The primary cause of late cardiac allograft loss is a unique form of coronary vasculopathy which superficially resembles coronary atherosclerosis and occurs at a rate of 15 to 20% of patients per year. The diffuse nature and rapid development of the vascular involvement, and the limitation of that involvement to donor tissue suggests an immunologic mechanism. The working hypothesis of this proposal is that a chronic low grade immunologic reaction (cellular and/or humoral immunity) to donor endothelium results in endothelial cell production of factors which stimulate smooth muscle cell proliferation. By harvesting and growing donor aortic endothelium at the time of organ donation, an assay system has been developed to investigate the cardiac allograft recipient's immunologic response to their specific donor's vascular endothelium in-vitro. This study proposes to investigate the following: 1) The recipient's lymphocyte proliferative response and expression of activation antigens when exposed to their specific donor's endothelium. 2) the presence of donor endothelium-specific antibody in recipient serum. 3) the response of the donor endothelium to incubation with recipient lymphocytes, serum or both; specifically measuring the expression of MHC class 1 and class 2 antigen, assaying for endothelial cell cytotoxicity, and assaying for the presence of endothelial cell-derived growth factors which are known to stimulate smooth muscle cell proliferation. 4) the correlation of the above assays in individual cardiac transplant patients to their development of accelerated transplant atherosclerosis. By understanding the specific immunologic response by the recipient to their donor vascular tissue, the specific response of the vascular endothelium to humoral and cellular immunity, and its subsequent interaction with smooth muscle, it is anticipated that this study will provide a better understanding of the mechanisms for initiation and progression of cardiac transplant atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL043369-01A1
Application #
3362002
Study Section
Pathology A Study Section (PTHA)
Project Start
1990-04-01
Project End
1995-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Arkonac, B; Mauck, K A; Chou, S et al. (1997) Low multiplicity cytomegalovirus infection of human aortic smooth muscle cells increases levels of major histocompatibility complex class I antigens and induces a proinflammatory cytokine milieu in the absence of cytopathology. J Heart Lung Transplant 16:1035-45
Hosenpud, J D; Mauck, K A; Hogan, K B (1997) Cardiac allograft vasculopathy: IgM antibody responses to donor-specific vascular endothelium. Transplantation 63:1602-6
Hosenpud, J D; Morris, T E; Shipley, G D et al. (1996) Cardiac allograft vasculopathy. Preferential regulation of endothelial cell-derived mesenchymal growth factors in response to a donor-specific cell-mediated allogeneic response. Transplantation 61:939-48
Mauck, K A; Hosenpud, J D (1996) The bronchial epithelium: a potential allogeneic target for chronic rejection after lung transplantation. J Heart Lung Transplant 15:709-14
Hosenpud, J D; Shipley, G D; Mauck, K A et al. (1995) Temporal reduction in acute rejection after heart transplantation is not associated with a reduction in cell-mediated responses to donor-specific vascular endothelium. J Heart Lung Transplant 14:926-37
Hosenpud, J D; Everett, J P; Morris, T E et al. (1995) Cardiac allograft vasculopathy. Association with cell-mediated but not humoral alloimmunity to donor-specific vascular endothelium. Circulation 92:205-11
Everett, J P; Shipley, G D; Mauck, K A et al. (1994) Phenotypic variations in resting and activated levels of ICAM-1 expression by cultured human aortic endothelial cells. Transplantation 58:946-50
Morris, T E; Shipley, G D; Wagner, C R et al. (1994) Time course and contact dependence of allogeneic lymphocyte-induced human aortic endothelial cell-derived interleukin-6. J Heart Lung Transplant 13:1081-94
Wagner, C R; Morris, T E; Shipley, G D et al. (1993) Regulation of human aortic endothelial cell-derived mesenchymal growth factors by allogeneic lymphocytes in vitro. A potential mechanism for cardiac allograft vasculopathy. J Clin Invest 92:1269-77
Hosenpud, J D; Shipley, G D; Morris, T E et al. (1993) The modulation of human aortic endothelial cell ICAM-1 (CD-54) expression by serum containing high titers of anti-HLA antibodies. Transplantation 55:405-11

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