Acute murine cytomegalovirus disrupts established transplantation tolerance and causes recipient allo-sensitization

Abstract

We have previously shown that acute cytomegalovirus (CMV) infection disrupts the induction of transplantation tolerance. However, what impact acute CMV infection would have on the maintenance of established tolerance and on subsequent recipient allo‐sensitization is a clinically important unanswered question. Here we used an allogeneic murine islet transplantation tolerance model to examine the impact of acute CMV infection on: (a) disruption of established transplantation tolerance during tolerance maintenance; and (b) the possibility of recipient allo‐sensitization by CMV‐mediated disruption of stable tolerance. We demonstrated that acute CMV infection abrogated transplantation tolerance during the maintenance stage in 50%‐60% recipients. We further demonstrated that acute CMV infection–mediated tolerance disruption led to recipient allo‐sensitization by reverting the tolerant state of allo‐specific T cells and promoting their differentiation to allo‐specific memory cells. Consequently, a second same‐donor islet allograft was rejected in an accelerated fashion by these recipients. Our study therefore supports close monitoring for allo‐sensitization in previously tolerant transplant recipients in whom tolerance maintenance is disrupted by an episode of acute CMV infection.

Negative Vaccination Strategies for Promotion of Transplant Tolerance

“…49 Importantly, it does appear that apoptotic donor cellinduced tolerance can be disrupted in the experimental setting by specific immunological challenges. Cytomegalovirus infection breaks established tolerance in a model of murine islet allotransplantation, 81 a mechanism that appears dependent on the conversion of anergic T cells to IFN-γproducing effector T cells. 82 Other similar models of tolerance using donor-specific transfusion have shown that disruption of tolerance also occurs with Toll-like receptor engagement after CpG (5-cytosine-phosphate-guanine-3) oligonucleotide administration.…”

Apoptotic Donor Cells in Transplantation

“…Our lab has demonstrated in a murine islet transplant model that acute murine-CMV(MCMV) infection alters MDSC differentiation, promoting maturation of immature myeloid cells to become inflammatory monocytes which subsequently prime alloreactive CD8 T cells that prevent the induction of tolerance ( 78 ). In mice where MCMV infection was introduced days after donor ECDI-SP infusions, it not only led to the disruption of tolerance otherwise induced by donor ECDI-SP infusions, but also resulted in accelerated rejection of a subsequent same-donor islet transplant as a consequence of anti-donor memory T cell response ( 118 ).…”

Conversion of CD73hiFR4hi anergic T cells to IFN-γ–producing effector cells disrupts established immune tolerance

“…We next perturbed this stable tolerance on day 95 after transplantation by giving acute murine cytomegalovirus (MCMV) infection to tolerized mice, which has been previously shown to precipitate allograft rejection in approximately 60%–70% recipients over the ensuing 5–6 weeks ( 5 ). Interestingly, at the time of rejection, we observed a significant reduction of the number of intragraft CD73 hi FR4 hi T AN cells, along with a significantly reduced level of CD73 and FR4 expression on remaining T AN cells ( Figure 1B ).…”