Schistosomiasis causes disease in nearly 200 million people. Clinical disease hepatic granulomas and fibrosis, result from an immunopathologic response to the parasite ova. We have developed an approach to target this pathological immune response, a fusion toxin, composed of antigen(Ag) derived from S. mansoni and the cytotoxic agent, daunomycin(Dm). This fusion toxin prevents immunopathology in an immunologically specific manner, avoiding the deleterious consequences of nonspecific immune suppression. Ag-Dm will be used alone and in conjunction with anthelminthic cure by Praziquantel to simulate its projected use in human disease. First, we will study the efficacy, safety, and specificity of action of Ag-Dm in murine schistosomiasis mansoni. Next we will study the mechanisms of action of Ag-Dm and its consequences on the host immune response. Because our initial studies suggest that Ag-Dm works by suppressing antigen presentation, we will first study the effects of Ag-Dm on B cell and macrophage antigen-presentation in mutant mice. Since antigen presentation results in skewing the immune response toward Th2 dominance, we next will examine the consequences of Ag-Dm treatment on discrete subpopulations of T cells. We will measure cell cycle and activation kinetics, cytokine production, and apoptosis. We will compare the effects of Ag-Dm on the systemic immune response and on the unique microenvironment within the granulomas. These studies are necessary to optimize the safety and efficacy of Ag-Dm for subsequent use in infected people. Defining the mechanisms of immunologic regulation by Ag-Dm will allow us to better target immunopathology and reduce immunopathology in humans.
| Rumbley, C A; Sugaya, H; Zekavat, S A et al. (2001) Elimination of lymphocytes, but not eosinophils, by Fas-mediated apoptosis in murine schistosomiasis. Am J Trop Med Hyg 65:442-9 |
