CMV-Infection leads to enhanced ICAM-1- and PDGF-β-expression in transplanted human vessels using a humanized mouse model

Introduction: Recent findings emphasised an important role of human cytomegalovirus infection (HCMV) in the development of transplant arteriosclerosis. Therefore, the aim of this study was to develop a human peripheral blood lymphocyte (hu-PBL)/RAG-2(-/-)gc(-/-) mousexenograft-model to investigate the immunological mechanisms of HCMV in the progression of transplant arteriosclerosis. Methods: Sidebranches from the internal mammarian artery were harvested during CABG surgery, tissue-typed and infected with a clinical isolate of HCMV (VR1814). In a next step size-matched sidebranches were implanted into the infrarenal aorta of RAG-2(-/-)yc(-/-) mice. The animals were reconstituted with approximately 5x10⁷ peripheral blood mononuclear cells (PBMCs) 7 days after transplantation. Arterial grafts were harvested on day 40 after transplantation and histological analysis was performed. Results: Analysis of artery grafts after HCMV infection showed significant amounts of viral DNA on days 7 and 14 after infection and immunohistochemical analysis revealed IE-2 protein expression on endothelial cells of the artery grafts. PBMC-reconstituted RAG-2(-/-) gc(-/-) animals showed splenic chimerism levels ranging from 28-40% human cells. After reconstitution with PBMCs, RAG-2(-/-) gc(-/-) developed human leukocyte infiltrates in their grafts and vascular lesions that were significantly elevated in the presence of HCMV infection. In addition, intra-graft ICAM-1 and PDGF-β mRNA expression was markedly higher after HCMV infection of the graft. Arterial grafts from unreconstituted RAG-2 (-/-)gc(-/-) recipients showed no vascular lesions. Conclusion: These data suggest that HCMV infection plays an important role in the development of transplant-arteriosclerosis in a humanised mouse arterial-xenograft-model, possibly via elevated ICAM-1 and PDGF-β expression.