*Purpose: Co-stimulation blockade (CoB) has emerged as a promising immunosuppression strategy and potential alternative to calcineurin inhibitors in solid organ transplantation. Despite recent advancements, CoB based regimens are hampered by increased rates of acute cellular rejection. Donor bone marrow derived mesenchymal stem cells (BM-MSCs) offer a clinically relevant cellular therapy as an approach to suppress T cell alloreactivity and prolong allograft survival. The purpose of this study was to investigate the effect of combined donor BM-MSCs and CoB on allograft survival.

*Methods: We utilized a murine model of MHC mismatched skin transplantation (Balb/C -> C57BL/6) and a fully MHC mismatched non-human primate (NHP) model of renal transplantation.

*Results: Combined CoB (CTLA-4Ig + anti-CD154) + donor (Balb/C) BM-MSCs administered intravenously on days 1,3, and 5 post-transplant (10⁵ cells per infusion) significantly prolonged skin graft survival compared to CoB + donor splenocytes and CoB alone (MST 40 d vs. 21 d vs. 18 d, p = 0.04*). In NHP, bimonthly infusions of donor BM-MSCs (2 x 10⁶ cells/kg per infusion) in combination with CoB (anti-CD28 + anti-CD154) (n=4) prolonged renal allograft survival compared to CoB alone (n = 3) (MST 228.5 days vs. 41 days, p = 0.09). In vitro, NHP BM-MSCs suppressed allo-stimulated T cell proliferation and cytokine effector function via IFN-gamma and TNF-alpha production in a contact independent fashion.

*Conclusions: These data demonstrate that donor BM-MSCs in combination with CoB treatment prolong allograft survival in both murine and NHP models of transplantation. Donor BM-MSCs are a promising cellular therapy to suppress co-stimulation resistant T cell alloreactivity and prevent cellular rejection in future large animal and clinical studies of CoB-resistant rejection.

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