CROSS-REGULATORY ROLE OF INTERFERON-GAMMA (IFN-GAMMA), IL-4 AND IL-10IN SCHISTOSOME EGG GRANULOMA-FORMATION - IN-VIVO REGULATION OF TH ACTIVITY AND INFLAMMATION

This study examined the relationship of IL-4, IL-10 and IFN-gamma with regard to the local granuloma (GR) and draining lymph node (LN) respo nse to Schistosoma mansoni eggs. Synchronized GR were induced in naive and schistosome-infected mice at the vigorous (8 weeks) and late chro nic (20 weeks) stages. In LN cultures, IL-10 and IFN production peaked on day 4 and was greatest for 8 week-infected mice. All GR cultures c ontained IFN, but compared with naive mice IL-10 production was accele rated at 8 weeks and abrogated at 20 weeks, consistent with expansion and abatement of Th2 activity. Cytokine neutralization was performed i n egg-challenged, naive mice that were adoptively sensitized with lymp hoid cells from 8 week-infected donors. GR size, GR macrophage tumour necrosis factor (TNF) production and egg antigen-elicited IL-2, IL-4, IL-5, IL-10 and IFN were examined on day 4 of GR formation. Anti-IFN a ugmented GR area by 40%, increased local IL-4 and IL-10, but decreased IFN and TNF production. In corresponding LN cultures, IFN decreased b y about 50%, while IL-2, IL-4, IL-10 and IL-5 increased by nearly two- , four-, five- and six-fold, respectively. Anti-IL-10 did not affect G R size or GR cytokines, but increased IFN levels in LN cultures four-f old and decreased IL-2, IL-4, IL-5 and IL-10. Anti-IL-4 abrogated GR a rea by 40%, along with a reduction in local IL-4 and TNF production. I n LN, IL-4 depletion reduced IL-4 and IL-5 by 60-70% and increased IFN levels. These results support the notion of a cross-regulatory networ k in which IFN inhibits Th2 and IL-10 inhibits Th1 cells. IL-4 fosters Th2 cell differentiation in LN, but also performs a critical recruitm ent function in the eosinophil-rich schistosome egg-induced CR, wherea s IFN contributes to enhanced GR macrophage function.