The natural killer (NK) lymphocyte is a cytotoxic cell that can limit growth of infectious organisms, lyse virus infected cells and tumor cells without prior sensitization to the antigens expressed on those cells. It is known that patients with Grave's disease, Immunodeficiency Syndromes and other disorders of immune regulation may express a suppressed level of NK activity despite normal numbers of NK cells in the peripheral blood. The increase in opportunistic infections and tumors in these patients may be causally related to the suppressed NK activity in these patients. Recent information has indicated that defective NK lymphocytes from AIDS patients are able to bind but unable to lyse their targets, suggesting that the defect is in the trigger mechanism of NK lymphocyte. The research presented in this application proposes to study the cytotoxic mechanism of the NK cell in normal and immunodeficient patients with defective NK activity, and will explore the defect in the trigger mechanism through the modulation of cell surface molecules that have been shown to induce secretion and release of lytic factors. Studies will use both bronchoalveolar lavage cells (BAC) and peripheral blood lymphocytes (PBL). Recently described monoclonal antibodies (G1.4, D7.5) define a specific molecule on the cell surface of the NK lymphocyte in hamsters, rats and humans that functions as a """"""""trigger"""""""" (TrgS) for the release of lytic factors. Functionally, the Moab reagents are able to exhaust the lytic capacity of the NK cells by causing the premature release of the lytic factors from the effector cells. Initially, lung and peripheral blood lymphocytes from normal volunteers as well as human lymphocyte clones will be used to define and characterize the expression of """"""""TrgS"""""""" and its relationship to transcription, translation, and the secretion of the lytic factors. In order to determine whether a relationship exists between TrgS function and the NK function, NK activity and TrgS expression will be monitored in PBL of HIV positive, AIDS related complex (ARC), AIDS patients and healthy, volunteers. Biological assays will be used to monitor the NK activity and activity of released soluble products. The regulation of the expression of the TrgS surface molecule and the secretion of the cytolysins will be studied using affinity purified antibodies, molecular probes for mRNA and DNA recognizing specific sequences for TrgS and known cytolysins. The effects of lympho- kines and cytokines that are known to augment or suppress NK activity will be evaluated for their ability to induce the expression and function of TrgS to release lytic factors in the normal and patient groups. Understanding the regulation of the NK trigger mechanism in normal lymphocytes may explain possible defective mechanisms in the NK process in AIDS and AIDS related syndrome. Results may lead to treatment or therapy that may reconstitute NK activity in individuals with AIDS related syndromes and prolong the time that the patient is free of opportunistic infections and cutaneous tumors.
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