The pathogenesis of coronary arteriosclerosis (“chronic rejection”) in transplanted hearts
Authors: Libby Peter , Tanaka Hiroyuki 
Published: September 2024

“Chronic rejection” of allografts may mean different things to different people. Some use this term to refer to a process more specifically described as arteriosclerotic obstruction of the coronary arteries of transplanted hearts. A number of mechanisms might contribute to the pathogenesis of this accelerated form of arterial disease, including administration of immunosuppressive agents such as corticosteroids with attendant hyperlipoproteinemia, viral infections, or ischemic injury of coronary artery endothelium occurring between harvest and reimplantation. However, involvement of the engrafted vessels with sparing of the host's native arteries suggested to us that immune phenomena underlie graft arteriosclerosis. In 1989 we proposed a model for the pathogenesis of accelerated arteriosclerosis associated with cardiac transplantation that linked a cellular immune response akin to delayed‐type hypersensitivity to leukocyte recruitment and altered vascular cell function via a cytokine cascade (1). In support of this concept, coronary artery endothelium can express class II histocompatibility antigens (HLA) that might elicit a cellular immune response (2, 3). Leukocytes including macrophages and T lymphocytes accumulate in transplanted coronary arteries, as would be expected if an ongoing immune or inflammatory response contributed to this type of “chronic rejection”. As we have previously suggested, T cells activated by graft endothelial cells that bear class II HLA probably secrete cytokines that could promote macrophage recruitment and activation, and proliferation and extracellular matrix synthesis by smooth muscle cells. Adhesion molecule expression by vascular cells may participate not only in recruitment and retention of leukocytes but also may promote immune responses by providing co‐stimulating or accessory function to T cells as well. We and others have noted a striking localization of T lymphocytes in an annular distribution just under the luminal endothelium in coronary arteries from transplanted hearts. This array of T lymphocytes immediately subjacent to the class II‐bearing endothelial cells suggests a localized allogeneic immune response in such vessels. Arteriosclerotic lesions in the coronary arteries of transplanted hearts contain increased levels of the cytokine monocyte‐chemoattractant and activating protein‐1 (MCP)‐1 (4). These data support the hypothesis that transplantation arteriosclerosis involves a cytokine cascade triggered by. and contributing to, a chronic cellular immune response. However, other mechanisms or combinations of various inciting factors may play a role in this process. Ultimately, experimental strategies that test various specific immunopathologic mechanisms will be required to ferret out their contributions to the development of this form of arteriosclerosis. Observations on human tissues, when available, will complement and test the clinical relevance of studies in experimental animals. It will be useful to distinguish various specific types of immune injury that could involve allografted vessels as we struggle to define our terms more precisely and arrange the pieces of the puzzle of the pathogenesis of transplantation‐associated arteriosclerosis in some logical order. The schema within represents an oversimplified attempt in this direction.