The thematic hypotheses of this SCOR are that CD4+ leukocytes have central roles in the inflammation associated with granuloma formation, and that cell surface CD4 is not only a marker of differentiation but plays an important receptor function in initiating immune, inflammatory and microbicidal activity. This SCOR represents the collaborative efforts of a group of scientists who have shared common interests for almost ten years. In four interrelated projects, we propose to study selected functions of the three major CD4+ cell types associated with granuloma formation, CD4+ T lymphocytes, CD4+ monocytes/macrophages and CD4+ eosinophils. Peripheral blood, bronchoalveolar lavage and tissue cells will be used in studies designed to determine the function of CD4 on normal leukocytes; on leukocytes from individuals with normal host defenses, but with infectious granulomatous diseases (i.e. M. tuberculosis); on leukocytes from individuals with non-infectious granulomatous lung disease (i.e. Sarcoidosis); and on leukocytes from individuals with immunodeficiency states known to affect CD4+ cells (i.e. HIV-1 infected individuals with and without opportunistic infections). Several discoveries by members of the SCOR make the proposed studies unique. Dr. Center's laboratory has cloned and Lymphocyte Chemoattractant Factor (LCF) which is a natural lymphokine ligand for CD4. This ligand makes it possible to identify the signal transduction pathways used by CD4, alternative functions for CD4 on the T cell, and to identify primary functions for CD4 on the monocyte, alveolar macrophage and eosinophil. Projects 1 (Dr. Center), 3 (Dr. Bernardo) and 4 (Dr. Berman) develop extensive preliminary data that LCF interacts with CD4 causing PI turnover into IP3, Ca++ mobilization, migratory responses and up regulation of IL2r and MHC II antigens on both T cells and monocytes; and Project 2 (Dr. Weller) has recently identified CD4 on the surface of eosinophils demonstrating it to be a functional chemotactic receptor for LCF. The SCOR is designed in a completely integrated fashion in which each of the four projects depends heavily upon the reagents, resources, and special methods of the others in order to study the function of CD4 on CD4+ cells and their participation in granulomatous lung diseases.
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