies and the IL-4Ra /IL-13a1 inhibitor pitrakinra in our mouse model. Results suggest that the animal model is highly reflective of the human disease, that therapeutic responses can be predicted by the computational model and that novel therapeutics emerge from this approach.

Biography:

Nicholas Young is a research scientist in the Division of Immunology and Rheumatology at The Ohio State University Wexner Medical Center. There, he has a role in both management/direction and at the bench in projects associated with myositis, Sjögren’s syndrome, systemic lupus erythematosus, rheumatoid arthritis, inflammation, cancer immunology, and exercise science. His collaborative work in this laboratory has shown a bench-to-bedside scope of research starting with basic scientific discovery, moving to animal models, performing preclinical validation, and advancing to human clinical trials with the goal being to identify a diagnostic biomarkers and/or therapeutic targets. Dr. Young has developed team-oriented communication, mentorship, management, and teaching skills through this experience and hopes to use this foundation of microbiology, immunology, and oncology to discover biological solutions through the use of a systems biology approach to treat disease.

Abstract:

Despite studies indicating the positive effects of exercise and psychological stress reduction in patients with autoimmune disease, this therapeutic modality is underemphasized due to the absence of comprehensive immunological characterization and regimen standardization. In order to examine the influence on the immune system at the cellular and tissue level, disease pathology was analyzed in the NZM2410 mouse model of lupus nephritis. Mice were either exercised daily at moderate intensity by treadmill walking or exposed to a previously established model of psychosocial stress induction. Psychosocial stress induction significantly exacerbated and daily moderate exercise significantly reduced lupus nephritis disease pathology, as measured by blood urea nitrogen levels, IgG and complement component 3 complex deposition in glomeruli, macrophage infiltration, and histopathological grading of H&E-stained kidney sections. Furthermore, stressors induced levels of IL-6, TNF-α, and IL-1β, while exercise suppressed IL-6, TNF-α, IL-10, and CXCL1. To translate these results and begin to characterize a standardized treatment regimen for patients, a pilot cohort with active systemic lupus erythematosus (SLE) was enrolled into a daily Tai Chi program, which emphasized moderate exercise levels with meditative breathing to provide daily physical activity and stress reduction. Compared to baseline data, questionnaires confirmed a significant reduction in perceived social stress and an increase in overall physical activity. Furthermore, fitness activity tracker data showed a significant increase in steps, distance, and activity calories with no changes in body mass index or vigorous activity levels. Interestingly, this correlated with an increased time in bed each night. Analysis of pro-inflammatory serum cytokines revealed suppression of IL-6 by 23%, IL-8 by 30%, TNF-α by 11%, and IFN-É£ by 21% with Tai Chi. These data suggest that moderate exercise and stress management can have potent immunoregulatory effects on the chronic inflammation associated with SLE and indicate that Tai Chi can be an effective adjunct therapy.