Background: Allogeneic thymus has been investigated to achieve donor-specific tolerance in organ transplantation. Often thymus co-transplantation induces long-term graft survival in immunodeficient and total lymphoid irradiated recipients. However, it has not been fully successful in immunocompetent recipients.

Methods: We transplanted cultured haplo-matched (F1(LEW/DA); RT-1^l/av1) thymus in conjunction with vascularized fully mismatched (DA; RT-1^av1) heart transplants into Lewis (RT-1^l) rats. The recipients were treated by thymectomy with T cell depletion (OX19) and cyclosporine (CsA) by osmotic pump for 4 months. The control group did not receive thymus transplants. Two months after complete discontinuation of immunosuppressive agents, fully MHC mismatched third-party heart (BN; RT-1ⁿ) transplantation was performed to confirm donor-specific tolerance.

Results: Recipients with thymus transplants showed repopulation of naïve CD4(CD62L⁺CD45RC⁺)T cells in the peripheral blood while control groups without thymus transplantation did not show circulating naïve CD4 T cells. Even after developing recent thymic emigrant CD4 (CD90⁺CD45RC⁺) T cells, recipients with thymus co-transplantation did not reject the cardiac allografts. Interestingly, controls also did not reject the graft due to lack of T cells. To confirm the donor-specific unresponsiveness in the context of immunocompetence, a third-party heart was transplanted on day 180 after the initial mismatched heart transplantation. Animals with thymus transplants rapidly rejected the third-party heart (mean time of rejection = 10d). The controls did not reject the third-party heart. Taken together, thymus co-transplantation resulted in specific tolerance to the allogeneic MHC expressed in the donor thymus and thus long term survival of the heart transplant. Immunocompetence was demonstrated in these rats by rapid rejection of 3^rd party hearts.

Conclusions: In the present study, we provide proof of concept that thymus transplantation (as currently used in athymic infants with DiGeorge syndrome) can achieve donor-specific tolerance to vascularized organ transplants. Importantly, this study showed that the donor specific tolerance could be achieved in an animal that was immunocompetent prior to transplantation.

CITATION INFORMATION: Kwun J., Li J., Rouse C., Park J., Kirk A., Markert L. Thymus Co-Transplantation Promotes Donor-Specific Tolerance in Allogeneic Heart Transplantation Am J Transplant. 2017;17 (suppl 3).

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