Mixed hematopoietic chimerism is a promising approach to achieving transplantation tolerance. Transient mixed chimerism leads to renal allograft tolerance in about 70% of cynomolgus macaques (CM) when a donor kidney (but not other less tolerogenic organs) is co-transplanted with MHC-mismatched bone marrow (BMT). The addition of regulatory T cells (Tregs) to BMT promoted durable chimerism and skin graft tolerance in mice. We aim to extend this approach in the pre-clinical CM model to achieve permanent chimerism and tolerance to any co-transplanted organ.

CM recipients were conditioned with total body irradiation (1.25Gy, days -6, -5), thymic irradiation (7Gy, day -1), ATGAM (days -2, -1, 0), anti-CD40L (days 0, 2, 5, 7, 9, 12) and rapamycin for 30 days (day -2 to 28). We have developed a protocol for the expansion of “off the shelf” polyclonal CM recipient Tregs (CD4+, CD25hi, CD127-/lo, FoxP3+) which are infused on days 0, 2, 5, 7 and (+/-50). To assess for tolerance, a skin allograft from the same donor was grafted four months post-BMT, after discontinuation of all immunosuppression.

CM received an average of 16.6±5.8×10^6 CD34+ cells/kg. 4/7 animals received Tregs and 3 animals were controls (no Tregs). Among the Treg treated animals, 3/4 developed high and long-lasting chimerism averaging 92 days (range 69-110 days). The fourth Treg treated animal developed substantial CMV viremia, associated with immune activation and loss of the BM graft early post-transplant. In vitro, Treg treated animals were donor-hyporesponsive unlike the controls. When the skin transplant was performed, the donor graft survived longer than the third-party graft, although both were eventually lost. In contrast, control animals lost chimerism around day 44 and the donor skin graft was rejected earlier than the third-party graft. In summary, expanded polyclonal recipient Tregs given at the time of BMT across MHC barriers prolongs donor chimerism up to 110 days without graft-versus-host disease and allows for longer survival of donor skin transplanted four months post-BMT compared to a third-party control.

CITATION INFORMATION: Alonso-Guallart P, Duran-Struuck R, Stern J, Kofman S, Danton M, Zitsman J, Kato Y, Berglund E, Sondermeijer H, McMurchy A, Levings M, Sykes M, Griesemer A. Induction of Durable Mixed Hematopoietic Chimerism and Immune Tolerance in Non-Human Primates. Am J Transplant. 2017;17 (suppl 3).

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