Chronic rejection in experimental cardiac transplantation in a rat model
Authors: Karnovsky Morris J. , Russell Mary E. , Hancock Wayne , Sayegh Mohamed H. , Adams David H. 
Published: September 2024

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 arc 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‐I is expressed by ED I‐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‐1β 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. Hypercholesterolemia did not enhance the severity of lesion development in long‐term surviving allografts, suggesting that lipid levels are not a major etiologic factor in graft arteriosclerotic lesion formation in the Lewis‐F‐344 model. Placing the recipients on a diet deficient in essential fatty acids (which modulates leukocyte functions and infiltration) reduced graft infiltration by mononuclear cells and markedly diminished arterial lesion development in chronically rejecting grafts. A key role for CD4 and mononuclear cells (T cells and/or macrophages) in the initiation and amplification of the vascular response is suggested because a short course of CD4 mAb‐ targeted therapy attenuated many of the vascular sequelae of chronic allograft rejection; there was an absence of myocardial necrosis, a lack of upregulation of ICAM and class II MHC antigens, and decreased expression of TNF, IL‐Iβ, TGF‐β, PDGF and protein S expression. Our data suggest that the activated macrophage is a major force in driving the system toward accelerated atherosclerosis, and that this model should prove useful in analyzing the pathogenesis and drug therapy of chronic rejection.