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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL027353-12
Application #
3780207
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
1993
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206
Kinder, Brent W; Brown, Kevin K; McCormack, Francis X et al. (2009) Serum surfactant protein-A is a strong predictor of early mortality in idiopathic pulmonary fibrosis. Chest 135:1557-1563
Kinder, Brent W; Brown, Kevin K; Schwarz, Marvin I et al. (2008) Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis. Chest 133:226-32
Perez, Rafael L; Kimani, Anthony P; King Jr, Talmadge E et al. (2007) Bronchoalveolar lavage fluid D dimer levels are higher and more prevalent in black patients with pulmonary sarcoidosis. Respiration 74:297-303
Schwarz, Marvin I; Albert, Richard K (2004) ""Imitators"" of the ARDS: implications for diagnosis and treatment. Chest 125:1530-5
Vourlekis, Jason S; Schwarz, Marvin I; Cool, Carlyne D et al. (2002) Nonspecific interstitial pneumonitis as the sole histologic expression of hypersensitivity pneumonitis. Am J Med 112:490-3
Inoue, Yoshikazu; King Jr, Talmadge E; Barker, Elizabeth et al. (2002) Basic fibroblast growth factor and its receptors in idiopathic pulmonary fibrosis and lymphangioleiomyomatosis. Am J Respir Crit Care Med 166:765-73
King Jr, T E; Schwarz, M I; Brown, K et al. (2001) Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. Am J Respir Crit Care Med 164:1025-32
King Jr, T E; Tooze, J A; Schwarz, M I et al. (2001) Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med 164:1171-81
Glazer, C S; Cohen, L B; Schwarz, M I (2001) Acute eosinophilic pneumonia in AIDS. Chest 120:1732-5
Martinez, J A; Nishimura, C; Guatura, S B et al. (2001) Elevation of soluble interleukin-2 receptor levels in the bronchoalveolar lavage from patients with systemic sclerosis. Rheumatol Int 21:122-6

Showing the most recent 10 out of 220 publications