These investigations in transplatation biology have been designed to define the interrelated host immunological events, both cellular and humoral, which occur in response to vascularized organ allografts. OUr efforts are concerned primarily with elucidating and amplifying the nature, function and dynamics of cell populations and subpopulations infiltrating both acutely rejecting and long surviving allografts and understanding the events occurring concomitantly in host lymphoid tissues. These data are integrated into parallel studies defining serial changes in lymphocyte migration patterns and in morphology of lymphoid tissues following modification of the graft recipient. Using primarily the heterotopic cardiac allograft transplanted between inbred strains of rats, three recipient models are under investigation; the enhanced graft recipient, the Cyclosporin A (CyA) treated host and the B recipient. Allograft survival is prolonged markedly in all three models, indefinitely in the latter two. Acute rejection will be re-established by adoptive transfer of unsensitized and sensitized lymphocytes with or without macrophages and with or without Interleukins (IL 1 and 2). Transferred leukocytes will be fractionated into subpopulations using monoclonal antibodies and will be expanded in vitro by stimulation into allogeneic cells and/or IL-2. Specificity of these effects will be ascertained using recipients of double heart grafts from specific and third party donors. To detect their differential effects upon production of specific unresponsiveness, lymphocyte subpopulations from enhanced and CyA treated recipients will be transferred into normal sysgeneic recipients of test grafts. Immunological events in grafts and graft recipients will be examined. Thus, we will attempt serially to isolate and understand individual components of the multifaceted host responses against organ allografts and their relationships with each other. Only with more precise understanding of these host responses can selective methods of immunosuppression be devised for use in clinical organ transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI019071-12
Application #
3128501
Study Section
Immunobiology Study Section (IMB)
Project Start
1982-08-01
Project End
1987-07-31
Budget Start
1985-08-01
Budget End
1986-07-31
Support Year
12
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
Kupiec-Weglinski, J W; Heemann, U W; Coito, A J et al. (1993) Adhesion molecule interaction with extracellular matrix. Exp Nephrol 1:78-82
Hancock, W H; Whitley, W D; Tullius, S G et al. (1993) Cytokines, adhesion molecules, and the pathogenesis of chronic rejection of rat renal allografts. Transplantation 56:643-50
Whitley, W D; Hancock, W W; Kupiec-Weglinski, J W et al. (1993) Iron chelation suppresses mononuclear cell activation, modifies lymphocyte migration patterns, and prolongs rat cardiac allograft survival in rats. Transplantation 56:1182-8
Diamond, J R; Tilney, N L; Frye, J et al. (1992) Progressive albuminuria and glomerulosclerosis in a rat model of chronic renal allograft rejection. Transplantation 54:710-6
Tanaka, K; Tilney, N L; Kupiec-Weglinski, J W (1992) Maturing thymocytes in accelerated rejection of cardiac allografts in presensitized rats. Transplantation 54:515-9
Sablinski, T; Sayegh, M H; Hancock, W W et al. (1991) Differential role of CD4+ cells in the sensitization and effector phases of accelerated graft rejection. Transplantation 51:226-31
Kupiec-Weglinski, J W; Sablinski, T; Hancock, W W et al. (1991) Synergistic interactions between anti-interleukin-2 receptor (IL-2R) MAb and CyA in sensitized rat recipients of cardiac allografts. Transplant Proc 23:285-6
Kupiec-Weglinski, J W; Sablinski, T; Hancock, W W et al. (1991) Modulation of accelerated rejection of cardiac allografts in sensitized rats by anti-interleukin 2 receptor monoclonal antibody and cyclosporine therapy. Transplantation 51:300-5
Sablinski, T; Hancock, W W; Tilney, N L et al. (1991) CD4 monoclonal antibodies in organ transplantation--a review of progress. Transplantation 52:579-89
Hancock, W W; Tanaka, K; Salem, H H et al. (1991) TNF as a mediator of cardiac transplant rejection, including effects on the intragraft protein C/protein S/thrombomodulin pathway. Transplant Proc 23:235-7

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