Xiubo Fan
Singapore General Hospital, Singapore
Title: Substitute mesenchymal stromal cells therapy in graft versus host disease with a chemically defined cocktail
Biography
Biography: Xiubo Fan
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.