Co-transplantation of donor kidneys and bone marrow enables the induction of tolerance of allogeneic hearts in NHPs. We have previously demonstrated that the state of cardiac tolerance induced by kidney co-transplantation was associated with reduced frequency of memory T cell response and loss of alloreactive B cell response. However, the mechanism by which tolerance of cardiac allografts is maintained even after the donor chimerism disappeared is not fully understood. Here, we assessed the contribution of donor kidney to maintenance of cardiac allograft tolerance after donor chimerism was lost.

MHC defined heart and kidneys were transplanted in heminephrectomized cynomolgus macaques with mixed chimerism induction protocols applied either simultaneously (Day 0 protocol) or 4 months after organ transplantation and the interval administration of triple drug immunosuppression (Delayed Protocol). Donor kidney graftectomy was performed after tolerance induction.

When kidney allografts were explanted on day 315 after tolerance induction in two animals that developed transient donor chimerism after the Day 0 protocol, the heart allografts were acutely rejected within 49 and 55 days of kidney graftectomy. When the allokidney was removed on day 434 after tolerance induction from an animal developed persistent chimerism after the Day 0 protocol, donor chimerism was lost but the alloheart was not affected. In contrast, removing the allokidney on days 315 and 742 after tolerance induction from the animals that developed transient chimerism after the Delayed Protocol had no effect on the allohearts. Of note, explantation of a native kidney on day 511 after tolerance induction in a control animal that developed transient chimerism after the Day 0 protocol did not affect the cardiac graft survival.

The donor kidney was necessary to maintain cardiac allograft tolerance in recipients treated with the Day 0 protocol whose donor chimerism was transient. However, in animals with durable chimerism or those undergoing the Delayed Protocol, late kidney graftectomy had no effect on the heart grafts. This suggests that delaying mixed chimerism conditioning until 4 months after organ transplantation results in a more robust state of unresponsiveness which may be attributable to enhanced regulatory mechanisms.

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