Immunology

Biography

Biography: Nathali Kaushansky

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS, associated with complex anti-myelin autoimmunity. Among all approaches proposed for MS therapy, an approach that neutralizes only the pathogenic T cells reacting against myelin, while leaving the innocent immune cells intact, is the ultimate goal in the immune-specific therapy for MS. The multiplicity of primary target antigens, along side the dynamic nature of autoimmunity in MS, whereby the specificity of anti-myelin pathogenic autoreactivities may shift or expand in the same patient with disease progression, impose major difficulties in devising immune-specific therapy to MS. To overcome this multiplicity and the potential complexity of pathogenic autoreactivities in MS, we have put forward the concept of concomitant multi-antigen/multi-epitope targeting as, a conceivably more effective approach to immunotherapy of MS. We constructed an EAE/MS-related synthetic human Target Autoantigen Gene (MS-shMultiTAG) designed to encode in tandem only EAE/MS related epitopes of all known encephalitogenic proteins. The MS–related protein product (designated Y-MSPc) was immunofunctional and upon tolerogenic administration, it effectively suppressed and reversed EAE induced by a single encephalitogenic protein. Furthermore, Y-MSPc also fully abrogated the development of “complex EAE” induced by a mixture of five encephalitogenic T-cell lines, each specific for a different encephalitogenic epitope of MBP, MOG, PLP, MOBP and OSP. Strikingly, Y-MSPc was consistently more effective than treatment with the single disease-specific peptide or with the peptide cocktail, both in suppressing the development of “classical” or “complex” EAE and in ameliorating ongoing disease. Overall, the modulation of EAE by Y-MSPc was associated with energizing the pathogenic autoreactive T-cells, downregulation of Th1/Th17 cytokine secretion and upregulation of TGF-b secretion. Moreover, we show that both suppression and treatment of ongoing EAE by tolerogenic administration of Y-MSPc is associated also with a remarkable increase in a unique subset of dendritic-cells (DCs), CD11c+CD11b+Gr1+-myeloid derived DCs in both spleen and CNS of treated mice. These DCs, which are with strong immunoregulatory characteristics and are functional in down-modulation of MS-like-disease displayed increased production of IL-4, IL-10 and TGF-b and low IL-12. Functionally, these myeloid DCs suppress the in-vitro proliferation of myelin-specific T-cells and more importantly, the cells were functional in-vivo, as their adoptive transfer into EAE induced mice resulted in strong suppression of the disease, associated with a remarkable induction of CD4+FoxP3+ regulatory cells. These results, which highlight the efficacy of “multi-epitope-targeting” agent in induction of functional regulatory CD11c+CD11b+Gr1+myeloid DCs, further indicate the potential role of these DCs in maintaining peripheral tolerance and their involvement in downregulation of MS-like-disease.