Carman Julie A, Davis Patricia M, Yang Wen-Pin, Zhu Jun, Chang Han, He Aiqing, Truong Amy, Suchard Suzanne J, Nadler Steven G
Discovery Biology, Bristol-Myers Squibb, Princeton, NJ, USA.
J Clin Immunol. 2009 Jul;29(4):479-89. doi: 10.1007/s10875-009-9282-z. Epub 2009 Mar 4.
It has been proposed that ligation of CD80 and CD86 induces reverse signaling into antigen-presenting cells. In this study, we tested the ability of abatacept, a soluble human fusion protein comprising the extracellular domain of cytotoxic T lymphocyte antigen 4 and a fragment of the Fc domain of IgG(1), to activate antigen-presenting cells by measuring changes in global transcriptional responses.
Affymetrix chips were used to measure gene expression levels using mRNA isolated from immature and mature human dendritic cells and a B cell line following 6 h of treatment with abatacept.
In contrast to robust transcriptional responses induced by the control treatment phorbol-12-myristate-13-acetate, abatacept induced minimal gene changes in three different populations of antigen-presenting cells. Furthermore, no gene changes were observed in response to belatacept, a modified version of abatacept that binds with higher avidity to CD80 and CD86.
We conclude that reverse signaling in antigen-presenting cells is unlikely to occur in response to either abatacept or belatacept, thereby supporting the modulation of CD28 signaling on T cells as the main mechanism of action for these therapeutics.
有人提出，CD80和CD86的连接会诱导抗原呈递细胞产生反向信号。在本研究中，我们通过测量整体转录反应的变化，测试了阿巴西普（一种可溶性人融合蛋白，由细胞毒性T淋巴细胞抗原4的细胞外结构域和IgG(1)的Fc结构域片段组成）激活抗原呈递细胞的能力。
使用阿巴西普处理未成熟和成熟的人树突状细胞以及一种B细胞系6小时后，从这些细胞中分离出mRNA，用Affymetrix芯片测量基因表达水平。
与对照处理佛波醇-12-肉豆蔻酸酯-13-乙酸酯诱导的强烈转录反应相反，阿巴西普在三种不同的抗原呈递细胞群体中诱导的基因变化极小。此外，与阿巴西普的修饰版本贝拉西普（它与CD80和CD86的结合亲和力更高）作用后，未观察到基因变化。
我们得出结论，抗原呈递细胞不太可能因阿巴西普或贝拉西普而发生反向信号，从而支持了对T细胞上CD28信号的调节是这些疗法的主要作用机制。
