Much is known concerning the immunobiology of antigen recognition by T lymphocytes. For example, the T cell receptor for antigen has been defined genetically, the association of this receptor with the CD3 complex of proteins has been established, and the accessory functions of the CD4 and CD8 proteins in stabilizing the recognition of antigen presented in association with either Class II or Class I MHC proteins has been demonstrated. What has not been established is what mechanisms are involved in T lymphocyte localization into sites of inflammation and antigen deposition, thereby allowing antigen-specific T cells to carry out their effector functions in vivo. The proposed studies are base don the central hypothesis that endothelial modification must occur at sites of inflammation to facilitate the extravasation of blood borne T lymphocytes into the tissues. Further, endothelial differentiation in inflammatory tissues would be regulated by cytokines produced by antigen-stimulated T cells. In these studies, polyurethane sponges will sere as a matrix for antigen deposition, endothelial differentiation, and lymphocytic infiltration. Specifically, we will: 1) demonstrate phenotypic changes in vascular endothelia associated with T cell entry into inflammatory tissues. We will use immunohistochemistry and mAb to identify alterations of the vascular endothelia in antigen-containing sponges. 2) identify receptor- ligand interactions which mediate T cell adhesion to inflammatory endothelia. mAb specific for differentiated endothelia and T cell surface proteins will be incorporated into ex vivo adhesion assays and in vivo lymphocyte homing assays to block lymphocyte adhesion and extravasation. 3) evaluate cytokine regulation of inflammatory endothelial differentiation. Cytokines with known activity on endothelial cell behavior in vitro will be assessed for a similar activity in vivo. 4) evaluate T cell subset participation in inflammatory endothelial differentiation. T cell subsets will be depleted in vivo to test the hypothesis that subsets of T cells regulate endothelial differentiation. 5) determine if immunosuppressive drugs which interfere with T cell accumulation at sites of antigen deposition do so by interfering with the development of inflammatory endothelia. These studies will provide a comprehensive analysis of T lymphocyte-inflammatory endothelia interactions which result in lymphocyte extravasation in vivo. In understanding the regulation of this process, future experimentation will be directed at pharmacologic manipulation of disease states characterized by lymphocytic infiltration into inflammatory tissues.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29AI030104-01
Application #
3455622
Study Section
Experimental Immunology Study Section (EI)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Wagoner, L E; Zhao, L; Bishop, D K et al. (1996) Lysis of adult ventricular myocytes by cells infiltrating rejecting murine cardiac allografts. Circulation 93:111-9
DeBruyne, L A; Chang, A E; Cameron, M J et al. (1996) Direct transfer of a foreign MHC gene into human melanoma alters T cell receptor V beta usage by tumor-infiltrating lymphocytes. Cancer Immunol Immunother 43:49-58
Bishop, D K; DeBruyne, L A; Chan, S et al. (1995) Dissociation of mouse cardiac transplant rejection and donor alloantigen-specific T cell responsiveness. Transpl Immunol 3:222-8
Chan, S Y; DeBruyne, L A; Goodman, R E et al. (1995) In vivo depletion of CD8+ T cells results in Th2 cytokine production and alternate mechanisms of allograft rejection. Transplantation 59:1155-61
DeBruyne, L A; Renlund, D G; Bishop, D K (1995) Evidence that human cardiac allograft acceptance is associated with a decrease in donor-reactive helper T lymphocytes. Transplantation 59:778-83
Bishop, D K; Li, W; Chan, S Y et al. (1994) Helper T lymphocyte unresponsiveness to cardiac allografts following transient depletion of CD4-positive cells. Implications for cellular and humoral responses. Transplantation 58:576-84
Bishop, D K; Chan, S; Li, W et al. (1993) CD4-positive helper T lymphocytes mediate mouse cardiac allograft rejection independent of donor alloantigen specific cytotoxic T lymphocytes. Transplantation 56:892-7
Bishop, D K; Shelby, J; Eichwald, E J (1992) Mobilization of T lymphocytes following cardiac transplantation. Evidence that CD4-positive cells are required for cytotoxic T lymphocyte activation, inflammatory endothelial development, graft infiltration, and acute allograft rejection. Transplantation 53:849-57
Bishop, D K; Li, W (1992) Cyclosporin A and FK506 mediate differential effects on T cell activation in vivo. J Immunol 148:1049-54
Bishop, D K; Shelby, J; Eichwald, E J (1991) Functional analysis of donor-reactive T cells infiltrating heterotopic cardiac transplants: effect of anti-CD4 MAb in vivo. Transplant Proc 23:287-9