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.
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