Biology Reference
In-Depth Information
Animal Models of CMV-Accelerated Graft Rejection
Determining the mechanisms involved in the development of HCMV-associated TVS
has been difficult because the etiology of this disease is multifactorial. In addition,
HCMV is ubiquitous throughout the human population, and hence negative controls are
rare. Furthermore, HCMV infections are lifelong, during which time the virus infects
all of the cell types involved in TVS formation including SMC, EC, macrophages, and
fibroblasts. Along these lines, HCMV evades the immune system by remaining latent
in monocytes, and HCMV reactivation in immunocompetent hosts is difficult to detect
when clinically silent (Lemstrom et al. 1993, 1995; Bruning et al. 1994; Orloff 1999;
Orloff et al. 2000). These undeniable factors make it difficult to determine a temporal
relationship between the virus infection and TVS, and for obvious ethical reasons,
human studies are impossible. Therefore, animal models provide an ideal tool to study
the association between CMV and TVS. In fact, the most compelling evidence that
herpesvirus infections play a role in the vascular disease process is exemplified through
the use of animal models. For example, in rat solid organ transplantation, acute infection
with rat (R)CMV infection accelerates TVS, which leads to untimely graft failure
(Orloff et al. 2002; Streblow et al. 2003; Soule et al. 2006). Similar to the human trans-
plantation setting, antiviral therapy reduces the acceleration of rejection in rat transplant
models, demonstrating that active CMV replication is required for these disease proc-
esses (Tikkanen et al. 2001b; Zeng et al. 2005). Importantly, the effects of RCMV on
the acceleration of TVS are not organ-type-specific but can occur in a broad range of
solid organ transplants, including heart, kidney, lung, and small bowel (Tikkanen et al.
2001a; Orloff et al. 2002; Streblow et al. 2003; Soule et al. 2006).
RCMV Accelerates TVS and CR in a Rat Heart
Transplantation Model
In order to study the role of CMV in the development of TVS, we have taken advan-
tage of the F344 into Lewis rat heterotopic solid organ transplant model (Ely et al.
1983; Klempnauer and Marquarding 1989; Lubaroff et al. 1989), which we have
used to study TVS/CR in transplanted heart, kidney, and small bowel grafts (Orloff
et al. 2002; Streblow et al. 2003, 2005, 2007; Soule et al. 2006). Since this strain
combination exhibits reduced allogenicity, acute rejection is prevented by a short
regimen of cyclosporine A, resulting in long-term surviving allografts developing
histological evidence of CR (Orloff et al. 2002). Heart allograft recipients not treated
with CsA acutely rejected, and syngeneic transplants failed to develop TVS/CR.
In the CsA-treated heart allograft recipients, the mean time to develop CR was 90
days, as determined by palpation of the abdomen for induration of the graft and
diminished pulsation of the heartbeat. The majority of the vessels in the rejecting
cardiac allografts showed the presence of TVS.
Using this rat heart transplant model, we have determined that RCMV accelerated
the time to develop TVS and graft failure from 90 to 45 days and increased the degree
