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Michel, S. G.; Madariaga, M. L. L.; LaMuraglia, G. M.; Villani, V.; Sekijima, M.; Farkash, E. A.; Colvin, R. B.; Sachs, D. H.; Yamada, K.; Rosengard, B. R.; Allan, J. S.; Madsen, J. C. (2018): The effects of brain death and ischemia on tolerance induction are organ-specific. In: American Journal of Transplantation, Vol. 18, No. 5: pp. 1262-1269
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Abstract

We have previously shown that 12days of high-dose calcineurin inhibition induced tolerance in MHC inbred miniature swine receiving MHC-mismatched lung, kidney, or co-transplanted heart/kidney allografts. However, if lung grafts were procured from donation after brain death (DBD), and transplanted alone, they were rejected within 19-45days. Here, we investigated whether donor brain death with or without allograft ischemia would also prevent tolerance induction in kidney or heart/kidney recipients. Four kidney recipients treated with 12days of calcineurin inhibition received organs from donors rendered brain dead for 4hours. Six heart/kidney recipients also treated with calcineurin inhibition received organs from donors rendered brain dead for 4hours, 8hours, or 4hours with 4 additional hours of cold storage. In contrast to lung allograft recipients, all isolated kidney or heart/kidney recipients that received organs from DBD donors achieved long-term survival (>100days) without histologic evidence of rejection. Proinflammatory cytokine gene expression was upregulated in lungs and hearts, but not kidney allografts, after brain death. These data suggest that the deleterious effects of brain death and ischemia on tolerance induction are organ-specific, which has implications for the application of tolerance to clinical transplantation. Donor brain death prevents tolerance induction in lung, but not isolated kidney or heart plus kidney, allograft recipients, suggesting that the deleterious effects of brain death on tolerance induction are organ specific.