Elucidation of the mechanisms responsible for regulating tissue localized cell-mediated immunologic responses in vivo is of tremendous importance, as we appreciate that a very fine line separates protective immunity from injurious responses capable of causing overt pathology. To date, most research conducted in the area of tissue-specific immunity has focused on afferent aspects. These studies have provided insight into the mechanism of action of the Ti/T3 complex in CD4+ and CD8+ T cells, the pathways involved in antigen processing and presentation to achieve MHC Class I or Class II molecule restriction, and the complexity of regulatory elements controlling afferent immune responses. Presently, far less is understood about the biologic and physiologic processes regulating the efferent phase of immune responses. Efferent phases are of importance since protective immunity requires specificity, intensity and duration for optimum function. For the past 13 years, our research has focused on the study of skin-associated immunity, including the immune responses involved in anti-tumor, delayed hypersensitivity (DH) and contact hypersensitivity (CH) reactions. This work provided us with an appreciation of the importance of lymphocyte and monocyte recirculation in the proper functioning of immune responses, at both the afferent and efferent levels. We now propose a rigorous analysis of the efferent phase of cell- mediated immune responses, concentrating on events subsequent to the stimulation, clonal expansion and differentiation of immune T lymphocytes. It is our plan to study 3 interrelated aspects of this efferent phase. The first phase will concentrate on immune T lymphocyte localization and adhesion to endothelial cells of the microvasculature. We will test the hypothesis that lymphocyte localization to tissues is facilitated through Ti/T3 recognition of antigen, followed by a synergistic lymphocyte/endothelial adhesion through LFA-1/CAM-1 interactions. The second phase will be to elucidate the stimulatory requirements, receptor-ligand interactions, and intracellular changes to cytoskeletal elements that affects the ability of antigen-specific T cells (Th1) to extravasate into non-lymphoid tissues. Once localized within a tissue, Th1 cells respond to antigen and elaborate the lymphokines which mediate the cascade of events of CH and DH responses. Our third phase will be to analyze this biochemical and cellular cascade, and to question whether physiologic factors serve to regulate the intensity and duration of tissue localized cell- mediated immunological responses in vivo. We now have strong evidence implicating neutrophils and neutrophil proteases as essential regulatory elements in the pathophysiology of tissue localized immune responses. Chemotactic peptides generated through the proteolysis of extracellular matrix proteins now appear to provide the signals important to mononuclear cell and fibroblast infiltration into the focal inflammatory lesions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA025917-11
Application #
3482036
Study Section
Experimental Immunology Study Section (EI)
Project Start
1979-08-01
Project End
1994-01-31
Budget Start
1990-02-01
Budget End
1991-01-31
Support Year
11
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
Zhang, Tian Y; Ding, Xiaohong; Daynes, Raymond A (2005) The expression of 11 beta-hydroxysteroid dehydrogenase type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities. J Immunol 174:879-89
Jones, Dallas C; Ding, Xiaohong; Zhang, Tian Y et al. (2003) Peroxisome proliferator-activated receptor alpha negatively regulates T-bet transcription through suppression of p38 mitogen-activated protein kinase activation. J Immunol 171:196-203
Daynes, Raymond A; Enioutina, Elena Y; Jones, Dallas C (2003) Role of redox imbalance in the molecular mechanisms responsible for immunosenescence. Antioxid Redox Signal 5:537-48
Enioutina, Elena Y; Visic, Dino M; Daynes, Raymond A (2002) The induction of systemic and mucosal immunity to protein vaccines delivered through skin sites exposed to UVB. Vaccine 20:2116-30
Jones, Dallas C; Manning, Bernadette M; Daynes, Raymond A (2002) A role for the peroxisome proliferator-activated receptor alpha in T-cell physiology and ageing immunobiology. Proc Nutr Soc 61:363-9
Jones, Dallas C; Ding, Xiaohong; Daynes, Raymond A (2002) Nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is expressed in resting murine lymphocytes. The PPARalpha in T and B lymphocytes is both transactivation and transrepression competent. J Biol Chem 277:6838-45
Heithoff, D M; Enioutina, E Y; Daynes, R A et al. (2001) Salmonella DNA adenine methylase mutants confer cross-protective immunity. Infect Immun 69:6725-30
Manning, B M; Enioutina, E Y; Visic, D M et al. (2001) CpG DNA functions as an effective adjuvant for the induction of immune responses in aged mice. Exp Gerontol 37:107-26
Enioutina, E Y; Visic, V D; Daynes, R A (2000) Enhancement of common mucosal immunity in aged mice following their supplementation with various antioxidants. Vaccine 18:2381-93
Chen, X P; Ding, X; Daynes, R A (2000) Ganglioside control over IL-4 priming and cytokine production in activated T cells. Cytokine 12:972-85

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