Differential effect of FasL on GvHD disease according to its source
Résumé
Objective: Hematopoietic stem cell transplantation is a potentially curative treatment for hematologic malignancies. An important limitation of its use is the frequent occurrence of graft versus host disease (GvHD). GvHD is associated with complex interactions between innate and adaptive immunity. The incidence of GvHD is 40 to 80% depending on donor-and transplant-characteristics. A number of pathways have been described on allogeneic T cell-mediated cytotoxicity, including the Fas/Fas ligand (FasL) pathway. However, the overall mechanistic findings on how FasL expression in donor cells affects target tissues remains poorly characterized. Methods: We used a well-defined CD4 and CD8-dependent sclerodermatous GvHD model. GvHD is induced by transplantation of low doses of T-and B-cell depleted BM cells and splenocytes from C57BL/6 mice into lethally irradiated BALB/c mice. Colon and skin samples were analyzed by flux cytometry and H&ES staining of fixed sections. Serum cytokines were measured by Multiplex ELISA. Results: Recipient from Fasl-KO BM mice exhibited exacerbate gut acute GvHD (diarrhea significantly higher compared to WT-BM recipient mice). Serum analysis at Day 10 post transplantation (PT) revealed a drastically reduced IL-18 level in these mice compared to WT-BM recipient mice. Cellular and histological analysis of colon biopsies showed significantly higher frequency of CD8 T cells and lymphocytic infiltrates in Fasl KO-BM recipient mice as compared to WT-BM. Recipients of FasL deficient T cells (transplanted with WT BM) displayed significantly reduced symptoms of acute (diarrhea) and chronic GvHD (skin lesion). Pathological skin analysis at Day 34 PT revealed that, unlike syngeneic control mice where cellular infiltrate was mostly of myeloid origin, the infiltrate in mice with GVHD included myeloid-cells and T-cells in similar proportion. In recipients of Fasl KO-splenocytes, proportions of Treg (FoxP3+CD25+) were significantly increased while those of IFN-γ + CD4 T-cells were significantly decreased as compared to WT-splenocytes recipients; suggesting a regulatory environment. Conclusion: These results indicate that FasL expression, either in BM or in in splenocytes, acts differentially in GvHD. FasL expression by donor myeloid cells confers protection from aGvHD via the production of IL-18. In contrast, FasL expression by donor T cells mediates cytotoxicity.