This proposal focuses upon understanding the functions of antigen activated populations of host leukocytes, their products and their interrelationships which are mobilized in response to a vascularized organ allograft; these responses include both the events of acute rejection of cardiac grafts in untreated histoincompatible rat recipients and those responsible for prolonged survival in immunologically modified hosts. The role of activated leukocytes developing receptors for interleukin 2 (IL2R+ cells) in rejection will be emphasized, and their modulation by various IL2R targeted therapies assessed, a novel approach to specific immunosuppression. In particular, these therapies will be used as probes to determine function and kinetics of IL2R+ cells infiltrating the graft and occurring in host peripheral lymphoid tissues, the influence of these cells on other populations and their effect on cytokine production. For comparison, IL2R+ cells will be investigated in other states of host unresponsiveness, including animals treated with cyclosporine (CsA), or in immunological enhancement. The differential functions, interactions and migrational properties of T helper (Th,CD4) and T cytotoxic/suppressor (Tc/s,CD8) phenotypes will be defined serially; specifically, the putative sparing effect of IL2R directed therapies on cells with suppressor activity will be examined. Isolated IL2R+ macrophages, an important component of the IL2R+ infiltrate, will be cultured then stimulated with cytokines or down regulated with CsA. Function of these regulated cells will then be assessed in vivo by transfer studies. Dendritic cells will be studied as inducers of immune responsiveness in the context of transplantation, with emphasis on their role in activating resting T lymphocytes to develop IL2R, as well as their migration patterns. The differential production and function of cytokines will be investigated in anti-IL2R treated recipients, stressing their effects on lymphocyte subpopulations in vivo. Taken together, these studies should delineate the role of antigen activated IL2R+ leukocytes in host responsiveness toward vascularized organ allografts. Their modulation by specific therapies may be critical in clinical transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI019071-16
Application #
3128504
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1982-08-01
Project End
1992-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
16
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
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
Kupiec-Weglinski, J W; Heemann, U W; Coito, A J et al. (1993) Adhesion molecule interaction with extracellular matrix. Exp Nephrol 1:78-82
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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