Amelioration of graft versus host disease in humanized mice by exopolysaccharide from a commensal bacterium

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Abstract Graft versus host disease (GVHD) is the major and often lethal complication of allogenic bone marrow transplantation. Prophylactic regimens for GVHD are given as standard pre-transplantation therapy; however, up to 60% of these patients develop GVHD, and require additional immunosuppressive intervention. We identified a probiotic exopolysaccharide (EPS) that induces inhibitory macrophages and tolerogenic dendritic cells (DCs) that inhibit T cell proliferation. We tested if EPS-treated human DCs, derived in vitrofrom CD34 +cord blood cells, would inhibit allogeneic T cell proliferation in a mixed lymphocyte reaction (MLR) and found that they did, demonstrating that EPS can induce tolerogenic DCs in vitro.We translated these studies in vivousing a humanized mouse model of aGvHD and demonstrated that EPS-treated human DCs administered at the time of transfer of human peripheral blood mononuclear cells (hPBMCs) significantly increased survival of these mice compared to mice given PBS-treated DCs, or no DCs. Several subsets of DCs have been described, e.g., cDCs, moDCs and plasmacytoid DCs, each with different phenotypes and functions. Using labeled EPS, we showed that the tolerogenic CD34-derived DCs generated by EPS treatment are conventional DCs (cDCs). We found that EPS binds to two cDC populations, conventional DC1 (cDC1) and conventional DC2 (cDC2), but only cDC1 were inhibitory in our MLR cultures. Our data indicate that EPS-DCs, potentially cDC1, can be used as a cell-based therapy to mitigate aGvHD in humans. NIH 1R41AI155281-01