The purpose of this research program is to elucidate the mechanisms of vaccine-induced immunity in schistosomiasis and to dissect the process of egg-induced granuloma formation, which leads to the development of severe hepatic fibrosis, portal hypertension, and ultimately death in some infected individuals. Several murine models of schistosomiasis are employed in these studies so that basic pathogenic processes can be investigated. Key findings in the 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 role of TNF-alpha in schistosomiasis pathogenesis was examined. For nearly a decade, TNF-alpha was believed to be the key mediator of egg-induced pathology in schistosomiasis. Our studies in severe combined immunodeficiency (SCID) mice demonstrated that TNF- alpha alone is incapable of reconstituting early fecundity, granuloma formation, or hepatic fibrosis in mice infected with either S. mansoni or S. japonicum. The presence of CD4+ T cell-derived Th2-type cytokines provided the strongest correlation for the development of disease. 2) A key role for IL-13 in schistosomiasis pathogenesis was identified. In these studies, we showed that in vivo blockade of the Th2 cytokine IL- 13, using sIL-13Ra2-Fc, significantly reduced the development of hepatic fibrosis in infected mice. Moreover, IL-13 was shown to directly stimulate collagen deposition in cultured fibroblast cells. These findings provide evidence that IL-13 inhibitors may be of general therapeutic benefit in preventing damaging tissue fibrosis resulting from Th2-dominated inflammatory responses, such as that seen in many autoimmune, allergic, and chronic infectious diseases.3) The role of inducible nitric oxide synthase in the protective response induced by a model anti-pathology vaccine was described. Our previous studies showed that much of the pathology associated with schistosome infections could be ameliorated by immunizing mice with egg antigens when combined with the Th1-inducing adjuvant IL-12. Our recent work focused on elucidating the mechanism of this protective response. By using inducible nitric oxide synthase-deficient mice, reactive nitrogen intermediates were identified as an indispensable component of this protective anti- pathology vaccine.4) Polarized Type-1 and Type-2 immune responses were shown to provide equivalent levels of vaccine-induced immunity to S. mansoni. Identifying the immunological mechanisms responsible for host resistance against an infectious organism is a fundamental step in rational vaccine design. Vaccine studies conducted in various cytokine- deficient mice revealed that Type-1 and Type-2 polarized immune responses provided nearly equivalent levels of protective immunity. These findings demonstrate that humoral and cell-mediated mechanisms contribute to immunity against schistosomes. 5) The first G-protein coupled receptor of S. mansoni was cloned and characterized. By using the schistosome EST database and conserved sequence motifs, a G-protein coupled receptor of S. mansoni was molecularly identified and characterized. This receptor has high sequence similarity to rhodopsin, a dim light sensing protein, and is expressed in miricidia, cercaria, schistosomula, and the adult life-stages. Currently, immunofluorescence and electron microscopy are being used to localize the expression of the receptor. 6) The production of IFN-gamma and IL-12 by Staphylococcus aureus (SAC)-stimulated peripheral blood mononuclear cells was shown to be reduced in patients infected with S. mansoni. A marked deficiency in IL-12 and IFN-gamma production (cytokines associated with cell-mediated immune responses) was identified in SAC- stimulated mononuclear cells obtained from infected individuals living in the Northeast of Brazil. These findings suggest that depressed Type- 1 responses may develop in chronically infected individuals as a consequence of reduced IL-12 production by macrophages and/or dendritic cells.
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