Granulomas are dynamic, focal, inflammatory, tissue-destructive reactions which involve intricate cell-cell interactions. The premise of this project is that granulomas of the liver and gut are subject to immunoregulation by both local factors and cells from gut-associated lymphoid tissue (GALT) and that Crohn's disease may be the consequence of a defect in this immunoregulatory process. The objectives of this investigation are to study the response of these organs to granulomatous stimuli using murine schistosomiasis as a model and to analyze immunoregulatory mechanisms and cellular interactions occurring during evolution of these lesions. Research Objectives I. Renin-Angiotensin System in Granulomatous Inflammation A. Determine effects of angiotensins on granuloma macrophage phagocytosis and prostaglandin synthesis using radioassay (RA), radioimmunoassay (RIA) and HPLC B. Define mechanisms of angiotensin action by identifying cell receptors and studying calcium flux and cyclic nucleotide metabolism utilizing RA and RIA C. Correlate functional and metabolic alterations using vaious chemical inhibitors of cellular metabolism D. Demonstrate angiotensin synthesis by radiolabeling proteins in cell culture E. Determine effect of regulatory T cells on angiotensin metabolism utilizing adoptive transfer and pharmacological methods II. Immunoregulation of Liver and Gut Granulomas by GALT A. Determine whether enterically-induced modulation of liver granulomas in infected mice is antigen-specific and alters granuloma cell composition/function B. Demonstrate the effect of adoptive transfer and enteric immunization on synchronous liver granulomas in uninfected, normal mice C. Induce synchronous gut granulomas by arterial embolization and study the effect of enteric immunization and adoptive transfer on granuloma size and cell composition/function III. Crohn's Disease A. Isolate intestinal granulomas and characterize cell composition/function Understanding these processes may provide insight into the etiology of inflammatory bowel disease and improve therapeutic modalities.
