The purpose of our research program is to elucidate the mechanisms of vaccine-induced immunity in schistosomiasis and to better understand the pathogenesis of the disease. 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) IL-13 was identified as a central pro-fibrogenic cytokine in schistosomiasis. Findings from these studies provided evidence that IL-13 inhibitors may be of general therapeutic benefit in preventing damaging tissue fibrosis resulting from Th2-dominated inflammatory responses, seen in many autoimmune, allergic, and chronic infectious diseases.2) CpG oligodeoxynucleotides were shown to suppress egg-induced pathology. CpG oligonucleotides were shown to prophylactically immunize against Th2-mediated schistosome egg-induced immunopathology and the mechanism was dissected by studying the adjuvant activity of CpG ODNs in various cytokine-deficient mice.3) Two distinct forms of lethal immunopathology were described for schistosomiasis. Studies conducted in cytokine-deficient mice revealed that excessive type-1 and type-2 cytokine responses induce distinct but equally detrimental forms of lethal immunopathology in murine schistosomiasis. IL-10 was identified as a critical host-protective cytokine. 4) NOS-2 was identified as a potent anti-inflammatory and antifibrotic mediator in schistosomiasis. Our previous studies showed that much of the pathology associated with schistosome infections is ameliorated if mice are immunized with egg antigens in the presence of the Th1-inducing adjuvant IL-12 prior to infection. Studies conducted in NOS-2-deficient mice demonstrated that the protective effects of this experimental """"""""anti-pathology"""""""" vaccine are completely dependent on nitric oxide. These results revealed a beneficial role for NOS-2 in the regulation of inflammation and suggest that the ultimate success of Th2-to-Th1 immune deviation strategies will rely on the efficient activation of NOS-2 expressi
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