Hypercostimulation through 4-1BB distorts homeostasis of immune cells.
Hypercostimulation through 4-1BB distorts homeostasis of immune cells.
复制标题
DOI：
10.4049/jimmunol.0803241
复制
发表时间：
2009-06-01
期刊：
影响因子：
--
通讯作者：
Croft M
中科院分区：
文献类型：
--
作者：
Lee SW;Salek-Ardakani S;Mittler RS;Croft M
与最近使用抗CD 28超激动剂抗体的临床试验相关的有害副作用已经质疑了在人类治疗中使用共刺激分子的试剂。我们现在表明，持续的信号从激动剂抗体4-1BB，肿瘤坏死因子受体（TNFR）超家族的成员，结果在免疫细胞的稳态有害影响。在植入骨髓的辐射小鼠或感染牛痘病毒的小鼠中，在造血细胞重建期间重复抗4-1BB治疗诱导骨髓中前和未成熟B细胞的异常凋亡，并导致外周B细胞耗竭。对B细胞发育的抑制是间接的，是由于CD 8 T细胞的共刺激和依赖于IFN-γ。此外，抗4-1BB也抑制NK和NKT细胞的发育，但在这种情况下，独立于T细胞和IFN-γ。NK细胞稳态的改变是由抗4-1BB触发的激活诱导的细胞死亡引起的。这些结果表明，超共刺激激发强大的T细胞免疫，但它可以同时扭曲免疫稳态，这表明，在任何免疫策略中，需要仔细注意的活动，剂量和治疗周期与共刺激分子的激动剂抗体。
The deleterious side-effects associated with a recent clinical trial with anti-CD28 super-agonist antibodies have questioned the use of reagents to costimulatory molecules in human therapy. We now show that sustained signaling from an agonist antibody to 4-1BB, a member of the tumor necrosis factor receptor (TNFR) superfamily, results in detrimental effects on immune cell homeostasis. Repeated anti-4-1BB treatment during the reconstitution of hematopoietic cells in irradiated mice engrafted with bone marrow, or in mice infected with vaccinia virus, induced abnormal apoptosis of pre- and immature-B cells in the bone marrow, and led to peripheral B cell depletion. Inhibition of B cell development was indirect and due to costimulation of CD8 T cells and dependent on IFN-γ. Moreover, anti-4-1BB also suppressed the development of NK and NKT cells, but in this case independently of T cells and IFN-γ. The altered NK cell homeostasis resulted from activation-induced cell death triggered by anti-4-1BB. These results show that hyper-costimulation elicits strong T cell immunity, but it can simultaneously distort immune homeostasis, suggesting that careful attention to activity, dose, and periodicity of treatment will be needed in any immunotherapeutic strategy with agonist antibodies to costimulatory molecules.
登录
查看更多内容
影响因子：
15.9
作者：
Polte, T;Foell, J;Hansen, G
通讯作者：
Hansen, G
影响因子：
4.4
作者：
Kim, Dong-Hyeon;Chang, Woo-Sung;Kang, Chang-Yuil
通讯作者：
Kang, Chang-Yuil
影响因子：
20.3
作者：
Bourdeau, Annie;Dube, Nadia;Tremblay, Michel L.
通讯作者：
Tremblay, Michel L.
影响因子：
32.4
作者：
Arens, R;Tesselaar, K;van Lier, RAW
通讯作者：
van Lier, RAW
影响因子：
4.4
作者：
Shaikh, RB;Santee, S;Ware, CF
通讯作者：
Ware, CF