The natural killer lymphocyte (NK) is a cytotoxic cell that can lyse virus infected cells, or tumor cells without prior sensitization to the antigens expressed on those cells. The NK lymphocyte is a bone marrow derived cell which enters the lung through the vascular endothelium. Once in the local pulmonary environment the NK cell is subject to local regulatory factors and does not recirculate through the thoracic duct lymph drainage system. The research presented in this application proposes to study the regulation of the pulmonary NK activity through modulation of the trigger mechanism for secretion of these cells. Monoclonal antibodies (G1.4, D7.5) that have been developed define molecules on the cell surface of the NK cell that can trigger secretion 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 cells. The D7.5 Moab will be used to develop molecular probes for mRNA and DNA specific sequences for the G1.4, D7.5 molecules on the NK cell. The reagents specific for G1.4, D7.5 molecule will be used to study the augmentation and suppression of the trigger mechanism, in general, and the D7.5 molecule on pulmonary NK cells, in particular. Moabs made to the idiotypic determinants on Moab G1.4 and D7.5 bind to NK-sensitive targets and not to NK-insensitive targets, studies will be performed to explore the possibility that Moab G1.4 and D7.5 and their respective anti-idiotype Moabs may define the actual molecules involved in signals for lysis by the NK effector cell and its target. Results of these studies may lead to the development of reagents and drugs that might correct defective trigger mechanism of NK cells in the lung and therefore be important in prevention or treatment of pulmonary disease in patients with AIDS, the elderly who are at risk for Influenza infection, and patients who might be at risk for lung metastasis or primary lung cancer.
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