Chronic rejection in experimental cardiac transplantation in a rat model

The most significant pathologic finding in chronically rejected organ grafts is diffuse concentric intimal proliferation in the arterial system. To develop a reproducible model of chronic vascular rejection in cardiac grafts which we could then use to study the pathogenesis and therapy of this disease process, we exchanged heterotopic cardiac allografts across minor histocompatibility barriers using commercially available Lewis rats as donors and F-344 rats as recipients. We found that all long-term surviving allografts developed diffuse graft arteriosclerotic lesions which were virtually identical in appearance to those seen in chronically rejected human cardiac grafts. Immunohistochemical studies confirm that end-stage lesions are similar in composition to human lesions and are made up predominantly of vascular smooth muscle cells with occasional monocytes and T cells. Analysis of continuous series of rejecting allografts demonstrates that a distinct inflammatory stage precedes smooth muscle cell accumulation in areas of intimal thickening, suggesting that mononuclear cells play a role in the developing lesion. Endothelial expression of class II and ICAM-1 probably underlies early mononuclear cell adherence to the endothelium. Analysis using quantitative RT-PCR and immunocytochemistry confirms MCP-1 is expressed by ED1-positive monocyte/macrophages in rejecting cardiac grafts, suggesting this chemoattractant may help drive mononuclear cell accumulation in the expanding intima. Immunohistochemical labelling of PDGF, TNF and IL-1 beta in vascular lesions suggests these factors may trigger intimal vascular smooth muscle cell proliferation in chronically rejecting allografts, as they, along with protein S, were closely associated with sites of intimal hyperplasia and smooth muscle cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)