Matsumoto Isao, Zhang Hua, Yasukochi Takanori, Iwanami Keiichi, Tanaka Yoko, Inoue Asuka, Goto Daisuke, Ito Satoshi, Tsutsumi Akito, Sumida Takayuki
Division of Clinical Immunology, Major of Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai, Tsukuba 305-8575, Japan.
Arthritis Res Ther. 2008;10(3):R66. doi: 10.1186/ar2437. Epub 2008 Jun 5.
Immunization with glucose-6-phosphate isomerase (GPI) induces severe arthritis in DBA/1 mice. The present study was designed to identify the cytokines and co-stimulatory molecules involved in the development of GPI-induced arthritis.
Arthritis was induced in DBA/1 mice with 300 microg human recombinant GPI. CD4+ T cells and antigen-presenting cells from splenocytes of arthritic mice were cultured in the presence of GPI. Tumor necrosis factor (TNF)-alpha, IFN-gamma, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12 levels were assessed using cytometric bead array. Monoclonal antibodies to TNF-alpha, IFN-gamma, IL-12, CD40L, inducible co-stimulator (ICOS), and cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA-4Ig) were used to block TNF-alpha and IFN-gamma production, examine clinical index in mice with GPI-induced arthritis, and determine anti-GPI antibody production.
Large amounts of TNF-alpha and IFN-gamma and small amounts of IL-2 and IL-6 were produced by splenocytes from mice with GPI-induced arthritis. Anti-TNF-alpha mAbs and CTLA-4Ig suppressed TNF-alpha production, whereas anti-IFN-gamma mAbs, anti-IL-12 mAbs, and CTLA-4 Ig inhibited IFN-gamma production. A single injection of anti-TNF-alpha and anti-IL-6 mAbs and two injections of CTLA-4Ig reduced the severity of arthritis in mice, whereas injections of anti-IFN-gamma and anti-IL-12 mAbs tended to exacerbate arthritis. Therapeutic efficacy tended to correlate with reduction in anti-GPI antibodies.
TNF-alpha and IL-6 play an important role in GPI-induced arthritis, whereas IFN-gamma appears to function as a regulator of arthritis. Because the therapeutic effects of the tested molecules used in this study are similar to those in patients with rheumatoid arthritis, GPI-induced arthritis appears to be a suitable tool with which to examine the effect of various therapies on rheumatoid arthritis.
用葡萄糖-6-磷酸异构酶（GPI）免疫可诱导DBA/1小鼠发生严重关节炎。本研究旨在确定参与GPI诱导性关节炎发生发展的细胞因子和共刺激分子。
用300微克人重组GPI诱导DBA/1小鼠发生关节炎。将关节炎小鼠脾细胞中的CD4+T细胞和抗原呈递细胞在GPI存在的情况下进行培养。使用细胞计数珠阵列评估肿瘤坏死因子（TNF）-α、干扰素-γ、白细胞介素-2、白细胞介素-4、白细胞介素-5、白细胞介素-6、白细胞介素-10和白细胞介素-12的水平。使用抗TNF-α、干扰素-γ、白细胞介素-12、CD40L、诱导性共刺激分子（ICOS）和细胞毒性T淋巴细胞抗原4免疫球蛋白（CTLA-4Ig）的单克隆抗体来阻断TNF-α和干扰素-γ的产生，检查GPI诱导性关节炎小鼠的临床指标，并确定抗GPI抗体的产生。
GPI诱导性关节炎小鼠的脾细胞产生大量TNF-α和干扰素-γ以及少量白细胞介素-2和白细胞介素-6。抗TNF-α单克隆抗体和CTLA-4Ig抑制TNF-α的产生，而抗干扰素-γ单克隆抗体、抗白细胞介素-12单克隆抗体和CTLA-4Ig抑制干扰素-γ的产生。单次注射抗TNF-α和抗白细胞介素-6单克隆抗体以及两次注射CTLA-4Ig可减轻小鼠关节炎的严重程度，而注射抗干扰素-γ和抗白细胞介素-12单克隆抗体则倾向于加重关节炎。治疗效果倾向于与抗GPI抗体的减少相关。
TNF-α和白细胞介素-6在GPI诱导性关节炎中起重要作用，而干扰素-γ似乎作为关节炎的调节因子发挥作用。由于本研究中使用的受试分子的治疗效果与类风湿关节炎患者的相似，GPI诱导性关节炎似乎是一种合适的工具，可用于研究各种疗法对类风湿关节炎的影响。
