The role of cytokines in the formation of the schistosome egg granuloma.

ABSTRACT

Schistosomiasis mansoni is a helminth-induced disease infecting over 120 million people in the tropics. Morbidity and mortality are caused by parasite eggs that evoke in the liver and intestines of infected persons, T cell-mediated granulomatous inflammation and irreversible fibrosis. In the murine model granulomatous inflammation is induced by CD4+ T helper lymphocytes. This short review summarizes recent observations that implicate a variety of lymphokines and cytokines as mediators of the granulomatous inflammatory response. Mediator production was examined in splenocyte as well as granuloma cell cultures of infected or egg granuloma-bearing mice. In the synchronous pulmonary granuloma model generated around i.v. injected eggs in naive mice IL-1 mRNA expression and IL-1 production were detectable within the first 4 days of granuloma growth. After 4-6 days TNF-alpha mRNA message appeared and cytokine production was observed. With the aging of the granuloma, production of both cytokines diminished. Thus, these cytokines are considered to be the primary recruiters of cellular aggregation in granuloma growth. The role of TNF-alpha in granuloma formation was also confirmed in infected mice. Whereas treatment of animals with anti-TNF-alpha antiserum diminished hepatic granuloma size, repeated injection of murine rTNF-alpha into chronically-infected mice enhanced the downmodulated granuloma response. With the administration of specific anti-lymphokine mAbs and recombinant murine lymphokines, as well as serial assays of lymphokine production by splenic, granuloma lymphocytes of infected mice, the role of INF-gamma, IL-2 and IL-4 was delineated. Interferon-gamma was found to be produced very early at the inception of the liver granulomatous response. By the time granulomas reached maximal size (8 wks post infection) production declined. Concurrently IL-2, IL-4 production peaked with maximal granuloma growth and declined with the onset of the immune modulation of the inflammation. Whereas these latter lymphokines appear to play a proinflammatory role, IFN-gamma when administered in large doses diminished granulomatous inflammation, plays a regulatory role in the maintenance of the granulomatous response. The T helper cell population of the granulomas may also influence the lymphokine profile of the developing granuloma. So far precursor type TH0, and TH2 subset of helper cells have been cloned from liver granulomas. The former secreted both IL-2, IL-4 and IFN-gamma lymphokines and adoptively transferred the granulomatous response.(ABSTRACT TRUNCATED AT 400 WORDS)