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IFN- Is Necessary But Not Sufficient for Anti-CD40 Antibody-Mediated Inhibition of the Th2 Response to Schistosoma mansoni Eggs¹

Diana L. Martin^*, Christopher L. King^*,, Eric Pearlman^*, Ellen Strine^* and Frederick P. Heinzel^2,*,

^* Department of Pathology and Division of Geographic Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106; and Research Service, Veterans Affairs Medical Center, Cleveland OH 44106

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 Th2 cytokine responses and eosinophilic tissue pathology in this model. Seven days after C57BL/6 mice were injected with eggs and the FGK45 anti-CD40 Ab, 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- and IL-12 were increased in both culture supernatants and in the serum. Similar changes in lymph node cytokine mRNA were observed in vivo, and tissue eosinophilia was reduced nearly 20-fold. Th2 cytokine responses in anti-CD40-treated IFN-^-/- and IL-12 p40^-/- C57BL/6 mice were unaffected, although anti-CD40 induced high levels of systemic and local IFN- production in both wild-type and IL-12 p40^-/- mice. We conclude that CD40-activating treatments strongly reverse the immune phenotype generated in response to a classic, Th2-biasing stimulus and stimulate IFN- through a novel IL-12-independent pathway. This model for Th1-deviating immune therapy may have relevance to the treatment of Th2-dependent diseases in general.

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