Our goal is to treat ineffective immune responses like Crohn's disease (CD) by pharmacological manipulation of endogenous immunoregulatory pathways. In CD, defective immunoregulatory circuits probably allow granulomatous inflammation, which leads to tissue damage and fibrosis. Neurokines like substance P (SP) can modulate immune function. Our hypothesis is that SP has a critical role in inflammation at mucosal surfaces and elsewhere, and that immune mechanisms govern SP receptor expression on leukocytes. Using murine schistosomiasis, a chronic granulomatous disease of the liver and intestines, we discovered a SP/SOM IFN-gamma immunoregulatory circuit. We will investigate further this important discovery with the following three specific aims: 1. The first specific aim derives from studies suggesting that SP receptors (SPr) are inducible on inflammatory cells, which could be an important mechanism allowing regulation of neurokine action. We will learn the full extent of SPr distribution among the various granuloma and mucosal immune cell subtypes. Also, we will resolve if antigenic stimulation and cytokines induce or modulate SPr expression. These studies will use a SPr receptor gene, quantitative mRNA analysis and competitive binding assays. 2. It remains unknown if SP is critically important for immune defense. Our second specific aim will use a SPr transgenic mouse to ascertain if normal immune responses need SP. Also, we will analyze the mechanisms leading to the immune disturbances. 3. SP controls IFN-gamma secretion, and IFN-gamma is centrally important to TH1-type immunity. We need to learn how SP regulations IFN-gamma within granulomas and the mucosa, since CD probably results from an inappropriately vigorous Th1 reaction to luminal factors. Thus, the third specific aim is to determine if SP modulates IL-12 production or if SP acts directly on lymphocytes to stimulate IFN-gamma secretion.
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