*Purpose: We have successfully achieved cardiac allograft tolerance in both pigs and NHP by donor kidney co-transplantation. The mechanism of Kidney Induced Cardiac Allograft Tolerance (KICAT) has not been fully investigated. In certain mouse strain combinations (DBA/2J to C57BL/6), kidney allografts can be spontaneously accepted without immunosuppressive treatment. By contrast, heart allografts from same strain combinations are acutely rejected. In this study, using co-transplantation of kidneys and hearts in mice, we have determined whether spontaneous tolerance of mouse kidney grafts induces systematic tolerance of heart grafts in the recipient. We have also begun to elucidate the possible mechanisms of kidney-induced tolerance. This may enable us potentially to induce tolerance of cardiac grafts independent of renal graft co-transplants.

*Methods: DBA/2J kidneys were transplanted into C57BL/6 recipients following a bilateral nephrectomy. Heart grafts were transplanted cervically at certain days after kidney transplant with or without renal graft excision.

*Results: We found that co-transplantation of DBA/2J kidney and DBA/2J heart induced tolerance of DBA/2J cardiac grafts in C57BL/6 recipients (all >day 100, n=5). Co-transplantation of a C57BL/6 kidney and DBA/2J heart resulted in rejection of DBA/2J cardiac allografts all by day 7 (n=5). The specificity of this tolerance was demonstrated by co-transplantation of DBA/2J kidneys and C3H/HeJ hearts that resulted in rejection of all C3H/HeJ heart allografts by day 12 (n=5). To understand if the continuous presence of kidney grafts is required for cardiac allograft tolerance, DBA2/J kidneys were first transplanted into unilaterally nephrectomized C57BL/6 recipients. Kidney allografts were removed 7 (Group A) or 14 (Group B) days later, and recipients received cervical DBA/2J heart transplants. In Group A, 2 out of 6 heart grafts achieved long-term survival (>day70); in Group B (n=6), all heart grafts demonstrated long-term acceptance (>day70). Depletion of Foxp3+ cells in a Group B scenario using Foxp3^DTR B6 recipients caused rejection of cardiac allografts by day 7 (n=5).

*Conclusions: Spontaneously tolerant kidney grafts are able to induce systemic, donor-specific tolerance of cardiac allografts. Cardiac tolerance induced by kidney grafts occurs within 2 weeks post-transplant and the continued presence of kidney is not required but is dependent on Foxp3+ Tregs. Understanding this process better will enable us to induce tolerance of cardiac grafts independent of renal graft co-transplants.

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