Morbidity, in schistosomiasis, is influenced by granuloma formation and fibrosis. The in vitro model of granuloma formation was developed in this laboratory to characterize the cellular and molecular mechanisms responsible for activation and control of granuloma formation and fibrogenesis. This system will be used to quantitatively analyze the kinetics and mechanisms of cellular recruitment and collagen synthesis in murine schistosomiasis. The usefulness of this model has been augmented by 3 recent developments: 1. SEA-reactive T cell clones, which produce granulomas in vitro and bear idiotypic receptors for S. mansoni antigens. These clones will be employed to examine specific inter- and intracellular signals. Particular emphasis will be placed on defining the effects of T cell factors on initial granuloma formation, fibroblast proliferation, and collagen synthesis. 2. Defined bead granulomas; Polystyrene beads, to which antigen has been covalently bound, serve as nidi of granuloma formation, permitting characterization of antigenic epitopes and conditions of cellular activation. 3. Liver function tests; Application of the aminopyrine breath test, serum bile acid determination, and other more conventional assays will facilitate quantitative investigation of the pathophysiologic effects of schistosomiasis on liver function. Thus, it will be become possible to correlate a variety of immunopathologic parameters of granuloma formation and fibrosis with quantitative indices of morbidity. The in vivo significance of these observations will be assessed through the adoptive transfer of cells and/or antigen coated beads to normal and S. mansoni infected animals. Once mechanisms are identified, a rational immunotherapeutic approach to granuloma modulation might be developed. Toward this end, we will assess the feasibility of immunizing with polyclonal T cell blasts, lines, or monoclonal T cells to elicit specific negative regulation of granuloma formation. These studies will provide valuable information with respect to basic mechanisms of granuloma formation as well as to the long range goal of reduced morbidity in schistosomiasis.
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