Immunology/Parasitology

T.A. Wynn, I. Eltoum, I.P. Oswald, A.W. Cheever, A. Sher, "Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology," Journal of Experimental Medicine, 179:1551-61, 1994. (Cited in nearly 50 publications as of February 1996) Comments by Thomas A. Wynn and Alan Sher, National Institute of Allergy and Infectious Diseases After malaria, schistosomiasis is the second most deadly parasitic disease. The worm-like parasite is prevalent in tropical and subtropical countries, afflicting more than 200 million people. It is responsible for about 800,000 deaths per year. Free-swimming larvae of this parasite penetrate the skin of people who swim or wade in contaminated waters. After invading its human host, larvae make their way to the liver, eventually maturing into adult worms. MODEL PARASITE: NIAID's Alan Sher, left, and Thomas Wynn use schistomsomes, seen here a plastic model, to study immunology. Serious complications of the disease occur when female worms deposit their eggs in human tissues, producing as many as 3,500 eggs per day. The eggs set the immune system into high gear, encapsulating them in microscopic lesions called granulomas. The granulomas and the subsequent fibrosis result in severe circulatory obstruction in the affected organs, which can lead to such problems as liver cirrhosis and kidney failure. Because schistosomiasis is difficult to treat, "the major goal of people who work on its immunology is to make a vaccine," says Alan Sher, a senior investigator in the parasitic diseases lab of the National Institute of Allergy and Infectious Diseases (NIAID). "We demonstrated in this paper that by using the cytokine interleukin 12 [IL-12], we could block granuloma formation in mice that were injected with [parasite] eggs," explains Thomas A. Wynn, a senior staff fellow who also works in NIAID's parasitic diseases lab. In additional experiments, they demonstrated that mice immunized with egg antigens plus IL-12 developed much smaller granulomas when subsequently given schistosome eggs, suggesting that an IL-12-based vaccine might be used to prevent this disease. In 1991, Sher and colleague Edward Pearce, an assistant professor of pathology at Cornell University, hypothesized that the lesions caused by granuloma formation are dependent on Th2 cells, cytokine-producing lymphocytes usually associated with the allergic response (E.J. Pearce et al., J. Exp. Med., 173:159, 1992). This work "led to the 1994 paper that we published in which IL-12 was used to suppress these harmful Th2 reactions," says Wynn. "Immunization against parasites is very difficult," notes Sher. "These are pathogens that are extremely well-adapted. They live with their hosts for many years and during their evolution have learned many tricks to evade the immune system." In the case of schistosomes, infections can survive in the host for up to 30 years. "Our approach for immunization involves not preventing the infection, but actually using the immune system to change the nature of the pathologic response so that it's no longer harmful." "We also showed that in animals that were sensitized to egg antigen, if we used IL-12 at the time of the challenge, the cytokine also blocked granuloma formation," reports Wynn. "So IL-12 could potentially be used therapeutically as well as prophylactically with vaccines." The authors speculate that the paper is cited so often because it has appeal to both basic and applied researchers. "On the basic side, it gives information on the fundamentals of inflammation," says Wynn. "On the more practical side, it's proposing a new strategy to use cytokines as adjuvants for preventing immunopathology." A little less than a year ago, the team demonstrated that this IL-12-based vaccination strategy protected mice from the liver fibrosis resulting from natural schistosome infections (T.A. Wynn et al., Nature, 376: 594-6, 1995). "We're now trying to dissect the immunological mechanisms underlying this prevention of chronic tissue pathology," remarks Wynn.

Immunology/Parasitology

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