Tolerance of allogeneic kidney transplants has been achieved in NHP and human recipients using a mixed chimerism approach. However, the same approach has failed to induce tolerance in NHP recipients of heart allografts. We have now asked whether tolerance of cardiac allografts can be achieved by co-transplantation of heart and kidney allografts from the same donors.
Allogeneic hearts alone or hearts plus kidneys from the same donors were transplanted into cynomolgus macaques, along with infusion of donor bone marrow cells. All recipients received a peri-transplant nonmyeloablative conditioning regimen consisting of 3 Gy total body irradiation, 7 Gy thymic irradiation, equine anti-thymocyte globulin, anti-CD154 monoclonal antibody and a 28-day course of cyclosporine. The immune response to the allograft was monitored by ELISPOT, mixed lymphocyte reaction (MLR) and alloantibody production assays. Graft rejection was assessed by serial biopsies.
All recipients developed transient multilineage chimerism. The four recipients of isolated heart allografts demonstrated severe rejection by 69, 70, 78, 82 days post-transplantation. In contrast, recipients of heart/kidney co-transplants (n=5) demonstrated no evidence of rejection for over 300 days. IFN gamma-ELISPOT and MLR assays performed in the co-transplanted monkeys revealed donor-specific T cell hyporesponsiveness. Although donor-reactive antibodies were detected in some monkeys, they were not specific for donor MHC antigens. Expansion of regulatory T cells was observed in the peripheral blood and in the kidney allografts of tolerant monkeys. Removal of the donor kidney transplants in the tolerant monkeys (at 300 days post-transplant) resulted in acute rejection of the heart transplants.
Tolerance of heart allografts has been achieved for the first time in NHPs using a mixed chimerism induction protocol and kidney co-transplantation from the same donor. The presence of the kidney allograft was necessary both for the induction and for the maintenance of tolerance. Work is in progress to elucidate the renal element(s) responsible for conferring unresponsiveness of cardiac allografts.
To cite this abstract in AMA style:Tonsho M, Benichou G, Boskovic S, Nadazdin O, Smith N, Colvin R, Sachs D, Cosimi A, Kawai T, Madsen J. Successful Tolerance Induction of Cardiac Allografts in Nonhuman Primates through Donor Kidney Co-Transplantation [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/successful-tolerance-induction-of-cardiac-allografts-in-nonhuman-primates-through-donor-kidney-co-transplantation/. Accessed November 23, 2020.
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