Cytomegalovirus Latency Promotes Cardiac Lymphoid Neogenesis and Accelerated Allograft Rejection in CMV Naïve Recipients

Abstract

Human Cytomegalovirus (HCMV) infection is associated with the acceleration of transplant vascular sclerosis (TVS) and chronic allograft rejection (CR). HCMV-negative recipients of latently HCMV infected donor grafts are at highest risk for developing CMV-disease. Using a rat heart transplant CR model, we have previously shown that acute rat CMV (RCMV) infection following transplantation significantly accelerates both TVS and CR. Here, we report that RCMV-naïve recipients of heart allografts from latently RCMV-infected donors undergo acceleration of CR with similar kinetics as acutely infected recipients. In contrast to acutely infected recipients, treatment of recipients of latently infected donor hearts with ganciclovir did not prevent CR or TVS. We observed the formation of tertiary lymphoid structures (TLOs) containing macrophages and T-cells in latently infected hearts prior to transplantation but not in uninfected rats. Moreover, pathway analysis of gene expression data from allografts from latently infected donors, indicated an early and sustained production of TLO-associated genes compared to allografts from uninfected donors. We conclude that RCMV-induced TLO formation and alteration of donor tissue T-cell profiles prior to transplantation in part mediate the ganciclovir-insensitive rejection of latently infected donor allografts transplanted into naïve recipients by providing a scaffold for immune activation.

Cytomegalovirus-Induced Expression of CD244 after Liver Transplantation Is Associated with CD8+ T Cell Hyporesponsiveness to Alloantigen

“…Indeed, reactivation of CMV infection, as well as primary CMV infection, abrogates transplant acceptance in mice and rats (47,48). However, several previously published observations in humans support our findings.…”

Cytomegalovirus CC Chemokine Promotes Immune Cell Migration

“…We have recently shown significant recruitment of T cells into RCMV-infected allografted hearts in our rat model of chronic rejection (41). Importantly, when donor animals are latently infected with RCMV, the chronic rejection phenotype is insensitive to ganciclovir treatment, suggesting that RCMV infection primes the inflammatory process in these organs and active CMV replication is not necessary to drive CR posttransplantation (25). Latently infected hearts contain large accumulations of T cells and macrophages prior to transplantation.…”

“…9). We performed heart transplants using the F344/Lewis rat model as previously described (25,26,(41)(42)(43) and infected allograft recipients with the r129⌬NT mutant virus (5 ϫ 10 5 PFU), and we compared the time to rejection and the severity of TVS to those of the recipients infected with RCMV-BAC (5 ϫ 10 5 PFU) and uninfected controls. The time to rejection was significantly longer in the RCMV-r129⌬NT recipients (100 Ϯ 0 days, study endpoint) than that inseen in the RCMV-BAC-infected recipients (46.25 Ϯ 2.8 days) (P Ͻ 0.0001) (Fig.…”

The Cell Biology of Cytomegalovirus: Implications for Transplantation

“…Surprisingly, in DNA microarray analyses comparing naive recipients of rat cardiac allografts from donors latently infected with RCMV and those with acute RCMV infection, both groups developed accelerated graft vasculopathy with similar kinetics. Nevertheless, in latently infected recipients, as might be the case for most allografts, viral replication is not required, and increased expression of genes involved in inflammation and fibrosis was observed (90). Anti-CMV immune responses have been demonstrated against latently infected ECs and serve to augment chronic inflammation in grafts undergoing allogenic immune responses; viral reactivation and inflammation are mediated in part by tumor necrosis factor a (TNF-a) released by activated NF-kB cells and in most febrile responses (91,92).…”