The broad objective of this application is to examine the population dynamics of individual antigen-specific T cells during the rejection of a cardiac allograft and the development of allograft tolerance. The application plans detailed examination of the allograft and lymphoid tissues in recipient mice using conventional morphologic examination, a series of immunohistochemical studies using monoclonal antibody staining, an extensive panel of in situ hybridization studies focused on cytokine gene expression, and correlative analysis of cytokine gene expression using QC-RT-PCR. The primary system for analysis will be adoptive transfer of CD4 positive T cells with single antigen-specificity into immunodeficent syngeneic mice, such as SCID or rag knockout animals, that are transplanted with an alloantigenic cardiac graft. The first specific aim is to determine whether the mechanisms of rejection vary dependent on cytokine expression pattern and TCR-specificity and avidity in adoptive transfers of T cells into transplanted mice. Both T cell clones and TCR-transgenic T cells using alloreactive TCRs will be used for these studies. The roles of precise TCR specificity in the cytokine gene expression pattern by particular T cells can be distinguished using adoptive transfer of TCR transgenic cells differentiated in vitro into distinct functional subsets. The second specific aim is to produce several transgenic mice which express an immunoregulatory molecule under the control of a cardiac-specific promoter to probe the role of the allograft histological microenvironment on the progress of the immune response mediated by different kinds of T cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050724-09
Application #
6490698
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Massicot-Fisher, Judith
Project Start
1994-01-01
Project End
2003-12-31
Budget Start
2002-01-01
Budget End
2003-12-31
Support Year
9
Fiscal Year
2002
Total Cost
$336,182
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Kapp, Judith A; Honjo, Kazuhito; Kapp, Linda M et al. (2007) Antigen, in the presence of TGF-beta, induces up-regulation of FoxP3gfp+ in CD4+ TCR transgenic T cells that mediate linked suppression of CD8+ T cell responses. J Immunol 179:2105-14
Kapp, Judith A; Honjo, Kazuhito; Kapp, Linda M et al. (2006) TCR transgenic CD8+ T cells activated in the presence of TGFbeta express FoxP3 and mediate linked suppression of primary immune responses and cardiac allograft rejection. Int Immunol 18:1549-62
Honjo, Kazuhito; Xu, Xiao Yan; Kapp, Judith A et al. (2004) Activation and migration of allo-peptide specific TCR transgenic T cells in cardiac allograft rejection. Cell Immunol 230:44-55
Honjo, Kazuhito; Yan Xu, Xiao; Kapp, Judith A et al. (2004) Evidence for cooperativity in the rejection of cardiac grafts mediated by CD4 TCR Tg T cells specific for a defined allopeptide. Am J Transplant 4:1762-8
Honjo, Kazuhito; Xu, Xiao yan; Bucy, R Pat (2004) CD4+ T-cell receptor transgenic T cells alone can reject vascularized heart transplants through the indirect pathway of alloantigen recognition. Transplantation 77:452-5
Honjo, K; Xu, X Y; Bucy, R P (2000) Heterogeneity of T cell clones specific for a single indirect alloantigenic epitope (I-Ab/H-2Kd54-68) that mediate transplant rejection. Transplantation 70:1516-24
Xu, X Y; Honjo, K; Devore-Carter, D et al. (1997) Immunosuppression by inhibition of cellular adhesion mediated by leukocyte function-associated antigen-1/intercellular adhesion molecule-1 in murine cardiac transplantation. Transplantation 63:876-85
Rogers, W O; Weaver, C T; Kraus, L A et al. (1997) Visualization of antigen-specific T cell activation and cytokine expression in vivo. J Immunol 158:649-57
Rice, J C; Bucy, R P (1995) Differences in the degree of depletion, rate of recovery, and the preferential elimination of naive CD4+ T cells by anti-CD4 monoclonal antibody (GK1.5) in young and aged mice. J Immunol 154:6644-54
Karr, L J; Panoskaltsis-Mortari, A; Li, J et al. (1995) In situ hybridization for cytokine mRNA with digoxigenin-labeled riboprobes. Sensitivity of detection and double label applications. J Immunol Methods 182:93-106

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