FIBROBLAST STIMULATION IN SCHISTOSOMIASIS

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Liver fibrosis is the major cause of serious morbidity and mortality in schistosomiasis mansoni. The long-range goal of this project is to define the molecular and cellular basis of hepatic fibrosis in schistosomiasis, knowledge that can have practical applications and could be relevant to a variety of other fibrotic diseases (such as pulmonary sarcoid and systemic sclerosis). Fibrogenic cytokines produced by hepatic egg granulomas (including fibroblast stimulating factor-1 [FsF-l], a novel heparin-binding lymphokine) apparently play an important role in hepatic fibrogenesis; down-regulation of this production or effect may have salutary consequences. FsF-l will be analysed by molecular cloning of FsF-l cDNA and expression in COS cells. Amino acid sequence of FsF-l will be derived from the nucleotide sequence of cDNA and compared to peptide sequences directly determined in natural FsF-l and to sequences for other proteins in a databank. Purified recombinant FsF-l will be used to assess FsF-l receptors on mesenchymal cells, and to prepare monoclonal and polyclonal antibodies for use in an immunoassay for FsF-l. This assay and FsF-l cDNA probes will be used to investigate aspects of the immunoregulation of FsF-1 in chronic schistosomiasis. Infected mice will be infused with splenocyte subpopulations from chronically-infected mice and with selected anticytokine antibody and the hepatic egg granulomas that develop at 8 weeks in the recipients will be analysed for FsF-l production.