Chronic beryllium disease, a granulomatous interstitial lung disease caused by the inhalation of beryllium metal or salts in the work environment, may have an underlying immunologic mechanism. Human and animal studies of beryllium disease suggest the presence of beryllium-specific T cells. In addition, beryllium has toxic effects on many kinds of cells, including cells involved in immune responses. The hypothesis to be tested here is that at least two events contribute significantly to development of chronic beryllium disease: 1) a beryllium-specific T cell- mediated immune response, and 2) an immunotoxic effect of beryllium on specific populations of immunoregulatory cells. Over the past year we have developed a mouse model in which beryllium lung disease is induced by injecting beryllium sulfate in adjuvant into sites remote from the lung. Such a model -- which is independent of local toxic responses but may require development of cell-mediated immunity to beryllium -- now can be utilized to examine the role of beryllium-specific cell in pathogenesis. This proposal will have three Specific Aims.
In Specific Aim 1, we will test the hypothesis that beryllium-specific T cells are sufficient to cause disease in the mouse by performing transfer experiments. We will characterize and clone these beryllium- specific cells -- determining cell phenotype, measuring their secretory products, and testing their effects on macrophage function in mice.
In Specific Aim 2, will will test the hypothesis that the toxic effects of beryllium may cause alterations in normal immunocompetence in vitro and in vivo. To do this we will examine the effects of acute and chronic beryllium exposure on humoral and cell-mediated immunity in mice.
In Specific Aim 3, we will test the hypothesis that humans with chronic beryllium disease have beryllium-reactive T cells. Our goal will be to characterize and clone these T cells. From these studies we will learn how beryllium-specific activation of cell-mediated immunity and beryllium-induced immunotoxicity contribute to pathogenesis of beryllium disease. These studies may lead to a better understanding not only of chronic beryllium disease, but also of similar immunologically- mediated lung diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Physician Scientist Award (K11)
Project #
5K11ES000173-02
Application #
3086675
Study Section
Environmental Health Sciences Review Committee (EHS)
Project Start
1987-08-01
Project End
1992-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206
Rose, C S; Martyny, J W; Newman, L S et al. (1998) ""Lifeguard lung"": endemic granulomatous pneumonitis in an indoor swimming pool. Am J Public Health 88:1795-800
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Newman, L S (1995) Beryllium disease and sarcoidosis: clinical and laboratory links. Sarcoidosis 12:7-19
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Newman, L S; Bobka, C; Schumacher, B et al. (1994) Compartmentalized immune response reflects clinical severity of beryllium disease. Am J Respir Crit Care Med 150:135-42
Newman, L S; Buschman, D L; Newell Jr, J D et al. (1994) Beryllium disease: assessment with CT. Radiology 190:835-40
Wade 3rd, J F; Newman, L S (1993) Diesel asthma. Reactive airways disease following overexposure to locomotive exhaust. J Occup Med 35:149-54
Kreiss, K; Wasserman, S; Mroz, M M et al. (1993) Beryllium disease screening in the ceramics industry. Blood lymphocyte test performance and exposure-disease relations. J Occup Med 35:267-74
Forrester, J M; Newman, L S; Wang, Y et al. (1993) Clonal expansion of lung V delta 1+ T cells in pulmonary sarcoidosis. J Clin Invest 91:292-300

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