The purpose of our research program is to elucidate the molecular and immunologic mechanisms regulating the pathogenesis of schistosomiasis and other parasitic diseases. Transgenic and knockout mice are employed in these studies so that basic pathogenic processes can be investigated. Key findings from our murine studies are then extended to the field, where the immune responses of schistosomiasis patients exhibiting different clinical forms of the disease are examined. The ultimate goal of this research is to understand the host immune response to infection so that immunologically based strategies might be employed in the development of a highly effective vaccine for schistosomiasis. Progress was achieved in the following areas during the year: 1) The activity of the IL-13 receptor was investigated in detail: studies showed that the fibrotic mechanism induced by IL-13 is directly controlled by the decoy IL-13Ra2. Mice deficient in this receptor developed much more severe liver fibrosis. There was also evidence that the receptor was influencing the viability of the parasite since fewer worms were detected in the knockout animals when chronically infected. 2) The role of IL-10 was invested in other infectious disease models and shown to promote resistance to the nematode parasite Trichuris muris. Strikingly, in contrast to the findings with T. muris, IL-10 knockout mice infected with L. major were completely resistant, suggesting that the cytokine is a key susceptibility factor. 3) Mouse cDNA microarrays were used to molecularly phenotype the gene expression patterns that characterize type-1 and type-2 cytokine-mediated inflammatory reactions. 4) Studies conducted in Brazilian schistosomiasis patients demonstrated that the deficiency in type-1 cytokine production, which often characterizes helminth infections, is not due to specific defects in IL-12, IL-10 or CD40 ligand activity. Changes in the functional status of antigen-presenting cells, however, appear to be involved.
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