We previously reported successful induction of renal allograft tolerance in nonhuman primates and humans by the mixed chimerism approach. Different from rodent studies, chimerism induced in these primate recipients was transient and peripheral mechanism of tolerance, rather than thymic deletion, is considered operative. In this study, we tested the effects of prolonged administration of IL-2 cytokine administration on transplant tolerance maintenance in monkeys.

Methods: 22 monkeys underwent MHC-mismatched bone marrow and kidney transplantation along with nonmyeloablative conditioning. 12/22 achieved long-term graft survival (>400 days) without immunosuppression. Among the long-term survivors, six recipients were treated with daily subcutaneous injection of IL-2 (1 to 3 million IU/m2). To evaluate involvement of CD8+ T cells in breakdown of tolerance, two animals were treated with anti-CD8 mAb to delete CD8+T cells during the IL-2 treatment.

Results: Kidney graft functions were impaired following daily administration of IL-2 (1 million IU/ m2) in 5/6 recipients after 3 to 15 days of IL-2 treatment, one animal required 3 million IU / m2. IL-2 administration was associated with an expansion of FoxP3+ Tregs but also CD4+/ CD8+ effector T cells in the peripheral blood. More importantly, IL-2 administration resulted in infiltration of kidney transplants by high numbers of donor-reactive T cells producing IFNΓ cytokine. No evidence of autoimmune pathology was found in any of the monkeys’ native organs. Interestingly, kidney functions rapidly returned to normal values following discontinuation of IL-2 treatment and tolerance was restored. The infiltration of kidney transplants by inflammatory cells vanished while some Treg-rich aggregates were re-formed in the biopsy samples 2 months after the IL-2 injection. Finally, IL-2 mediated allograft rejection could be partially prevented via CD8+ T cell depletion.

Conclusions: Maintenance of tolerance to kidney allografts induced via mixed chimerism in this primate model can be abrogated via IL-2 administration of recipients, a process associated with reactivation, expansion and graft infiltration of effector/memory alloreactive inflammatory T cells. This further supports the view that maintenance of tolerance in this setting relies on T cell regulatory rather than deletional mechanisms.

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