*Purpose: Achieving robust and durable host immune tolerance of allogeneic transplants is the ultimate goal in clinical transplantation. Mixed chimerism induced via donor bone marrow transplantation and host non-myeloablative conditioning has reliably achieved tolerance of allogeneic organ transplants in mice and humans. Tolerance in this model is believed to rely essentially on the presentation of donor MHC molecules in the host’s thymus. In this study, we investigated whether donor MHC chimerism could be achieved via donor exosome injections and subsequent cross-dressing of recipient cells in the host’s thymus.

*Methods: Conditioned SJL (CD45.1⁺, H2-K^s+) recipient mice received a single IV dose of purified bone marrow derived exosomes (BMexo) isolated from C57BL/6 (CD45.2⁺, H2-K^b+) donors. Image flow cytometry was used to detect the presence of cross-dressed cells from day 10 through 100 after exosome injection. For NHP studies, MHC class I H38+ BMexo were injected into a H38- conditioned cynomolgus macaque prior to a combined heart and kidney transplant. PBMCs, thymus, spleen and mesenteric lymph nodes were collected for image flow cytometry

*Results: Intravenous injection of BMexo into conditioned mice resulted in the presentation of donor MHC and CD45.1 molecules by host’s thymic and splenic cells. Similarly, H38+ cross-dressed cells were detected at D33 after exosome injection in all of the NHP recipient tissues collected. In mice, donor but not syngeneic or third-party exosomes significantly prolonged skin allograft survival (median survival=17 VS 11 days, p<0.001).

*Conclusions: These results show that delivery of donor-derived exosomes can induce donor MHC chimerism via cross-dressing of recipient APCs with allogeneic MHC molecules in the host’s thymus. This suggests that donor exosomes could be used in place of bone marrow cells to induce chimerism and allograft survival with minimal conditioning and no risk of graft versus host disease (GVHD).

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