Heart and Kidney Cotransplantation in Non Human Primates (NHPs)

Makoto Tonsho¹, Svjetlan Boskovic¹, Tatsuo Kawai¹, Derek Klarin¹, Ognjenka Nadazdin¹, Robert B. Colvin², Gilles Benichou¹, A. Benedict Cosimi¹, Joren C. Madsen¹

¹Transplant Center, Divisions of Cardiac Surgery and Abdominal Transplantation; ²Department of Pathology; Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

Background: The induction of immune tolerance would allow a heart allograft to survive long term without the need for dangerous immunosuppressive drugs. Tolerance has been achieved in NHP and human recipients of kidney transplants using a mixed chimerism approach. However, the same protocol could not induced tolerance in NHP recipients of heart allografts. We hypothesize that tolerance to cardiac allografts will be achieved when heart and kidney allografts from the same donor are cotransplanted.

Methods: Cynomolgus macaques were infused with allogeneic bone marrow cells and received either a heart alone or a combined heart/kidney transplant from the same donor. Prior to transplantation, recipients received a nonmyeloablative conditioning regimen consisting of two doses of 1.5 Gry total body irradiation (day -6, -5), one dose of 7 Gry thymic irradiation (day -1), three doses of 50 mg/kg equine anti-thymocyte globulin (day -2, -1, 0).  Starting at day 0, six doses of anti-CD154 monoclonal antibody and a 28-day course of cyclosporine were administered. Immune competence was monitored with ELISPOT, mixed lymphocyte reaction (MLR) and alloantibody production. Graft rejection was assessed by serial biopsies.

Result: Biopsies in three recipients of isolated heart allografts that developed transient multilineage chimerism demonstrated severe rejection as early as 69, 78, 82 days after transplantation despite survival to 489, 154 and 82 days. In contrast, the two combined heart and kidney recipients that developed transient multilineage chimerism demonstrated no evidence of acute rejection for over 260 days. In vitro studies in the longest heart/kidney survivor revealed that regulatory T cells were enriched from 5 % to 20 % of all CD4+ lymphocytes in periphery, and that gamma IFN-ELISPOT and MLR exhibited donor specific hyporesponsiveness despite detection of an alloantibody.

Conclusion: The tolerogenic effects of kidney allografts can be conferred upon cardiac allografts when the two organs are cotransplanted in recipients undergoing a mixed chimerism conditioning regimen. This effect may be related to the ability of the kidney, but not the heart, to transfer or expand regulatory T cells.