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 experimental 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. An offshoot of our research is to understand the basic mechanisms of tissue remodeling and fibrosis, which are debilitating and life-threatening sequelae of a number of chronic inflammatory diseases. Strikingly, almost 45% of the deaths in the U.S.A. are believed to result from chronic fibroproliferative diseases. Progress was achieved in the following areas during the year: 1) Using diseased lung tissue and DNA microarrays, we found that mice with type-1 polarized cytokine responses do not elaborate collagens or MMPs and therefore do not have a significant capacity for tissue repair. We concluded that Th1-mediated inflammation is characterized by tissue damage, while Th2 cytokines direct wound healing and fibrosis; 2) Mice deficient in the vitamin D receptor displayed increased granulomatous inflammation during S. mansoni infection, suggesting that vitamin D exhibits an anti-inflammatory effect in vivo; 3) A synthetic lipopeptide was shown to suppress granuloma formation and tissue eosinophilia in the lungs of egg challenged mice: 4) We showed that the IL-13 receptor alpha 2 is a critical mediator of immune down-modulation, identifying the receptor as a life-sustaining off signal for chronic and pernicious inflammation in schistosomiasis; 5) We showed that innate effectors cells and regulatory T cells producing IL-10 cooperate to reduce morbidity and prolong survival in schistosomiasis, and finally; 6) We showed that P-selectin can suppress hepatic inflammation and fibrosis in mice by reducing interferon gamma and increasing IL-13 receptor alpha 2 levels.
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