Granulomatous inflammation in response to parasite eggs is the central pathogenic mechanism in hepatic schistosomiasis. We propose to identify and define the role of the key molecular signals involved in this process. This is critical to rational development of immunoprophylaxis or therapy aimed at minimizing schistosome egg pathology. Our previous work identified TNF-alpha as necessary in the induction and amplification of the granulomatous response. We will now study the effects of modulating TNF-alpha in the activation of lipocytes and collagen synthesis, and in the induction of egg laying by schistosome females. Another group of signals that are important to granuloma formation results from interactions between immune cells and endothelial cell adhesion molecules that localize inflammatory cells at the site of egg deposition. We will follow up on our preliminary work, using immunohistochemistry and lymphocyte binding assays, to identify the major endothelial cell adhesion molecules involved in hepatic schistosomiasis. We will correlate the results of both these studies with analysis of schistosome infection in a set of transgenic mice. These include mice in which the interferon-gamma gene, TNF receptor genes, macrophage inhibitory protein (MIP-1) gene and ICAM-1 gene have been deleted. We will compare three models of schistosome infection in our in vivo work. Aside from natural infections, we will analyze the response to eggs injected directly into the liver via the portal vein, and the effect of adults in single-sex infections. We will follow up on our observation that reaction to adult worms primes the liver for granuloma formation by identifying the specific adult worm antigens responsible for this phenomenon. Finally, using in situ hybridization in frozen sections, and liver cell culture models, we will identify the host cells responsible for production of TNF-alpha and other major cytokines we find are expressed during granuloma induction.
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