*Purpose: Allogeneic transplant tolerance has been achieved by inducing mixed hematopoietic chimerism via donor bone marrow transplantation. Tolerance mechanisms in this model involve the presentation of donor MHC molecules in the host’s thymus resulting in deletion of alloreactive T cell clones and Treg differentiation. Exosomes are small extracellular vesicles that are able to transfer surface molecules and antigens from their parent cells. In this study, we investigated whether donor MHC chimerism and allograft tolerance could be achieved via donor exosome injections.

*Methods: BALB/c (H2-d) or SJL (H2-s) recipient mice were conditioned with total body irradiation (TBI) or a radiation-free, minimally immunosuppressive regimen (MIR) prior to receiving a single IV dose of purified bone marrow derived exosomes (BMexo) isolated from C57BL/6 (H2-b) donors. After a month, animals received a skin or islet allograft. Image flow cytometry was used to detect the presence of cross-dressed cells in the recipient thymi and spleen. Syn-chimeras generated by injecting OT-II bone marrow cells into C57BL/6 animals were conditioned using the MIR protocol and received a dose of BMexo isolated from B6.Act-mOVA bone marrow cells (OVAexo).

*Results: IV injection of BMexo into conditioned mice resulted in the presentation of donor MHC by host’s thymic and splenic cells. Donor but not syngeneic or third-party exosomes significantly prolonged skin allograft survival (median survival=17 VS 11 days, p<0.001) in the TBI group, while animals in the MIR group achieved long-term survival of over 100 days of skin (p=0.0005) or islet (p=0.0033) allografts compared to control conditioning alone. In synchimeric mice, the number of peripheral TCR transgenic OT-II (Va2+ Vb5+) T cells among CD3+ cells was significantly reduced in the OVAexo injected mice as early as 10 days after exosome injection as compared to control (p=0.029).

*Conclusions: BMexo can induce donor MHC presentation via cross-dressing of recipient APCs in the host’s thymus. This translates into long-term survival of skin and islet transplants when using thymic-sparing conditioning. Results in the syn-chimera experiments suggest that T cell deletion plays a role in this tolerance model. These findings pave the way towards the usage of donor exosomes in place of bone marrow cells to induce allograft survival with minimal conditioning and no risk of graft versus host disease.

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