Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that involves the lungs in over 90% of affected individuals. Chronic progressive pulmonary sarcoidosis can result in end-stage fibrosis and cor pulmonale. Treatment with corticosteroids may be toxic and ineffective. As many as 5% of individuals with pulmonary sarcoidosis die of causes directly related to the disease. With an incidence in the U.S. of 11-4- per 100,000 people, sarcoidosis represents a significant health problem. The overall objective of this proposal is to further our understanding of the immunologic and inflammatory processes mediating granulomatous inflammation in pulmonary sarcoidosis. T-cells are involved in the pathogenesis of the disease since """"""""activated"""""""", lymphokine-releasing CD4+ T- cells accumulate at sites of disease such as the lung. The accumulation of these T-cells in the lung is selective and oligoclonal, characterized by the preferential usage of T-cell response. Analysis of the pattern of cytokines expressed in the sarcoid lung have demonstrated that IFNgamma and to a lesser extent, IL2 are strongly expressed while IL4 and IL5 are expressed at very low or nondetectable levels. This polarization towards a Th1 immune response is likely playing a key role in the development and perpetuation of granulomatous inflammation in sarcoidosis since Th1 responses are critical in mediating cell-mediated immune responses in many infectious and autoimmune diseases. Our preliminary data demonstrate that IL12, a cytokine critical to the initiation of Th1 immune responses, is markedly upregulated in the sarcoid lung. The experiments proposed in this application are aimed at testing the hypothesis that sarcoidosis is a Th1-mediated disease driven by the dysregulated production of Il12. This hypothesis will be tested by studies with the following Specific Aims; 1) Determine whether polarization towards Th1 associated cytokine expression in characteristic of tissues affected by granulomatous inflammation in sarcoidosis, 2) characterize and compare the regulation of IL12 expression in sarcoid and normal human alveolar macrophages and peripheral blood, and 3) determine the role of IL12 in the Th1 deviation of immune responses in pulmonary sarcoidosis. These studies should increase our understanding of the processes controlling Th1 polarization in sarcoidosis and provide insights into the effects and regulatory determinants of chronic expression of Il12 in the human lung. Thus, these studies may assist in the development of new therapies designed to halt the granulomatous and fibrotic responses that lead to end-stage pulmonary disease in sarcoidosis.
