Cytomegalovirus infection-enhanced allograft arteriosclerosis is prevented by DHPG prophylaxis in the rat.

Lemström, Karl; Bruning, J. H.; Bruggeman, C. A.; Koskinen, Petri; Aho, Päivi; Yılmaz, Serdar; Lautenschlager, I; Häyry, P

doi:10.1161/01.cir.90.4.1969

Cited by 57 publications

(25 citation statements)

References 32 publications

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“…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 infection with vascular disease, leading to graft failure (7,21,24,36,39). Studies by Bruggeman and colleagues have shown that treatment of CMV-infected graft recipients with ganciclovir, a potent inhibitor of viral replication and CMV disease, resulted in the elimination of virus-induced TVS and prolonged graft survival (22,23). In a study by Merigan et al, treatment of human recipients of heart transplants with ganciclovir delayed the time to allograft rejection (31).…”

Section: Posttransplantation) Grafts From Rcmv-infected Recipients Hmentioning

confidence: 99%

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

Streblow¹,

Kreklywich²,

Yin

et al. 2003

J Virol

108

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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 ...

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Section: Posttransplantation) Grafts From Rcmv-infected Recipients Hmentioning

confidence: 99%

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

Streblow¹,

Kreklywich²,

Yin

et al. 2003

J Virol

108

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“…These observations sugget that the endothelium on vessel walls may be persistent sites of virus and have generated an interest in the association of HCMV with the development of atherosclerosis [30]. This hypothesis has been further reinforced by animal models which have directly implicated CMV in the development of vascular sclerosis in transplanted organs (chronic rejection) [31,32] and in restenosis in the arteries of patients following angioplasty [15]. In addition, these observations suggest that persistently infected EC release infectious virus into the blood and that these cells can transfer infection to circulating blood cells.…”

Section: Hcmv Infection In Ecmentioning

confidence: 99%

Human Cytomegalovirus Latency and Reactivation – A Delicate Balance between the Virus and Its Host’s Immune System

Söderberg‐Nauclér

Nelson

1999

Intervirology

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Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that still causes severe morbidity and mortality in immunocompromised individuals. During its evolution, the virus has developed sophisticated methods to evade immune recognition and to establish life-long persistence in its host. Today, we know that the virus establishes latency in myeloid lineage cells and that the virus is dependent on immune activation mechanisms to reactivate it from latency to produce a new viral progeny. During this process, a number of viral proteins are produced that interfere with different immune recognition pathways. The current knowledge of the delicate balance between the virus‘ continuous existence and its host’s immune system will be summarized in this chapter.

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“…Animal models provide an ideal tool to study associations between CMV and TVS. In rat solid organ transplantation, rat CMV (RCMV) accelerates TVS, leading to graft failure (5)(6)(7)(8). In a rat heart transplantation (HTx) model of CR, we have demonstrated that acute RCMV infection dramatically decreases the mean time to develop TVS and graft failure, and increases the degree of TVS in graft vessels (9,10).…”

Section: Introductionmentioning

confidence: 99%

The Role of Angiogenic and Wound Repair Factors During CMV-Accelerated Transplant Vascular Sclerosis in Rat Cardiac Transplants

Streblow

Kreklywich²,

Andoh³

et al. 2008

American Journal of Transplantation

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Human cytomegalovirus (HCMV) accelerates transplant vascular sclerosis (TVS), a consequence of angiogenesis (AG) and wound repair (WR). While HCMV can be localized to TVS lesions, the low number of infected cells suggests a global effect on target tissues. We used microarray analysis followed by real-time-polymerase chain reaction (RT-PCR) in an RCMV-accelerated TVS rat cardiac transplant model to determine whether CMV activates host WR and AG factors. Dysregulated cellular genes in allografts from RCMV-infected recipients were compared to those from uninfected recipients and native hearts. We demonstrated that RCMV upregulates the genes involved in WR and AG, which was highest during the critical time of TVS acceleration (21-28 days). Using a standard in vitro AG assay, virus and serum-free supernatants collected at 48 h postinfection significantly induced endothelial cell (EC) migration, branching and tubule formation compared to supernatants from mock-infected cells. Supernatants from ultraviolet (UV)-inactivated RCMV-infected cells failed to induce AG, indicating that virus replication is required. Upregulation of WR and AG genes occurs during the critical period of CMV-accelerated TVS. Targeting these genes may prevent this process and improve allograft survival.

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Cytomegalovirus infection-enhanced allograft arteriosclerosis is prevented by DHPG prophylaxis in the rat.

Cited by 57 publications

References 32 publications

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

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

Human Cytomegalovirus Latency and Reactivation – A Delicate Balance between the Virus and Its Host’s Immune System

The Role of Angiogenic and Wound Repair Factors During CMV-Accelerated Transplant Vascular Sclerosis in Rat Cardiac Transplants

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