BACKGROUND

The role of vascularized thymus on tolerance induction has been well studied in swine recipients of kidney allografts, but not in NHP recipients of heart allografts. Here, we investigate whether co-transplantation of vascularized donor thymus would prolong the survival of allogeneic cardiac allografts without chronic immunosuppression.

METHODS

MHC-mismatched heart en bloc thymus allografts were transplanted into thymectomized cynomolgus macaques treated with equine ATG (days -2, -1, 0), anti-IL-6R mAb (days 0, 7), and conventional immunosuppression, consisting of tacrolimus, mycophenolate mofetil, and methylprednisolone. Starting on POD 166, the immunosuppressive drugs were slowly weaned; and by POD 207, all drugs were stopped. Thymopoiesis was monitored with T cell receptor excision circles (TREC), as well as phenotypic markers of peripheral recent thymic emigrants. The alloreactive T cell and B cell responses were serially assessed, and the grafts were examined by serial biopsies.

RESULTS

The first animal treated this way has achieved acute rejection-free cardiac survival with preserved cardiac function for over 537 days. Thymopoiesis by the donor thymus was detected early after transplantation and donor-specific T cell hyporesponsiveness was observed in γ-IFN ELISPOT. The recipient developed alloantibody and allograft vasculopathy by day 300, but never demonstrated evidence of acute cellular rejection. Two other recipients are currently >97 and >57 days posttransplant without signs of acute rejection.

CONCLUSION

This is the first demonstration of long-term cardiac allograft survival induced by the co-transplantation of vascularized donor thymus in nonhuman primates. The apparent split tolerance achieved by this strategy may be overcome by adding a B cell depleting agent to the protocol.

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