Foell Juergen, McCausland Megan, Burch Jennifer, Corriazzi Nicholas, Yan Xiao-Jie, Suwyn Carolyn, O'Neil Shawn P, Hoffmann Michael K, Mittler Robert S
Department of Surgery, Emory University School of Medicine, Atlanta, Georgia 30329, USA.
Ann N Y Acad Sci. 2003 Apr;987:230-5. doi: 10.1111/j.1749-6632.2003.tb06052.x.
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 naïve and activated T cells. The proto-typical 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.
T细胞对抗原和主要组织相容性复合体的识别（信号1）以及T细胞共刺激（信号2）对于初始T细胞和活化T细胞的完全激活、分化及存活至关重要。典型的T细胞共刺激受体CD28是一种组成性表达的I型整合跨膜蛋白，属于免疫球蛋白超家族成员。自其被发现以来，已鉴定出其他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。该组包括CD137（4-1BB），一种激活诱导型I型跨膜蛋白。通过CD137对T细胞进行共刺激可有效上调CD8 T细胞的激活和存活。尽管CD4(+) T细胞可通过T细胞受体和CD137受体被有效激活，但它会引发CD4(+) T细胞无反应性并阻断T细胞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，我们证明了激动性抗CD137 mAb在阻断NZB/W F1小鼠系统性红斑狼疮（SLE）疾病进展中的保护作用。抗CD137 mAb治疗对SLE的保护作用不仅限于使小鼠免于疾病进展；相反，它能完全保护幼鼠不出现任何疾病症状。我们还进一步发现，用抗CD137治疗蛋白尿小鼠可阻断正在进行的抗双链DNA自身抗体的产生。
