The immune response to transplanted tissue is a complex event involving a wide range of inducer and effector mechanisms. Recent studies have suggested that the murine T cell helper/inducer subset characterized by cell surface expression of the CD4 molecule is necessary in the initiation of islet allograft transplantation rejection. Understanding the mechanisms of anti-CD4 mediated unresponsiveness is one of the major aims of this grant application. Data presented below support the central hypothesis to be examined that T cell anergy is induced in recent thymic migrants following depletive anti-CD4 treatment and organ allograft transplantation. A second question will address the potential use of anti-CD4 immunotherapy in islet transplantation as a treatment for autoimmune insulin dependent diabetes mellitus (IDDM). The autoimmune nature of IDDM may preclude the use of anti-CD4 therapy for islet transplants because of the underlying """"""""autoimmune"""""""" mechanisms which could destroy transplanted islet tissue despite effective transplantation tolerance strategies for """"""""alloimmunity"""""""". Only by determining if anti-CD4 mediated transplantation tolerance is effective in genetically predisposed animal models of IDDM will it be possible to decide whether anti-CD4 mediated islet transplantation tolerance induction provides a potentially successful therapeutic strategy for the treatment of human IDDM. The last aim is to attempt to identify the protein product(s) whose synthesis is required for the induction of anergy. These studies have significance for potential insight into human transplantation tolerance induction regimens and for understanding mechanisms of anti-CD4 induced unresponsiveness. More importantly, they may provide insight into the potential use of anti-CD4 immunotherapy to allow islet transplantation as a treatment of human type I diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK043711-01A1
Application #
3245148
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1992-05-01
Project End
1997-04-30
Budget Start
1992-05-01
Budget End
1993-04-30
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Krieger, N R; Fathman, C G; Shaw, M K et al. (2000) Identification and characterization of the antigen-specific subpopulation of alloreactive CD4+ T cells in vitro and in vivo. Transplantation 69:605-9
Krieger, N R; Yuh, D; McIntyre, W B et al. (1998) Prolongation of cardiac graft survival with anti-CD4Ig plus hCTLA4Ig in primates. J Surg Res 76:174-8
Yin, D P; Sankary, H N; Talor-Edwards, C et al. (1998) Anti-CD4 therapy in combined heart-kidney, heart-liver, and heart-small bowel allotransplants in high-responder rats. Transplantation 66:1-5
Krieger, N R; Fathman, C G (1997) The use of CD4 and CD8 knockout mice to study the role of T-cell subsets in allotransplant rejection. J Heart Lung Transplant 16:263-7
Krieger, N R; Ito, H; Fathman, C G (1997) Rat pancreatic islet and skin xenograft survival in CD4 and CD8 knockout mice. J Autoimmun 10:309-15
Yin, D P; Sankary, H N; Williams, J et al. (1996) Induction of tolerance to small bowel allografts in high-responder rats by combining anti-CD4 with CTLA4Ig. Transplantation 62:1537-9
Krieger, N R; Yin, D P; Fathman, C G (1996) CD4+ but not CD8+ cells are essential for allorejection. J Exp Med 184:2013-8
Yin, D; Fathman, C G (1995) Induction of tolerance to heart allografts in high responder rats by combining anti-CD4 with CTLA4Ig. J Immunol 155:1655-9
Yin, D; Fathman, C G (1995) Tissue-specific effects of anti-CD4 therapy in induction of allograft unresponsiveness in high and low responder rats. Transpl Immunol 3:258-64
Charlton, B; Meltzer, J; Fathman, C G (1994) CD4-positive/heat-stable antigen-positive thymocytes cause graft-versus-host disease across non-major histocompatibility complex incompatibilities. Eur J Immunol 24:1706-9

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