The same mixed chimerism-based protocol that induces tolerance of nonhuman primate kidney allografts results in rejection of heart allografts. However, when the two organs from the same donor are co-transplanted, tolerance of the cardiac allografts is achieved. Here we investigate the mechanism of kidney-induced cardiac allograft tolerance (KICAT) using a MHC disparate mouse strain combination (DBA/2J to C57BL/6) wherein kidney allografts are spontaneously accepted without immunosuppression but heart allografts are acutely rejected. The aim is to compare systemic and local Treg levels after kidney versus heart transplantation and to determine if KICAT occurs following heart and kidney co-transplantation in this model.Methods: DBA kidneys or hearts were transplanted separately into different B6 recipients. These animals were sacrificed 7 days after transplant. Co-transplantation was performed by placing the kidney in the abdomen and heart in the neck. Tissue was analyzed via immunohistochemistry and isolated cells analyzed via flow cytometry.Results: H&E staining showed that at day 7 post-transplant, isolated heart and kidney grafts both exhibited massive infiltrates of mononuclear cells (n=5/group). However, CD3/Foxp3 co-staining showed numerous single CD3⁺ and CD4⁺Foxp3⁺ cells in the kidney grafts, whereas in heart grafts, most cells were CD3⁺Foxp3^–. FACS analysis showed the percentage of CD4⁺Foxp3⁺ Tregs among all TCRb⁺CD44^highCD62L^– effector T cells in kidney grafts was significantly higher than that in heart grafts (15%±2.6 vs 2.2%±0.67, respectively). Furthermore, the percentage of circulating CD4⁺Foxp3⁺ Tregs among all TCRb⁺CD44^highCD62L^– effector T cells in the kidney recipients was significantly higher than in heart recipients (17%±3.0 vs 6.3%±0.68, respectively). More than 80% of the renal Tregs expressed Helios, suggesting these Tregs either migrated from the thymus or developed within the graft. Our initial kidney/heart co-transplant recipient demonstrated long-term acceptance of both organs (>12 weeks).Conclusion: Spontaneous acceptance of kidney allografts may result from the systemic and local increase of Tregs compared to the rejecting heart. Organ-specific augmentation of Tregs may explain the mechanism by which kidney allografts confer unresponsiveness upon resistant heart allografts.

CITATION INFORMATION: Yang C., Ashry T., Rosales I., Ge J., O'Shea T., White R., Russell P., Madsen J., Colvin R., Alessandrini A. Kidney Allografts Confer Tolerance upon Co-Transplanted Heart Allografts by Promoting Tregs Am J Transplant. 2017;17 (suppl 3).

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