CHRONIC EXPOSURE TO TUMOR-NECROSIS-FACTOR (TNF) IN-VITRO IMPAIRS THE ACTIVATION OF T-CELLS THROUGH THE T-CELL RECEPTOR CD3 COMPLEX - REVERSAL IN-VIVO BY ANTI-TNF ANTIBODIES IN PATIENTS WITH RHEUMATOID-ARTHRITIS
CHRONIC EXPOSURE TO TUMOR-NECROSIS-FACTOR (TNF) IN-VITRO IMPAIRS THE ACTIVATION OF T-CELLS THROUGH THE T-CELL RECEPTOR CD3 COMPLEX - REVERSAL IN-VIVO BY ANTI-TNF ANTIBODIES IN PATIENTS WITH RHEUMATOID-ARTHRITIS
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DOI：
10.1172/jci117394
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发表时间：
1994-08-01
影响因子：
15.9
通讯作者：
FELDMANN, M
中科院分区：
文献类型：
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作者：
COPE, AP;LONDEI, M;FELDMANN, M
实验旨在验证慢性暴露于肿瘤坏死因子α (TNF)会改变活化T淋巴细胞功能的假设。用TNF预处理破伤风类毒素特异性T细胞克隆长达16天，以剂量和时间依赖的方式损害对抗原的再挑战增殖反应。IL-2和PHA反应得以保留。与未处理的对照细胞相比，长期使用TNF治疗后，固定OKT3刺激后IL-2、IL-10、IFN γ、TNF和淋巴素（LT）的产生受损，导致IL-2R α链（Tac）的表达不佳，但CD3、CD4或HLA-DR抗原的表达不佳。相比之下，用中和的抗tnf单克隆抗体（mAb）在体外长时间预处理T细胞，可以增强增殖反应，增加淋巴因子的产生，并在OKT3刺激后上调Tac的表达。为了确定TNF是否在体内对T细胞产生免疫抑制作用，我们研究了活动性类风湿关节炎（RA）患者在使用嵌合抗TNF单抗治疗前后的细胞介导免疫。抗肿瘤坏死因子治疗恢复了PBMC对有丝分裂原的增殖反应，并使所有患者的抗原恢复正常。这些数据表明，TNF在体外和体内的持续表达会损害细胞介导的免疫反应。
Experiments were designed to test the hypothesis that chronic exposure to tumor necrosis factor alpha (TNF) alters the function of activated T lymphocytes. Pretreatment of tetanus toxoid-specific T cell clones with TNF for up to 16 d impaired rechallenge proliferative responses to antigen in a dose- and time-dependent fashion. IL-2 and PHA responses were preserved. Prolonged treatment with TNF impaired production of IL-2, IL-10, IFN gamma, TNF, and lymphotoxin (LT) following stimulation with immobilized OKT3, and resulted in suboptimal expression of the IL-2R alpha chain (Tac) but not CD3, CD4, or HLA-DR antigens, when compared to untreated control cells. By contrast, pretreatment of T cells for prolonged periods in vitro with neutralizing anti-TNF monoclonal antibodies (mAb) enhanced proliferative responses, increased lymphokine production, and upregulated Tac expression following stimulation with OKT3. To determine whether TNF exerts immunosuppressive effects on T cells in vivo, we studied cell-mediated immunity in patients with active rheumatoid arthritis (RA), before and after treatment with a chimeric anti-TNF mAb. Treatment with anti-TNF restored the diminished proliferative responses of PBMC to mitogens and recall antigens towards normal in all patients tested. These data demonstrate that persistent expression of TNF in vitro and in vivo impairs cell-mediated immune responses.