*Purpose: Cytomegalovirus (CMV) infection has been associated with allograft rejection in immunosuppressed transplant recipients. We have previously shown that acute CMV infection impairs the induction of transplantation tolerance. In the present study, we investigated the outcome of subsequent transplantation in those recipients having previously rejected a same donor allograft upon CMV infection.

*Methods: Fully-mismatched pancreatic islets from BALB/c mice were transplanted under the kidney capsule of streptozotocin-induced diabetic C57BL/6 recipients. Transplantation tolerance was induced by infusing donor apoptotic splenocytes (treated with the chemical cross-linker ethylenecarbodiimide, termed “ECDI-SP”) on days -7 and 1. Transplant recipients were infected intraperitoneally with murine CMV (MCMV, 10⁸ PFU) on day 14 post-transplantation. Allografts were considered rejected in those recipients which showed elevated blood glucose levels (>250mg/dL) for two consecutive days. 10 days after rejection of the first islet allograft, these recipients were re-transplanted with a second BALB/c islet allograft under the kidney capsule of the contralateral kidney.

*Results: MCMV infection on day 14 post-transplantation prevented the induction of transplantation tolerance by donor ECDI-SP in 40% of the recipients and allografts were rejected within 2-3 weeks following infection. Uninfected transplant recipients infused with donor ECDI-SP permanently accepted the islet allografts as expected. Interestingly, re-transplantation of pancreatic islets from BALB/c donors in these recipients previously rejected a BALB/c islet allograft in setting of acute MCMV infection showed accelerated rejection (within 2-3 days post-transplantation) of the second islet allograft. CD4 and CD8 T cells isolated these mice demonstrated a heightened recall response when stimulated in vitro with BALB/c antigen-presenting cells, suggesting their development into a memory phenotype. In addition, they lost the “anergic” phenotype (CD73⁺FR4⁺) which was otherwise induced by donor ECDI-SP in the absence of acute MCMV infection.

*Conclusions: Our data show that CMV infection not only impairs tolerance induction by donor ECDI-SP, but also sensitizes transplant recipients by reverting the anergic phenotype of anti-donor T cells and promoting their memory responses, resulting in accelerated rejection of subsequent same-donor transplantation. Thus, post-transplant CMV infection can be potentially sensitizing.

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