Background: Achieving tolerance of vascularized composite allografts (VCAs) would improve the risk-to-benefit ratio in patients who undergo this life-enhancing transplant. Kidney co-transplantation along with a short course of high-dose immunosuppression enables tolerance of heart allografts across a full MHC mismatch. In this study, we investigated whether tolerance of VCA across full MHC disparities could be achieved in animals already tolerant of heart and kidney allografts.

Methods: Miniature swine that were tolerant of heart and/or kidney allografts long-term underwent transplantation of myocutaneous VCA across the same MHC barrier without additional immunosuppression. Prior to VCA transplant, Group 1 (n=3) underwent Class I-mismatched kidney transplantation; Group 2 (n=3) underwent two sequential Class I-mismatched kidney transplantations; Group 3 (n=2) underwent haploidentical MHC-mismatched heart/kidney transplantation; and Group 4 (n=2) underwent full MHC-mismatched heart/kidney transplantation.

Results: All three animals in Group 1 and two of three animals in Group 2 showed skin rejection in under 85 days; one animal in Group 2 showed prolonged skin survival >200 days. Animals in Groups 3 and 4 showed skin rejection in under 30 days and regained in vitro evidence of donor responsiveness.

Conclusion: This is the first pre-clinical study in which hearts, kidneys, and VCAs have been transplanted into the same recipient. Despite VCA rejection, tolerance of heart and kidney allografts was maintained. These results suggest that regulatory tolerance of skin is possible but not generally achieved by the same level of immunomodulation that is capable of inducing tolerance of heart and kidney allografts. Achieving tolerance of skin may require additional immunomodulatory therapies.

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