ADMINISTRATION OF INTERLEUKIN-12 IN COMBINATION WITH TYPE-II COLLAGEN INDUCES SEVERE ARTHRITIS IN DBA/1 MICE
ADMINISTRATION OF INTERLEUKIN-12 IN COMBINATION WITH TYPE-II COLLAGEN INDUCES SEVERE ARTHRITIS IN DBA/1 MICE
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DOI：
10.1073/pnas.92.11.4823
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发表时间：
1995-05-23
影响因子：
11.1
通讯作者：
RUDE, E
中科院分区：
文献类型：
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作者：
GERMANN, T;SZELIGA, J;RUDE, E
在DBA/1小鼠中诱导关节炎通常需要用在油中与结核分枝杆菌乳化的抗原II型胶原免疫。在这里，我们描述了白细胞介素12（IL-12）可以取代分枝杆菌和DBA/1小鼠的严重关节炎时，与II型胶原蛋白联合给药。用乳化在油中的II型胶原单独免疫DBA/1小鼠导致弱的免疫应答，并且只有少数动物（10 - 30%）发展关节炎。与每次免疫同时施用IL-12 5天强烈增强了抗II型胶原免疫应答。通过离体活化的脾细胞的胶原特异性干扰素γ（IPN-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，用胶原蛋白加IL-12免疫的小鼠组中关节炎的发病率非常高（80 - 100%）。发展中的关节炎是严重的，涉及约50%的所有肢体，在大多数情况下，足垫厚度强烈增加。此外，组织学检查发现大量的，主要是多核细胞浸润，滑膜增生，软骨和骨破坏，以及新骨形成。在许多情况下，这导致关节结构的完全丧失。IFN-γ在体内的中和防止了胶原免疫和IL-12处理的小鼠中关节炎的发展。总之，我们的数据表明，在体内给予IL-12可以深刻上调辅助性T细胞1型自身免疫反应，导致严重的关节疾病的DBA/1小鼠。
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 (IPN-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 approximate to 50% of all limbs with strongly increased footpad thickness in most cases. Furthermore, histological examination revealed massive, mainly polymerphonuclear 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 1-type autoimmune response, resulting in severe joint disease in DBA/1 mice.