Parasitic invasion is accompanied by a spectrum of pathological sequelae that result in large part from the production of host-derived inflammatory cytokines. In malaria for example, host production of TNF has been linked directly to the development of cerebral disease, a frequently fatal complication of childhood malaria. Similarly, in leishmaniasis, outcome from infection has been shown to result from the differential expression of IL-4, IFNgamma, TNF, and other cytokines which regulate helper T-cell responses. We recently isolated and cloned the murine homolog of human macrophage migration inhibitory factor, MIF, after having identified this cytokine to be a pivotal mediator in the inflammatory response to LPS (endotoxin). Anti-MIF antibody was found to fully protect mice from the lethal effects of endotoxemia. In parallel experiments, we observed that macrophages stimulated with the malaria pigment, hemozoin, produced significant levels of MIF. In vivo, serum MIF levels were elevated both in hemozoin-injected mice and in mice with low levels of Plasmodium infection. The objective of this grant proposal is to investigate the role of MIF in the host response to parasitic infection and to determine the extent to which anti-MIF therapy ameliorates the pathological effects of parasite- induced cytokines. In vitro and in vivo studies have shown that MIF augments TNF production and that anti-MIF antibody treatment can decrease TNF levels by more than 40%. Because plasma MIF levels are sustained for long periods of time and at low levels of parasite burden, anti-MIF therapy may be an effective means to reduce complications, such as cerebral malaria, that result from the persistent production of TNF and other TNF-induced cytokines.
Our specific aims are to: 1) Elucidate the role of MIF in two models of parasitic invasion: murine malaria and murine cutaneous leishmaniasis, 2) Develop a neutralizing, monoclonal anti-MIF antibody and map the neutralizing MIF epitopes, 3) Clone and express, as a soluble MIF- inhibitor, the murine MIF receptor, and 4) Elucidate the three-dimensional structure of murine MIF and the MIF/MIF-receptor complex. These studies will form the basis for the future, rational design of pharmacological inhibitors of the MIF/MIF-receptor interaction.
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