The overall goal of this application is to define the mechanisms responsible for long term tolerance of allografts. Treatments and agents discussed in this program project which have been shown by previous work in our group, to prolong allograft survival include Major Histocompatibility Antigens and their peptides, peptides generated from T cell receptors, injection of cells and antigens into the thymus and treatment of animals with antibodies to adhesion molecules. Program #1 will determine mechanisms by which human liver allografts are immunologically accepted. Recipients of liver allografts delete cytotoxic T lymphocyte clones specific for donor HLA antigens, develop autoantibodies to donor reactive T-cell receptors and shed don or HLA antigens into the serum. Proposed studies will examine the mechanisms by which these events lead to specific immunological unresponsiveness. Program #2 will determine the mechanisms by which peptides derived from the TCR or MHC induce prolongation of allograft survival in murine allograft models. These studies will employ Vb8 negative mice, site specific Ld mutants and photocoupling. In addition to Ld, other MHC class I antigens will also be analysed. Program #3 will examine the molecular basis for coupling T cell death to TCR stimulation in mature T cells, determine its role in model of tolerance induction for cardiac allografts. Animals and cells from wild type (C57BL/6) mice and autoimmune, congenic mutants (B6.MRL-lpr and B6.C3H-gld) will be used to understand the role of responding cell suicide during tolerance induction and maintenance. Project #4 will address the mechanisms by which allograft tolerance occurs following intrathymic injection of alloantigens or their peptides in a murine model of cardiac transplantation. It is our aim that the results obtained from the above projects will facilitate the development of strategies for induction and maintenance of allograft tolerance without the need for continued immunosuppressive therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI035121-01
Application #
3092209
Study Section
Special Emphasis Panel (SRC (23))
Project Start
1993-09-30
Project End
1997-06-30
Budget Start
1993-09-30
Budget End
1994-06-30
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Motoyama, K; Arima, T; Yu, S et al. (2000) The kinetics of tolerance induction by nondepleting anti-CD4 monoclonal antibody (RIB 5/2) plus intravenous donor alloantigen administration. Transplantation 69:285-93
Arima, T; Rehman, A; Flye, M W (1997) Reversal of CTLA4Ig-mediated tolerance to cardiac allografts by exogenous interleukin-2. Transplant Proc 29:1305-6
Tu, Y; Arima, T; Flye, M W (1997) Effect of donor irradiation or recipient interleukin-2 treatment on survival of spontaneously accepted rat liver allografts. Transplant Proc 29:856-7
Lepley, D M; Gillanders, W E; Myers, N B et al. (1997) Biochemical and functional characterization of soluble multivalent MHC L(d)/Fc gamma 1 and L(d)/Fc mu chimeric proteins loaded with specific peptides. Transplantation 63:765-74
Sivasai, K S; Alevy, Y G; Duffy, B F et al. (1997) Peripheral blood microchimerism in human liver and renal transplant recipients: rejection despite donor-specific chimerism. Transplantation 64:427-32
Tu, Y; Arima, T; Flye, M W (1997) Effects of intrathymic tolerance on mouse heart and skin allograft acceptance. Transplant Proc 29:1063-4
Gillanders, W E; Arima, T; Tu, F et al. (1997) Evidence for clonal deletion and clonal anergy after intrathymic antigen injection in a transplantation model. Transplantation 64:1159-66
Tu, Y; Arima, T; Flye, M W (1997) Rejection of spontaneously accepted rat liver allografts with recipientinterleukin-2 treatment or donor irradiation. Transplantation 63:177-81
Tu, Y; Rehman, A; Flye, M W (1997) CTLA4-Ig treatment prolongs rat orthotopic liver graft survival. Transplant Proc 29:1036-7
Motoyama, K; Arima, T; Lehmann, M et al. (1997) Tolerance to heart and kidney grafts induced by nondepleting anti-CD4 monoclonal antibody (RIB 5/2) versus depleting anti-CD4 monoclonal antibody (OX-38) with donor antigen administration. Surgery 122:213-9; discussion 219-20

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