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Human coronary transplantation-associated arteriosclerosis. Evidence for a chronic immune reaction to activated graft
R N Salomon1, C C Hughes, F J Schoen
1Department of Pathology, New England Medical Center, Boston, Massachusetts.
Insights
Transplanted heart arteries show immune cells expressing HLA-DR, driving T cell responses. This suggests a mechanism for coronary artery disease in heart transplants.
Area of Science:
- Immunology
- Cardiovascular Science
- Transplantation Biology
Background:
- Coronary artery disease is a major cause of graft failure in heart transplantation.
- The exact mechanisms driving this process, known as cardiac allograft vasculopathy, are not fully understood.
Purpose of the Study:
- To identify and localize immune cells within cardiac allograft arteriosclerosis lesions.
- To investigate the role of human leukocyte antigen-DR (HLA-DR) expression in these lesions.
- To determine the functional significance of HLA-DR positive cells in T cell activation.
Main Methods:
- Analysis of coronary artery biopsies from human cardiac allografts.
- Immunohistochemical staining for T lymphocytes (CD4+, CD8+), macrophages, and HLA-DR expression.
- In vitro co-culture experiments with allogeneic T cells and cultured arterial endothelial cells.
Main Results:
- Transplantation-associated arteriosclerosis lesions contain T lymphocytes and HLA-DR positive macrophages near the endothelium.
- Endothelial cells in transplanted coronary arteries express high levels of HLA-DR, unlike normal arteries.
- Cultured endothelial cells stimulated allogeneic CD4+ T cell proliferation and interleukin-2 secretion.
Conclusions:
- HLA-DR positive endothelium in donor coronary arteries may sustain recipient T cell immune responses.
- This sustained immune response, involving cytokine release, could contribute to smooth muscle cell proliferation and matrix accumulation.
- Findings suggest a pathway for immune-mediated coronary artery disease development in heart transplant recipients.
Abstract:
Occlusive disease of coronary arteries of engrafted hearts is the major obstacle to long-term survival of human cardiac allografts. The pathogenesis of this process remains uncertain. The identity and localization of cells found in transplantation-associated arteriosclerosis lesions from human cardiac allografts were evaluated, and their expression of class II major histocompatibility complex (human leukocyte antigen-DR [HLA-DR]), surface molecules required for recognition of foreign cells by CD4+ T lymphocytes, was noted. Expanded intimas of transplanted coronary arteries contain T lymphocytes (both CD4+ and CD8+ in approximately equal number) and HLA-DR+ macrophages, both localized primarily in a ring immediately below the luminal endothelium, a distribution strikingly different from that in typical atherosclerosis. Coronary arterial endothelium from six of six transplanted hearts studied bore high levels of HLA-DR. Normal human arteries or usual atherosclerotic lesions have few if any HLA-DR+ endothelial cells. The significance of these findings was tested by evaluating the ability of HLA-DR+ arterial cells to interact with allogeneic T cells in vitro. Endothelial cells (but not smooth muscle cells) cultured from human arteries stimulated foreign CD4+ T cells to proliferate and augmented their secretion of interleukin-2. These findings suggest that ongoing stimulation of recipient T lymphocytes by HLA-DR+ endothelium of donor coronary arteries contributes to a sustained regional immune response. Consequent local release of cytokines may regulate smooth muscle cell proliferation and matrix accumulation within the coronary arteries of allografted hearts.