Mechanism of action and therapeutic utility of immunosuppressive oligonucleotide

表达重复TTAGGG基序的合成寡核苷酸（ODN）， 在哺乳动物端粒中以高频率存在的六聚体序列下调 由广泛的TLR配体和适应性免疫引起的炎症免疫应答 由多克隆活化剂和抗原诱导的细胞应答。这些抑制性ODN是有用的 用于治疗以过度旺盛的免疫应答为特征的疾病，包括 感染性休克和自身免疫我们最近的研究表明，抑制性ODN也 可用于预防/治疗由二氧化硅引起的危及生命的炎症 吸入（急性硅肺）。具体地说，抑制性ODN治疗显示， 显著降低二氧化硅引起死亡率和发病率。尽管取得了这些进展，但 关于抑制性ODN的细胞靶点，即负责 它们的识别/吸收，或它们的作用机制。我们用微阵列技术 确定基因和调控网络，使抑制性ODN破坏正在进行的 炎症反应，并确定其体内免疫抑制活性的持续时间。 通过这些研究获得的见解，我们计划确定负责的受体 用于识别TTAGGG基序，该基序是这种抑制活性的关键。收集的信息 关于抑制性ODN作用的靶点和机制的研究将支持旨在 探索它们的治疗效用最近的结果表明，全身给药 抑制性ODN可以改变宿主的免疫环境，这种作用被用来减少宿主的免疫应答。 易患炎症诱发的癌症。已启动两项调查 来实现这一目标。第一，抑制性ODN在小鼠模型中的作用， 正在评估化学诱导的皮肤癌。初步证据显示， 影响化学诱导的乳头状瘤的频率和生长。第二，研究 抑制性ODN在慢性矽肺中的作用及其对肺发育的影响 癌症已经开始。希望抑制性ODN的治疗效用 通过这些研究计划确定可以利用，以显着减少主机 对肿瘤发展和进展的易感性。

Synthetic oligonucleotides (ODN) expressing repetitive TTAGGG motifs patterned after hexameric sequences present at high frequency in mammalian teleomeres down-regulate the inflammatory immune responses elicited by a broad range of TLR ligands and the adaptive immune cell responses induced by polyclonal activators and antigens. These suppressive ODN are useful in the treatment of diseases characterized by over-exuberant immune responses, including septic shock and autoimmunity. Our recent studies demonstrate that suppressive ODN are also useful in the prevention/treatment of the life-threatening inflammation caused by silica inhalation (acute silicosis). Specifically, suppressive ODN treatment was shown to significantly reduce silica-induced mortality and morbidity. Despite this progress, very little is known about the cellular targets of suppressive ODN, the receptors responsible for their recognition/uptake, or their mechanism of action. We are using microarray technology to identify the genes and regulatory networks that enable suppressive ODN to disrupt ongoing inflammatory responses and determine the duration of their immuno-inhibitory activity in vivo. With the insight gained from these studies, we plan to identify the receptor(s) responsible for the recognition of the TTAGGG motif key to this suppressive activity. Information gathered on the targets and mechanism(s) of action of suppressive ODN will support studies designed to explore their therapeutic utility. Recent results suggest that systemically administered suppressive ODN can alter the hosts immune milieu, an effect being harnessed to reduce host susceptibility to inflammation-induced cancers. Two lines of investigation have been initiated to achieve this goal. First, the effect of suppressive ODN in a murine model of chemically-induced skin cancer is being evaluated. Preliminary evidence indicates that ODN impact the frequency and growth of chemically induced papillomas. Second, studies examining the effect of suppressive ODN in chronic silicosis, and the attendant development of lung cancer, have been initiated. It is hoped that the therapeutic utility of suppressive ODN identified through these research program can be harnessed to significantly reduce host susceptibility to tumor development and progression.