Mechanism of action and therapeutic utility of immunosuppressive oligonucleotide

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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 in a relevant murine model. We are in the process of examining whether susceptibility to silica-induced pulmonary tumors can also be reduced by early Rx with suppressive ODN. 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. Microarray studies indicate that very large numbers of genes are rapidly down-regulated following administration of suppressive ODN. We are in the process of studying the regulation of this generalized reduction in mRNA expresssion. 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. Results from a series of experiments indicates that ODN significantly reudce the frequency and size of chemically induced papillomas. Moreover, initiation of therapy after papilloma formation reduces tumor size. 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.