Cytomegalovirus-Mediated Upregulation of Chemokine Expression Correlates with the Acceleration of Chronic Rejection in Rat Heart Transplants

Abstract

Cytomegalovirus (CMV) infections have been shown to dramatically affect solid organ transplant graft survival in both human and animal models. Recently, it was demonstrated that rat CMV (RCMV) infection accelerates the development of transplant vascular sclerosis (TVS) in both rat heart and small bowel graft transplants. However, the mechanisms involved in this process are still unclear. In the present study, we determined the kinetics of RCMV-accelerated TVS in a rat heart transplant model. Acute RCMV infection enhances the development of TVS in rat heart allografts, and this process is initiated between 21 and 24 days posttransplantation. The virus is consistently detected in the heart grafts from day 7 until day 35 posttransplantation but is rarely found at the time of graft rejection (day 45 posttransplantation). Grafts from RCMV-infected recipients had upregulation of chemokine expression compared to uninfected controls, and the timing of this increased expression paralleled that of RCMV-accelerated neointimal formation. In addition, graft vessels from RCMV-infected grafts demonstrate the increased infiltration of T cells and macrophages during periods of highest chemokine expression. These results suggest that CMV-induced acceleration of TVS involves the increased graft vascular infiltration of inflammatory cells through enhanced chemokine expression.With the escalation in the number of immunosuppressed patients undergoing immunosuppressive therapy following solid organ or bone marrow transplantation, human cytomegalovirus (HCMV) disease has now become a major clinical problem. While the majority of HCMV infections result in subclinical disease in healthy individuals, HCMV is a significant pathogen in immunocompromised patients (1,3,4,9,26,33,34,50,51,56). Primary HCMV infection is followed by lifelong persistence of the virus in a latent state, and reactivation of the latent virus is considered to be the major source of virus in these immunocompromised individuals. HCMV has been linked to the development of atherosclerosis, arterial restenosis following angioplasty, and solid organ transplant vascular sclerosis (TVS) (26)(27)(28)47). HCMV infection doubles the 5-and 3-year rates of graft failure due to accelerated TVS in cardiac and liver transplant patients, respectively (15; L. W. Miller, Editorial, J. Heart Lung Transplant. 11:S1-S4, 1992). The observation that HCMV infects many of the cell types involved in vascular disease, including monocyte-derived macrophages, endothelial cells, and smooth muscle cells (SMC), suggests that HCMV may play a role in these disease processes. Because of the similarities between the CMV-speciesspecific viruses, animal models provide an ideal tool to study the association between CMV and TVS.The most compelling evidence that herpesviruses play a role in vascular disease comes from studies in animal models. Using a rat CMV (RCMV) solid organ transplant model, researchers have demonstrated, in light of the RCMV-associated acceleration of TVS, an association of herpesvirus ...

Mechanisms of Cytomegalovirus-Accelerated Vascular Disease: Induction of Paracrine Factors That Promote Angiogenesis and Wound Healing

“…Similar to the human transplantation setting antiviral therapy reduces the acceleration of rejection in rat transplant models demonstrating that active CMV replication is required for these disease processes (Tikkanen et al 2001a;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 2001b;Orloff et al 2002;Streblow et al 2003;Soule et al 2006).…”

“…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 of TVS from a mean neointimal index (NI)=42.9 to 82.9 (Streblow et al 2003). RCMV infection failed to induce TVS in syngeneic cardiac grafts by the study endpoint of 120 days (mean NI=4.2 versus uninfected controls mean NI=8.8).…”

“…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 transplantation setting antiviral therapy reduces the acceleration of rejection in rat transplant models demonstrating that active CMV replication is required for these disease processes (Tikkanen et al 2001a;Zeng et al 2005).…”

“…In order to study the role of CMV in the development of TVS, we have taken advantage 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;Streblow et al 2005;Soule et al 2006;Streblow et al 2007). 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).…”

Rat Cytomegalovirus Vaccine Prevents Accelerated Chronic Rejection in CMV-Naïve Recipients of Infected Donor Allograft Hearts

“…DNA (0.5 μg) was analyzed by TaqMan PCR using a probe/primer set recognizing RCMV DNA polymerase sequence (sensitivity <100 copies) 33, 35.…”