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we have found that supernatants from HCMV-infected cells (HCMV secretome) induce
WH and AG using in vitro models. Taken together, these findings suggest that one
mechanism for HCMV acceleration of TVS is mediated through induction of secreted
cytokines and growth factors from virus-infected cells that promote WH and AG in the
allograft, resulting in the acceleration of TVS. We review here the ability of CMV infec-
tion to alter the local environment by producing cellular factors that act in a paracrine
fashion to enhance WH and AG processes associated with the development of vascular
disease, which accelerates chronic allograft rejection.
Introduction
The importance and interest of HCMV as a pathogen has increased over the last few
decades, with the escalation in the number of immunosuppressed patients, either under-
going immunosuppressive therapy following solid organ or bone marrow transplanta-
tion, or with AIDS patients. Primary HCMV infection is followed by a lifelong
persistence of the virus in a latent state, and reactivation of latent virus is considered to
be the major source of virus in immunocompromised individuals (see the chapter by
.
Reeves and J. Sinclair, this volume). HCMV is linked to the development of arterial
restenosis following angioplasty, atherosclerosis, and solid organ TVS (Melnick et al.
1983; Speir et al. 1994; Melnick et al. 1998). HCMV infection nearly doubles the 5-
year rate of cardiac graft failure due to accelerated TVS (Grattan et al. 1989), and prior
to the advent of ganciclovir therapy, it doubled the rate of liver graft loss at 3 years
(Deotero et al. 1998; Rubin 1999). In recipients of heart transplants, treatment with
ganciclovir, a potent inhibitor of viral replication and CMV disease, delayed the time to
allograft rejection (Merigan et al. 1992). A subsequent post-hoc analysis of these data
confirmed that prophylactic ganciclovir treatment delayed graft rejection compared to
controls (Valantine et al. 1999). Moreover, the early control of subclinical HCMV rep-
lication after cardiac transplantation by T cell immunity reduces allograft TVS and CR
(Tu et al. 2006). Additional proof to HCMV's affect on graft TVS comes from the find-
ing of a higher incidence of viral DNA detected in the explant vascular intima of those
patients with cardiac allograft TVS than in those explants without vasculopathy (Wu
et al. 1992). In fact, the mere presence of HCMV infection in kidney transplant patients,
whether displaying asymptomatic or overt symptoms, was shown to negatively impact
allograft survival (Fitzgerald et al. 2004). While a number of studies have provided
strong evidence for a role of HCMV in the development of TVS and accelerated CR,
the precise mechanisms involved in this process are still unknown.
Μ
Tissue Repair and Angiogenic Factors Mediate TVS
Despite recent medical advances, the long-term survival of solid organ allografts
has not improved, largely due to CR. The high prevalence of CR is of particular
concern given that to date the only effective therapy is retransplantation. The primary
