Characterization of the adjuvant effect of IL-12 and efficacy of IL-12 inhibitors in type II collagen-induced arthritis.
A destructive joint disease can be induced in susceptible DBA/1 mice by immunization with type II collagen emulsified with oil and either killed Mycobacterium tuberculosis or IL-12 as adjuvant. Cellular and humoral anti-collagen immune mechanisms appear to be involved in the pathogenesis of arthritis. We have characterized the adjuvant effect or IL-12 in more detail and addressed the question whether mycobacteria might act via the induction of endogenous IL-12. Injections of IL-12 into collagen-immunized DBA/1 mice promoted the development of IFN-gamma-producing CD4+ T cells and strongly upregulated the production of complement-fixing IgG2a and IgG2b antibodies resulting in severe arthritis. Neutralization of IFN-gamma in vivo largely inhibited the increase in antibody synthesis and prevented joint disease in IL-12-treated mice. However, collagen-specific IFN-gamma synthesis by T cells was further enhanced in these animals. Furthermore, IL-12 treatment promoted the development of IFN-gamma-producing T cells but failed to enhance antibody synthesis and to induce arthritis in C57BL/6 or BALB/c mice immunized with collagen in oil. These results indicate that the induction (by IL-12) of a strong collagen-specific T-cell response alone is not sufficient to trigger arthritis. Attempts to show a role for endogenous IL-12 in DBA/1 mice immunized with collagen with mycobacteria as adjuvant gave no reliable results. Whereas anti-IL-12 treatment delayed the onset and ameliorated the disease in some experiments, it failed to do so in other experiments, or, control reagents also had some effect. A slight inhibition of collagen-specific IgG2a synthesis was observed in most experiments in the sera of anti-IL-12-treated mice. Taken together, the results show that exogenous IL-12 can promote arthritis via its direct effect on T cells and its effect on antibody production, which is at least in part IFN-gamma-dependent. On the other hand, whether or not endogenous IL-12 is involved in the adjuvant effect of mycobacteria needs further clarification.
Germann
T
T
Universität Mainz, Institut für Immunologie, Germany.
Hess
H
H
Szeliga
J
J
Rüde
E
E
D000276:Adjuvants, Immunologic; D000818:Animals; D000917:Antibody Formation; D001168:Arthritis / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D003094:Collagen / Q000276:immunology*; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D013154:Spleen / Q000378:metabolism
D000276:Adjuvants, Immunologic; D018664:Interleukin-12; D007371:Interferon-gamma; D003094:Collagen