Chronic beryllium disease (CBD) is an occupational lung disease characterized by chronic granulomatous inflammation. The disease appears to be closely associated with the development of a T cell immune response directed to beryllium. Our past studies have shown that individuals exposed to beryllium may develop a) no immunologic response, b) beryllium- specific T cells in blood but without lung disease, or c) beryllium- specific T cells in both blood and bronchoalveolar lavage (BAL) accompanied by granuloma formation in the lungs. Based on this previous work, it is hypothesized that beryllium-sensitization and the development of beryllium- reactive T cells is an early (and necessary) phase in development of disease. Furthermore, we propose that only a subset of beryllium-specific T cells are involved in the pulmonary pathologic process. These T cells, through local release of lymphokines, may mediate disease by modulating pulmonary macrophage phenotype and cytokine synthesis. The experiments outlined in the current proposal are designed to study beryllium-reactive blood and BAL T cells and pulmonary macrophages in two ways: a) by cross-sectional comparison of cells of subjects with and without beryllium sensitization or disease, and b) by serial, longitudinal evaluation of cells of subjects during the progression from sensitization to disease. Specifically, we propose to determine whether beryllium- reactive T cells in the BAL are a subset of those found in the blood in CBD. This will be done in two ways: a) by examining T cell receptor utilization in BAL and blood, and b) by examining the T cell receptor utilization and specificity for antigen of beryllium-specific T cell clones derived from blood and BAL. Furthermore, it will be determined whether progression from sensitization to disease occurs and involves the generation of new (pathogenic) beryllium-specific T cells. To do this we will determine a) whether new beryllium-reactive T cell clones emerge in the lung and blood as sensitized individuals are followed longitudinally for evidence of progression to disease and b) whether particular beryllium- reactive T cell clones are missing from the blood of beryllium-sensitized individuals without disease, compared to those with CBD. This study also will analyze alveolar and interstitial macrophage cytokine gene expression and alveolar macrophage HLA phenotype expression in individuals who are beryllium-sensitized, beryllium-diseased, or normal and non-exposed. As in the T cell experiments above, subjects' macrophages will be examined in a) a cross-sectional design to test for differences among groups, and b) a longitudinal design, to test for pulmonary macrophage changes within sensitized individuals being followed for progression. Furthermore, we will determine whether changes in macrophage phenotype and cytokine synthesis coincide with the local expression of T cell lymphokines which may modulate macrophage activity at the site of pathology. These studies may lead to a better understanding not only of CBD, but also of similar immunologically-mediated interstitial and granulomatous lung diseases.

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National Heart, Lung, and Blood Institute (NHLBI)
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