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

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...

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Bibliographic Details
Published in:	American journal of transplantation 2021-02, Vol.21 (2), p.515-524
Main Authors:	Yu, Shuangjin, Dangi, Anil, Burnette, Melanie, Abecassis, Michael M., Thorp, Edward B., Luo, Xunrong
Format:	Article
Language:	eng
Subjects:	alloantibody Allografts Animals basic (laboratory) research/science Cell differentiation Cytomegalovirus Cytomegalovirus Infections immunobiology Immunological tolerance immunosuppression/immune modulation infection and infectious agents ‐ viral: Cytomegalovirus (CMV) Infections Islet cells islet transplantation Lymphocytes T Memory cells Mice Muromegalovirus Pancreas Pancreatic islet transplantation rejection: T cell–mediated (TCMR) re‐transplantation Syngeneic grafts tolerance Transplantation Tolerance Transplantation, Homologous Transplants & implants
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Summary:	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. In an allogeneic mouse islet transplantation model, acute murine CMV infection disrupts established transplantation tolerance by reverting previously inhibited allogeneic T cell immune responses, leading to memory T cell generation and recipient allosensitization.
ISSN:	1600-6135 1600-6143