Yue David, Brintnell William, Mannik Lisa A, Christie Darah A, Haeryfar S M Mansour, Madrenas Joaquín, Chakrabarti Subrata, Bell David A, Cairns Ewa
The University of Western Ontario, London, Ontario, Canada.
Arthritis Rheum. 2010 Oct;62(10):2941-52. doi: 10.1002/art.27597.
To assess the role of T cells in the mouse model of citrullinated human fibrinogen-induced rheumatoid arthritis (RA) using CTLA-4Ig, an agent that blocks T cell costimulation, which is required for T cell activation.
Humanized HLA-DRβ1*0401-transgenic (DR4-Tg) mice were immunized with Cit-human fibrinogen to induce arthritis. Prior to, and at the onset or peak of, arthritis, the DR4-Tg mice were treated with CTLA-4Ig or control human IgG1 or were left untreated. Arthritis development and progression were monitored by measuring ankle swelling with calipers and by assessing histopathologic changes. The immune responses to the citrullinated antigens and the corresponding unmodified antigens, as well as the arthritogenicity of lymphocytes from these mice, were examined. The latter was performed using lymphocyte transfers from CTLA-4Ig-treated or control mice via intraperitoneal injection into naive DR4-Tg mice. Recipient mice also received an intraarticular injection of Cit-human fibrinogen, unmodified human fibrinogen, or vehicle.
CTLA-4Ig-treated, but not human IgG1-treated, arthritic mice had significantly reduced ankle swelling and pathologic joint damage. Treatment with CTLA-4Ig, but not human IgG1, suppressed Cit-human fibrinogen-induced T cell activation, including citrulline-specific T cell activation, when given prior to disease onset. Transfer of splenic lymphocytes from untreated or human IgG1-treated arthritic mice caused arthritis in recipients, and this occurred when Cit-human fibrinogen, but not unmodified fibrinogen, was deposited into the joint. Splenocytes from CTLA-4Ig-treated mice were unable to transfer arthritis.
Activated citrulline-specific T cells play a direct role in the development and progression of arthritis in this model of Cit-human fibrinogen-induced RA.
使用CTLA-4Ig评估T细胞在瓜氨酸化人纤维蛋白原诱导的类风湿性关节炎（RA）小鼠模型中的作用，CTLA-4Ig是一种阻断T细胞共刺激的药物，而T细胞共刺激是T细胞活化所必需的。
用人源化HLA-DRβ1*0401转基因（DR4-Tg）小鼠免疫瓜氨酸化人纤维蛋白原以诱导关节炎。在关节炎发作前、发作时或高峰期，给DR4-Tg小鼠注射CTLA-4Ig或对照人IgG1，或不进行治疗。通过用卡尺测量踝关节肿胀和评估组织病理学变化来监测关节炎的发展和进展。检测对瓜氨酸化抗原和相应未修饰抗原的免疫反应，以及这些小鼠淋巴细胞的致关节炎性。后者通过将CTLA-4Ig处理的或对照小鼠的淋巴细胞经腹腔注射到未致敏的DR4-Tg小鼠中来进行。受体小鼠还接受关节内注射瓜氨酸化人纤维蛋白原、未修饰的人纤维蛋白原或赋形剂。
接受CTLA-4Ig治疗而非人IgG1治疗的关节炎小鼠踝关节肿胀和病理性关节损伤明显减轻。在疾病发作前给予CTLA-4Ig而非人IgG1可抑制瓜氨酸化人纤维蛋白原诱导的T细胞活化，包括瓜氨酸特异性T细胞活化。将未治疗的或人IgG1治疗的关节炎小鼠的脾淋巴细胞转移可导致受体小鼠发生关节炎，且当瓜氨酸化人纤维蛋白原而非未修饰的纤维蛋白原注入关节时会出现这种情况。CTLA-4Ig处理的小鼠的脾细胞不能转移关节炎。
在该瓜氨酸化人纤维蛋白原诱导的RA模型中，活化的瓜氨酸特异性T细胞在关节炎的发生和发展中起直接作用。
