ADMINISTRATION OF INTERLEUKIN-12 IN COMBINATION WITH TYPE-II COLLAGENINDUCES SEVERE ARTHRITIS IN DBA 1 MICE/

The induction of arthritis in DBA/1 mice usually requires immunization with the antigen type II collagen emulsified with Mycobacterium tuber culosis in oil. Here we describe that interleukin 12 (IL-12) can repla ce mycobacteria and cause severe arthritis of DBA/1 mice when administ ered in combination with type II collagen. Immunization of DBA/1 mice with type II collagen emulsified in oil alone resulted in a weak immun e response, and only a few animals (10-30%) developed arthritis. Admin istration of IL-12 for 5 days simultaneously with each immunization st rongly enhanced the anti-type II collagen immune response. Collagen-sp ecific interferon gamma (IPN-gamma) synthesis by ex vivo activated spl een cells was enhanced 3- to 10-fold. IFN-gamma was almost completely produced by CD4(+) T cells. Furthermore, the production of collagen-sp ecific IgG2a and IgG2b antibodies was upregulated 10- to 100-fold. As a consequence, the incidence of arthritis in the group of mice immuniz ed with Collagen plus IL-12 was very high (80-100%). The developing ar thritis was severe, involving approximate to 50% of all limbs with str ongly increased footpad thickness in most cases. Furthermore, histolog ical examination revealed massive, mainly polymerphonuclear cell infil tration, synovial hyperplasia, cartilage and bone destruction, as well as new bone formation. In many cases, this resulted in the complete l oss of joint structure. Neutralization of IFN-gamma in vivo prevented the development of arthritis in collagen-immunized and IL-12-treated m ice. In conclusion, our data show that in vivo administered IL-12 can profoundly upregulate a T helper 1-type autoimmune response, resulting in severe joint disease in DBA/1 mice.