Administration of Interleukin 12 in Combination with Type II Collagen Induces Severe Arthritis in DBA/1 Mice

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 92; no. 11; pp. 4823 - 4827
• Main Authors: Germann, Tieno, Szeliga, Jacek, Hess, Henry, Storkel, Stefan, Podlaski, Frank J., Gately, Maurice K., Schmitt, Edgar, Rude, Erwin
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 23.05.1995; National Acad Sciences; National Academy of Sciences
• Subjects: Animals; Antibodies; Antibody Formation; Arthritis; Arthritis, Experimental - chemically induced; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; CD4-Positive T-Lymphocytes - immunology; Chickens; Collagen; Collagens; Drug Interactions; Hindlimb; Histology; Immunity (Disease); Immunization; Inflammation; Interferon-gamma - biosynthesis; Interleukin-12; Joint diseases; Mice; Mice, Inbred DBA; Rodents; Spleen cells; Swelling; T lymphocytes; Time Factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.11.4823

The induction of arthritis in DBA/1 mice usually requires immunization with the antigen type II collagen emulsified with Mycobacterium tuberculosis in oil. Here we describe that interleukin 12 (IL-12) can replace mycobacteria and cause severe arthritis of DBA/1 mice when administered in combination with type II collagen. Immunization of DBA/1 mice with type II collagen emulsified in oil alone resulted in a weak immune response, and only a few animals (10-30%) developed arthritis. Administration of IL-12 for 5 days simultaneously with each immunization strongly enhanced the anti-type II collagen immune response. Collagen-specific interferon γ (IFN-γ) synthesis by ex vivo activated spleen cells was enhanced 3- to 10-fold. IFN-γ was almost completely produced by CD4+T cells. Furthermore, the production of collagen-specific IgG2a and IgG2b antibodies was upregulated 10- to 100-fold. As a consequence, the incidence of arthritis in the group of mice immunized with collagen plus IL-12 was very high (80-100%). The developing arthritis was severe, involving ≈50% of all limbs with strongly increased footpad thickness in most cases. Furthermore, histological examination revealed massive, mainly polymorphonuclear cell infiltration, synovial hyperplasia, cartilage and bone destruction, as well as new bone formation. In many cases, this resulted in the complete loss of joint structure. Neutralization of IFN-γ in vivo prevented the development of arthritis in collagen-immunized and IL-12-treated mice. 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.