Accelerated rejection of murine cardiac allografts by murine cytomegalovirus-infected recipients. Lack of haplotype specificity.

Abstract

Clinical studies have revealed a correlation between cytomegalovirus (CMV) infection and acute allograft rejection. Likewise, for a murine model we observed that C3H (H-2k) recipients infected with murine CMV (MCMV) rejected BALB/c (H-2") cardiac allografts earlier than uninfected recipients (6.9±0.1 d compared with 8.1±0.6 d; P < 0.001). It has been hypothesized that MCMV epitopes crossreact with alloantigens and in this manner induce rejection. However, we also demonstrated that MCMV caused accelerated rejection in the reverse combination (C3H heart engrafted to BALB/c recipient; 7.2±0.3 and 9.4±0.4 d for infected and control animals, respectively; P < 0.001 ) and accelerated rejection of grafts of a third, unrelated haplotype (C57BI/6; H-2b; 8.0±0.7 d compared with 10.1±0.6 for infected and control C3H recipients, respectively; P < 0.03). Ultraviolet (UV) inactivation of MCMV before administration to the graft recipient abrogated the ability to induce rapid rejection. Activated T lymphocytes were present in grafts from infected recipients 2 d before control recipients (P < 0.02) and, at the time of graft rejection, were almost exclusively CD8+ for both infected and control recipients. Thus, MCMV accelerated rejection appears not to result from crossreaction between MCMV epitopes and MHC products. The failure of UV-inactivated virus to accelerate rejection and the high proportion of CD8+ T cells recovered from all rejected grafts suggest that the class I pathway of antigen presentation may be important in the induction of early rejection. (J. Clin. Invest. 1993.91:2602-2608

Cytomegalovirus Induction of Interleukin‐6 in Lung Fibroblasts Occurs Independently of Active Infection and Involves a G Protein and the Transcription Factor, NF‐𝛋B

“…Greater than 7-fold increases in IL-6 quantities were produced by MRC-5 cells treated with 10 Ϫ1 and 10 Ϫ2 dilutions of CMV-UV (A 450 and , respec-1.61 ‫ע‬ 0. 3 1.48 ‫ע‬ 0.27 tively, vs. A 450 for control cells; , unpaired 0.13 ‫ע‬ 0.003 P ! .001 t test).…”

“…Other complications associated with CMV infection suggest interactions with host immune and cellular mechanisms. For example, CMV infection has been shown to be a risk factor for graft rejection among cardiac and renal transplant recipients [1,2], and the ability of CMV to actually accelerate graft rejection has been demonstrated in animal models [3]. Among cardiac transplant recipients, CMV infection promotes the development of posttransplant graft atherosclerosis, the leading cause of graft loss and mortality in recipients surviving 11 year [2].…”

The impact of infection and tissue damage in solid-organ transplantation

“…The broad cell tropism of CMV suggests that both local and systemic effects of CMV infection are likely to impact on early alloreactivity and long-term graft outcome. Acute infections of mice with MCMV in the peri-transplant period across different allogeneic combinations 36 , as have the re-activation of latent MCMV infection 37 . Furthermore, the impact of infection on graft survival in mice was greater with some types of viral infections, such as LCMV and Pichinde virus, compared with other viruses, and when infection occurred at or shortly after transplantation 38,39 .…”

Occult cytomegalovirus in vivarium-housed mice may influence transplant allograft acceptance

“…CMV has an obvious well established association with graft loss following human transplantation (reviewed in [25]). Because we have recently shown that latent MCMV can influence allograft acceptance for murine cardiac transplantation [5], and others have shown accelerated cardiac allograft rejection in mice following acute infection [26, 27], we were interested to evaluate tissues from “naïve” mice with unexpected graft losses. There is a strikingly high rate of graft failure associated with occult MCMV suggested by the current report, although this finding is admittedly circumstantial.…”