Murine cytomegalovirus infection leads to increased levels of transplant arteriosclerosis in a murine aortic allograft model.
BACKGROUND
Cytomegalovirus infection after heart transplantation is considered as risk factor for the development of transplant arteriosclerosis. Therefore, the aim of this study was to investigate the effect of murine cytomegalovirus (MCMV) as a single risk factor on transplant arteriosclerosis in an experimental aortic allograft model.


METHODS
Major histocompatibility complex class I-mismatched aortas of C.B10-H2(b)/LilMcdJ donor were transplanted into BALB/c recipients, which were either mock-infected or infected with MCMV (strain Smith) on day 7 and harvested 37 days after transplantation. In one experimental group animals received a daily dose of everolimus to increase the viral load of recipients. Grafts were analyzed by histology, morphometry, and immunofluorescence. Intragraft cytokine mRNA production was analyzed by real-time polymerase chain reaction (PCR), and persistence of cytomegalovirus infection was confirmed by TaqMan PCR.


RESULTS
After infection with MCMV, there was significantly more intimal proliferation when compared with uninfected controls (intimal proliferation 83.5%+/-9.6% [MCMV] vs. 43.9%+/-5.1% [MCMV]), indicating that MCMV plays a role in the development of transplant arteriosclerosis. Even after treatment with everolimus, MCMV infection pronounced significantly more intimal proliferation (intimal proliferation 52.5%+/-7.3% [MCMV] vs. 20.2%+/-1.7% [MCMV]). Intragraft mRNA expression showed significantly higher production of CD62E, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 after infection with MCMV. Cellular infiltration revealed significantly more CD4, CD8, and dendritic cells. We could also confirm the presence of MCMV for the duration of the experimental protocol by PCR within the spleen, liver, salivary glands, lung, and the aortic transplant.


CONCLUSIONS
These data suggest that MCMV infection plays an important role in the development of transplant arteriosclerosis.
Heim
Christian
C
Department of Cardiac Surgery, Friedrich-Alexander University Erlangen-Nuremberg, Germany.
Abele-Ohl
Silke
S
Eckl
Sebastian
S
Ramsperger-Gleixner
Martina
M
Mahmoudian
Shohreh
S
Weyand
Michael
M
Stamminger
Thomas
T
Ensminger
Stephan M
SM
D000818:Animals; D001012:Aorta, Abdominal / Q000502:physiology / Q000637:transplantation* / Q000821:virology; D001161:Arteriosclerosis / Q000209:etiology*; D003586:Cytomegalovirus Infections / Q000150:complications* / Q000209:etiology; D017931:DNA Primers; D015342:DNA Probes; D019040:E-Selectin / Q000235:genetics; D000068338:Everolimus; D005805:Genes, MHC Class I; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000235:genetics; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D014184:Transplantation, Homologous / Q000009:adverse effects* / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D017931:DNA Primers; D015342:DNA Probes; D019040:E-Selectin; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D000068338:Everolimus; D020123:Sirolimus