CD137-mediated T cell co-stimulation terminates existing autoimmune disease in SLE-prone NZB/NZW F1 mice
CD137-mediated T cell co-stimulation terminates existing autoimmune disease in SLE-prone NZB/NZW F1 mice
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DOI：
10.1111/j.1749-6632.2003.tb06052.x
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发表时间：
2003-01-01
期刊：
影响因子：
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通讯作者：
Mittler, RS
中科院分区：
文献类型：
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作者：
Foell, J;McCausland, M;Mittler, RS
T细胞受体对抗原和主要组织相容性复合体的识别（信号1）和T细胞共刺激（信号2）对于T细胞的完全激活、分化以及初始和活化T细胞的存活至关重要。一种典型的T细胞共刺激受体CD28是一种组成性表达的I型整体跨膜蛋白，是Ig超家族的成员。自发现以来，已经发现了更多的T细胞共刺激受体，其中许多属于肿瘤坏死因子受体超家族。这一组包括CD137 (4-1BB)，一种激活诱导的I型跨膜蛋白。通过CD137共刺激T细胞可有效上调CD8 T细胞的活化和存活。虽然CD4(+) T细胞通过T细胞受体和CD137受体有效激活，但它会激发CD4(+) T细胞能量并阻断T依赖性体液免疫反应。因此，我们测试了激动性抗cd137单克隆抗体（mab）是否能有效阻断B细胞依赖性自身免疫性疾病的诱导或进展。在此，我们在NZB/W F1小鼠中证明了拮抗cd137单抗在阻断系统性红斑狼疮（SLE）疾病进展中的保护作用。抗cd137单抗治疗对SLE的保护并不局限于从疾病进展中拯救小鼠；相反，它完全保护幼鼠不出现任何疾病症状。我们进一步发现，用抗cd137治疗蛋白尿小鼠可阻断正在进行的抗dsdna自身抗体的产生。
T cell receptor recognition of antigen and major histocompatibility complex (signal 1) and T cell co-stimulation (signal 2) are essential for full T cell activation, differentiation, and survival of naive and activated T cells. ne prototypical T cell co-stimulatory receptor, CD28, is a constitutively expressed type I integral transmembrane protein and member of the Ig superfamily. Since its discovery, additional T cell co-stimulatory receptors have been identified, a number of which belong to the tumor necrosis factor receptor superfamily. Included within this group is CD137 (4-1BB), an activation-inducible, type I transmembrane protein. Co-stimulation of T cells through CD137 effectively up-regulates CD8 T cell activation and survival. Although CD4(+) T cells are efficiently activated through the T cell receptor and CD137 receptor, it provokes CD4(+) T cell anergy and blockade of T-dependent humoral immune responses. Therefore, we tested whether agonistic anti-CD137 monoclonal antibodies (mAbs) would be effective in blocking the induction or progression of B cell dependent autoimmune disease. Herein, we demonstrate the protective effect of agonistic anti-CD137 mAbs in blocking systemic lupus erythematosus (SLE) disease progression in NZB/W F1 mice. Protection from SLE following anti-CD137 mAb treatment is not confined to rescuing mice from disease progression; rather, it fully protects young mice from developing any symptoms of disease. We further found that treatment of proteinuric mice with anti-CD137 blocks ongoing anti-dsDNA autoantibody production.