Work on this project will continue to proceed on three fronts: 1. Activation and expression of allograft immunity. It is now established that a metabolically active stimulator cell (the antigen presenting cell) is a major source of tissue immunogenicity. However, there is still uncertainty concerning the mechanism whereby alloantigen bearing S+ cells activate CD8 T cells; the CD8 cell we have shown to mediate islet allograft rejection in vivo. Work in this area will investigate the potential of different cytokines to act a costimulators for the CD8 T cell, and the conditions of antigen presentation that influence the expression of costimulator activity by active cytokines. At the level of expression of allograft immunity, progress has been made in defining the role of lymphokines in the effector function of CD8 cells in vivo. Preliminary data using cloned CD8 T cells has focused attention on the role of gamma-IFN in this process. The involvement of this lymphokine in the rejection process will be examined in more detail during the forthcoming grant period. 2. Tolerance induction in adult animals. We have now established that cultured islet allografts following transplantation induce a suppressive form of tolerance in the recipient animal. Apart from knowing what this tolerance is mediated by some form of suppression rather than clonal deletion, we have no further information on the detailed mechanisms mediating this suppression. This portion of the grant will investigate the role of cellular and humoral components in the mediation of this suppressor form of tolerance. 3. Disease recurrence in islets transplanted to spontaneously diabetic animals. Islet tissue grafted to spontaneously diabetic allogeneic recipients is under threat of disease recurrence. This process is mediated by CD4 T cells and may be the result of oxygen radical damage to the grafted B cells. Preliminary evidence indicates that the disease process can be controlled by oxygen radical scavengers (superoxidedisputase and catalase). Work in this area will be expanded to define the effect of these enzymes both in combination and separately, on the natural history of disease recurrence in the grafted tissue. There is still uncertainty concerning the susceptibility of allogeneic islet tissue to disease recurrence in the spontaneously diabetic BB rat. The present data suggests that difference reported by different laboratories may reflect differences in sensitivity of islet tissue to the disease process. The grafting of islet tissue from a number of different allogeneic strains to spontaneously diabetic BB rats will be used to define and investigate this problem in greater depth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK033470-07
Application #
3231861
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1984-04-01
Project End
1994-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Grazia, Todd J; Plenter, Robert J; Weber, Sarah M et al. (2010) Acute cardiac allograft rejection by directly cytotoxic CD4 T cells: parallel requirements for Fas and perforin. Transplantation 89:33-9
Gill, Ronald G (2010) NK cells: elusive participants in transplantation immunity and tolerance. Curr Opin Immunol 22:649-54
Sarkar, S A; Gunter, J; Bouchard, R et al. (2007) Dominant negative mutant forms of the cAMP response element binding protein induce apoptosis and decrease the anti-apoptotic action of growth factors in human islets. Diabetologia 50:1649-59
Grazia, Todd J; Plenter, Robert J; Doan, An N et al. (2007) Spontaneous allograft tolerance in B7-deficient mice independent of preexisting endogenous CD4+CD25+ regulatory T-cells. Transplantation 83:1449-58
Sleater, M; Diamond, A S; Gill, R G (2007) Islet allograft rejection by contact-dependent CD8+ T cells: perforin and FasL play alternate but obligatory roles. Am J Transplant 7:1927-33
Nicolls, M R; Gill, R G (2006) LFA-1 (CD11a) as a therapeutic target. Am J Transplant 6:27-36
Grazia, Todd J; Gill, Ronald G; Gelhaus Jr, H Carl et al. (2005) Perturbation of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 results in differential outcomes in cardiac vs islet allograft survival. J Heart Lung Transplant 24:1410-4
Murakawa, Tomohiro; Kerklo, Michelle M; Zamora, Martin R et al. (2005) Simultaneous LFA-1 and CD40 ligand antagonism prevents airway remodeling in orthotopic airway transplantation: implications for the role of respiratory epithelium as a modulator of fibrosis. J Immunol 174:3869-79
Beilke, J; Johnson, Z; Kuhl, N et al. (2004) A major role for host MHC class I antigen presentation for promoting islet allograft survival. Transplant Proc 36:1173-4
Johnson, Z; Beilke, J; Pietra, B et al. (2004) Distinct requirements for host CD80/CD86 costimulatory molecules in cardiac versus islet rejection. Transplant Proc 36:1171-2

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