We have previously demonstrated that a kidney allograft has the ability to confer tolerance on a co-transplanted heart allograft procured from a class I-mismatched donor. However, kidney-induced cardiac allograft tolerance (KICAT) has not been tested in a fully MHC-disparate strain combination. The purpose of this study was to determine whether tolerance could be induced in heart/kidney transplant recipients across a more clinically relevant full-MHC barrier. Heart allografts (n=3) or heart/kidney allografts (n=5) were transplanted heterotopically into fully mismatched recipients that were treated with high-dose tacrolimus for 12 days. All isolated heart allografts rejected by POD 40. In contrast, all heart/kidney allografts survived for >100 days, with no evidence of rejection on serial cardiac biopsies. Heart/kidney recipients lost donor-specific responsiveness in CML and MLR assays, and did not develop alloantibody. These results show that KICAT can be extended to fully mismatched allografts in a consistent and robust manner. Elucidating the renal element responsible for KICAT could provide mechanistic information that leads to protocols aimed at inducing tolerance in recipients of isolated heart allografts.

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