Schistosomiasis causes disease in nearly 200 million people. An immunopathologic response to the parasite ova causes disease in the form of granulomas and fibrosis. This immunopathologic response is dependent upon discrete populations of T lymphocytes. We wish to understand how these T cells interact to produce and regulate granulomas and fibrosis. Our previous studies have suggested the hypothesis that the granuloma is an organelle which locally regulates T cell activation thereby controlling systemic immunopathology. Early in the disease, T cells specifically migrate to the granuloma wherein they are activated. The granuloma increases systemic pathology by exporting these activated, pathogenic cells. Later, activated cells enter the granuloma wherein they are inactivated. The granuloma reduces systemic pathology by removing pathogenic cells. We further hypothesize that this regulation is contingent on the ability of the granuloma to effect specific pathways of T cell activation, differentiation, and death. We propose to test these hypotheses and study their implications. First, we will assess the ability of adoptively transferred, cloned, fluorochrome-labeled T lymphocytes to migrate into the spleens and granulomas of S. mansoni infected mice. Next we will recover these adoptively transferred, cloned T lymphocytes by FACS. We will assess these cells for division, selected cytokine production, granuloma formation, fibrogenesis and apoptosis. Next, we will study how the granulomas produce their effects. We will evaluate the intragranuloma milieu, the in vivo effects of specific cytokine or costimulatory receptor antagonists and the interactions of signal pathways and cytokines by selective in vitro studies. Defining the loci and mechanisms of the immunologic regulation of pathology will further our goal of reducing disease due to schistosomiasis.
