The key regulatory events behind granuloma formation and particularly the role of the granuloma matrix are not well understood. We have recently demonstrated the presence of the early T-cell activation gene Eta-1 (also known as osteopontin {OPN}, a bone matrix acidic glycoprotein) in active granulomatous lesions of tuberculosis rid sarcoidosis. Our preliminary data demonstrate that Eta-1/OPN is a potent chemoattractant, adhesin and proliferative co-stimulant for T lymphocytes in vitro. These data, the association of reduced osteopontin in mice with defective host response to intracellular pathogens such as Rickettsia tsutsugamushi in vivo, and the fact that steopontin is a potent chemoattractant for monocytes and macrophages suggest that Eta-1/OPN represents a new class of RGD-containing cytokine which regulates T cell and macrophage function, serving a key role in the initiation and maintenance of (lung) granulomatous inflammation. Specifically, we hypothesize that the expression of Eta-1/OPN by macrophages, lymphocytes, endothelial and epithelial cells is an early and important event in granuloma formation which regulates inflammatory cell traffic, cellular activation and cytokine production, proliferation, and cell death. This grant proposes to elucidate its immunologic functions and study its role in granuloma formation. In vitro studies include characterizing the production of Eta-1/OPN by immune cells and lung cells and the phosphorylation and glycosylation variants produced by these cells. The effects on T cell function of purified and recombinant OPN will be studied. In vivo studies will be performed to determine the role of Eta-1/OPN in the formation of granulomas in he lung. A model will be used in which granulomas are induced by the embolization of sepharose beads containing antigens which induce the formation of granulomas dependent on Th1 and Th2 cytokines. The model will be applied to a genetically engineered Eta-1/OPN deficient mouse and wild type controls.
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