Klinman Dennis M, Tross Debbie, Klaschik Sven, Shirota Hidekazu, Sato Takeshi
Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland 21702, USA.
Ann N Y Acad Sci. 2009 Sep;1175:80-8. doi: 10.1111/j.1749-6632.2009.04970.x.
Synthetic oligodeoxynucleotides (ODN) capable of "neutralizing" or "inhibiting" immune responses have been described. This review will focus on the properties of phosphorothioate ODN that mimic the immunosuppressive activity of the repetitive TTAGGG motifs present in mammalian telomeres. These TTAGGG multimers block the production of pro-inflammatory and T helper type 1 cytokines elicited when immune cells are activated by a wide variety of Toll-like receptor ligands, polyclonal activators, and antigens. Several mechanisms contribute to the suppressive activity of such ODN. Ongoing microarray studies indicate that suppressive ODN interfere with the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT4, thereby blocking the inflammation mediated by STAT-associated signaling cascades. In animal models, suppressive ODN can be used to prevent or treat diseases characterized by persistent immune activation, including collagen-induced arthritis, inflammatory arthritis, systemic lupus erythematosus, silicosis, and toxic shock. These findings suggest that TTAGGG multimers may find broad use in the treatment of diseases characterized by over-exuberant/persistent immune activation.
能够“中和”或“抑制”免疫反应的合成寡脱氧核苷酸（ODN）已被报道。本综述将聚焦于硫代磷酸酯ODN的特性，其可模拟哺乳动物端粒中存在的重复TTAGGG基序的免疫抑制活性。这些TTAGGG多聚体可阻断多种Toll样受体配体、多克隆激活剂和抗原激活免疫细胞时引发的促炎细胞因子和辅助性T1型细胞因子的产生。多种机制促成了此类ODN的抑制活性。正在进行的微阵列研究表明，抑制性ODN会干扰信号转导和转录激活因子1（STAT1）和STAT4的磷酸化，从而阻断由STAT相关信号级联介导的炎症反应。在动物模型中，抑制性ODN可用于预防或治疗以持续性免疫激活为特征的疾病，包括胶原诱导的关节炎、炎性关节炎、系统性红斑狼疮、矽肺和中毒性休克。这些发现表明，TTAGGG多聚体可能在治疗以过度活跃/持续性免疫激活为特征的疾病中得到广泛应用。
