Kidney-Induced Cardiac Allograft Tolerance in Miniature Swine is Dependent on MHC-Matching of Donor Cardiac and Renal Parenchyma

Abstract

Kidney allografts possess the ability to enable a short course of immunosuppression to induce tolerance of themselves and of cardiac allografts across a full-MHC barrier in miniature swine. However, the renal element-(s) responsible for kidney-induced cardiac allograft tolerance (KICAT) are unknown. Here we investigated whether MHC disparities between parenchyma versus hematopoietic-derived “passenger” cells of the heart and kidney allografts affected KICAT. Heart and kidney allografts were co-transplanted into MHC-mismatched recipients treated with high-dose tacrolimus for 12 days. Group 1 animals (n=3) received kidney and heart allografts fully MHC-mismatched to each other and to the recipient. Group 2 animals (n=3) received kidney and heart allografts MHC-matched to each other but MHC-mismatched to the recipient. Group 3 animals (n=3) received chimeric kidney allografts whose parenchyma was MHC-mismatched to the donor heart. Group 4 animals (n=3) received chimeric kidney allografts whose passenger leukocytes were MHC-mismatched to the donor heart. Five of six heart allografts in Groups 1 and 3 rejected <40 days. In contrast, heart allografts in Groups 2 and 4 survived >150 days without rejection (p<0.05). These data demonstrate that KICAT requires MHC-matching between kidney allograft parenchyma and heart allografts, suggesting that cells intrinsic to the kidney enable cardiac allograft tolerance.

Organ-specific differences in achieving tolerance

“…We also found that the host thymus played a critical role during the induction phase of KICAT (47) as did MHC matching of the heart and kidney allografts (48). We have examined the phenotypes of graft infiltrating lymphocytes (GILs) retrieved from isolated kidneys transplanted across a class I barrier which accepted versus rejected (49).…”

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

“…The critical role of the kidney was compellingly demonstrated by the prompt rejection of co-transplanted heart after kidney allograft removal [42]. Moreover, the re-transplantation of a tolerated class I MHC-mismatched kidney allograft plus lymphocytes from the tolerant animal leads to acceptance of a donor-matched naive kidney allograft with systemic donor-specific hyporesponsiveness [106, 107]. This “kidney effect” might be related to its ability to establish an immunologic environment conducive to tolerance.…”

FOXP3-Positive Regulatory T Cells and Kidney Allograft Tolerance

“…Interestingly, recipients of allograft kidneys develop systemic tolerance to skin and heart allografts from the same donor strain. This phenomenon has also been demonstrated in pigs (49–51), non-human primates (52), and to a limited extent in humans (53–55). The advantage of the mouse lies in the opportunity to design definitive experiments using inbred, transgenic, and knock out mouse strains.…”