Anti-IL-12 antibody prevents the development and progression of collagen-induced arthritis in IFN-gamma receptor-deficient mice.
In several models of inflammation, including collagen-induced arthritis (CIA), the disease-promoting effect of IL-12 has been attributed to its well-known ability to produce IFN-gamma. However, IFN-gamma receptor knockout (IFN-gammaR KO) mice of the DBA/1 strain have been reported to be more susceptible to CIA than corresponding wild-type mice, indicating the existence of an IFN-gamma-mediated protective pathway in this model. In the present study the development of CIA was found to be completely prevented by pretreatment with a neutralizing anti-IL-12 antibody, not only in wild-type, but significantly also in IFN-gammaR KO mice. In both strains of mice, the protective effect of anti-IL-12 was associated with lower production of anti-collagen type II antibodies. In vivo stimulation with anti-CD3 antibody in arthritic IFN-gammaR KO mice resulted in production of higher levels of circulating IFN-gamma, TNF and IL-2 than in corresponding control mice that had not received the arthritis-inducing immunization. This was not the case in arthritis-developing wild-type mice. Furthermore, the protective effect of anti-IL-12 antibody in mutant, but not in wild-type mice, was associated with lower circulating IFN-gamma, TNF and IL-2 and higher IL-4 and IL-5 cytokine levels following an anti-CD3 challenge. The data indicate that IL-12 promotes the development of arthritis independently of its ability to induce or favor production of IFN-gamma. In fact, any IFN-gamma produced in the course of the disease process rather exerts a protective effect. Furthermore, our study suggests that, in the absence of a functional IFN-gamma system, endogenous IL-12 exerts its disease-promoting effect by favoring production of other Th1-associated cytokines (IL-2 and TNF), by inhibiting development of IL-4- and IL-5-producing T cells and by stimulating production of anti-collagen autoantibodies.
Immunobiology, Rega Institute, University of Leuven, Belgium. patrick.matthys@rega.kuleuven.ac.be
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Matthys
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Vermeire
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Mitera
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Heremans
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Huang
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Billiau
D000818:Animals; D001168:Arthritis / Q000517:prevention & control*; D003094:Collagen / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology*; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000096743:Interferon gamma Receptor
D003094:Collagen; D016207:Cytokines; D007074:Immunoglobulin G; D007371:Interferon-gamma; D018664:Interleukin-12; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor