Inhalation of metals fumes or dusts can induce environmental lung disease when the immune system mounts a metal-antigen-specific cellular immune response within the lung. Individuals who inhale beryllium metal and oxides can insidiously develop chronic beryllium disease, associated with a beryllium-specific T cell proliferative response. Low levels of exposure can cause beryllium disease, and cessation of exposure does not prevent progression, limiting the value of primary preventive strategies. Secondary preventive strategies are needed. In field investigations, we have shown that a biological marker of this beryllium-specific lymphocyte response, called the beryllium lymphocyte transformation test (BeLT) identifies individuals who a) are beryllium sensitized but who do not yet have disease or b) have beryllium disease at a subclinical stage. Either can develop clinically-significant illness, but not everyone progresses. Although treatment is available, early treatment of BeLT surveillance- identified subclinical cases has not been prescribed because 1) we have no means of identifying who will or will not progress, and 2) we lack sensitive biological markers with which to gauge disease activity, severity, and response to therapy. Our central hypothesis is two-fold: l) that the dysregulated release of two key cytokines--interleukin-2 and interleukin-6--results in the amplification of the beryllium-specific cellular immune response; and 2) that we can employ assays that measure the release of these cytokines and their receptors as biological markers. The experiments outlined in the current proposal are designed to study the mechanism of this cytokine amplification circuit, and determine the value of these immune markers in ameliorating disease. First, we will determine the influence of macrophage-derived IL-6 on beryllium-specific T cell responses in humans with beryllium disease, and determine the mechanisms regulating IL-6 in this disorder, in vitro. Second, we will develop cytokine and cytokine receptor biomarkers of this cellular immune response to beryllium, and determine their value as indicators of clinical severity and degree of pulmonary inflammation. To do this we will determine levels of IL-6, IL-2 and shed soluble IL-2 receptor (slL-2R) in serum and bronchoalveolar lavage, and correlate these levels with clinical parameters of disease activity and severity, cross- sectionally. Third, we will determine the value of these immune biomarkers as indicators of disease prognosis and response to therapy, by quantitating these markers in serum and lavage serially, and relating longitudinal changes in patients who progress and who respond to therapy. These studies may lead to a better understanding of not only beryllium disease, but of other immunologically-mediated disorders resulting from environmental exposure; and validate these biologically-relevant markers of the immune response for potential epidemiologic and clinical application.
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