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 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-gamma 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-gamma-/- and IL-12 p40-/- C57BL/6 mice were unaffected, although anti-CD40 induced high levels of systemic and local IFN-gamma 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-gamma 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.
Martin
D L
DL
Department of Pathology, Division of Geographic Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
King
C L
CL
Pearlman
E
E
Strine
E
E
Heinzel
F P
FP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D019013:CD40 Antigens / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004802:Eosinophilia / Q000276:immunology / Q000469:parasitology / Q000628:therapy; D005260:Female; D006614:Hindlimb; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007271:Injections, Intradermal; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018664:Interleukin-12 / Q000172:deficiency / Q000235:genetics; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010063:Ovum / Q000276:immunology*; D012550:Schistosoma mansoni / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism* / Q000469:parasitology
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D016207:Cytokines; D007166:Immunosuppressive Agents; D018793:Interleukin-13; D015848:Interleukin-5; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma