Mechanism of action and therapeutic utility of immunosuppressive oligonucleotide

根据哺乳动物端粒中高频存在的六聚体序列，表达重复的TTAGGG基序的人工合成寡核苷酸(ODN)下调广泛的TLR配体诱导的炎性免疫反应以及多克隆激活剂和抗原诱导的获得性免疫细胞反应。这些抑制性ODN在治疗以过度活跃的免疫反应为特征的疾病方面很有用，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在预防/治疗由二氧化硅吸入引起的危及生命的炎症(急性矽肺)方面也是有用的。具体地说，抑制性ODN治疗被证明显著降低了二氧化硅诱导的死亡率和发病率。尽管取得了这些进展，但对抑制性ODN的细胞靶点、负责识别/摄取它们的受体或它们的作用机制知之甚少。我们正在使用微阵列技术来识别使抑制性ODN能够扰乱正在进行的炎症反应的基因和调控网络，并确定它们在体内的免疫抑制活性的持续时间。根据这些研究获得的见解，我们计划确定负责识别这种抑制活动的关键的TTAGGG基序的受体(S)。收集到的有关抑制性寡核苷酸作用靶点和作用机制(S)的信息将支持旨在探索其治疗效用的研究。最近的研究结果表明，全身给药的抑制性ODN可以改变宿主的免疫环境，这种作用被利用来降低宿主对炎症诱导的癌症的易感性。为实现这一目标，已经启动了两条调查路线。首先，正在评估抑制性ODN在化学诱导的皮肤癌小鼠模型中的作用。初步证据表明，ODN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在慢性矽肺及其伴随的肺癌发展中的作用的研究已经启动。希望通过这些研究项目确定的抑制性ODN的治疗作用可以被利用来显著降低宿主对肿瘤发生和进展的易感性。

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.