Germann T, Szeliga J, Hess H, Störkel S, Podlaski F J, Gately M K, Schmitt E, Rüde E
Institut für Immunologie, Mainz, Germany.
Proc Natl Acad Sci U S A. 1995 May 23;92(11):4823-7. 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 gamma (IFN-gamma) synthesis by ex vivo activated spleen cells was enhanced 3- to 10-fold. IFN-gamma 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 approximately 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-gamma 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 I-type autoimmune response, resulting in severe joint disease in DBA/1 mice.
在DBA/1小鼠中诱导关节炎通常需要用结核分枝杆菌乳化的II型胶原抗原进行免疫。在此我们描述，白细胞介素12（IL-12）可替代分枝杆菌，与II型胶原联合给药时可导致DBA/1小鼠发生严重关节炎。单独用油性乳化的II型胶原免疫DBA/1小鼠会导致免疫反应较弱，只有少数动物（10%-30%）发生关节炎。每次免疫时同时给予IL-12 5天可强烈增强抗II型胶原免疫反应。体外激活的脾细胞产生的胶原特异性干扰素γ（IFN-γ）合成增强3至10倍。IFN-γ几乎完全由CD4+T细胞产生。此外，胶原特异性IgG2a和IgG2b抗体的产生上调10至100倍。因此，用胶原加IL-12免疫的小鼠组中关节炎的发生率非常高（80%-100%）。所发生的关节炎很严重，大多数情况下约50%的四肢受累，足垫厚度显著增加。此外，组织学检查显示有大量主要为多形核细胞浸润、滑膜增生、软骨和骨破坏以及新骨形成。在许多情况下，这导致关节结构完全丧失。体内中和IFN-γ可预防胶原免疫和IL-12处理的小鼠发生关节炎。总之，我们的数据表明，体内给予IL-12可显著上调辅助性T1型自身免疫反应，导致DBA/1小鼠发生严重关节疾病。
