IFN-gamma is necessary but not sufficient for anti-CD40 antibody-mediated inhibition of the Th2 response to Schistosoma mansoni eggs

The injection of Schistosoma mansoni eggs into the footpads of mice results in a localized Th2 cytokine response and tissue eosinophilia, We examined whether treatment with CD40-activating Abs would block the development of T h2 cytokine responses and eosinophilic tissue pathology in this model. Seve n days after C57BL/6 mice were injected with eggs and the FGK45 anti-CD40 A b, Ag-specific synthesis of IL-4, IL-5, and IL-13 in lymph node culture was reduced (>10-fold) relative to control mice treated with eggs and rat IgG, In contrast, IFN-gamma and IL-12 were increased in both culture supernatan ts and in the serum. Similar changes in lymphnode cytokine mRNA. were obser ved in vivo, and tissue eosinophilia was reduced nearly 20-fold. Th2 cytoki ne responses in anti-CD40-treated IFN-gamma(-/-) and IL-12 p40(-/-) C57BL/6 mice were unaffected; although anti-CD40 induced high levels of systemic a nd local IFN-gamma production in both wild-type and IL-12 p40(-/-) mice. We conclude that CD40-activating treatments strongly reverse the immune pheno type generated in response to a classic, Th2-biasing stimulus and stimulate IFN-gamma through a novel IL-12-independent pathway. This model for Th1-de viating immune therapy may have relevance to the treatment of Th2-dependent diseases in general.