Mechanism of action and therapeutic utility of immunosuppressive oligonucleotide

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Studies conducted in my laboratory established that synthetic ODN expressing repetitive TTAGGG motifs (patterned after hexameric sequences present at high frequency in mammalian teleomeres) can down-regulate the inflammatory response elicited by a broad range of TLR ligands and the T cell responses induced by polyclonal activators and antigens. We further documented that suppressive ODN were useful in the treatment of diseases characterized by over-exuberant immune responses, including septic shock and both systemic and organ-specific forms of autoimmunity. 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. Ongoing studies are designed to resolve these questions. We are using fluorescent-labeled probes to identify the cell subsets that bind and internalize suppressive ODN, with plans to track their intracytoplasmic localization using confocal microscopy. We are using microaarray 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 tumor cell growth. Second, studies examining the effect of suppressive ODN on the life-threatening pulmonary inflammation induced by acute silicosis were conducted. Initial results indicate that ODN treatment significantly reduces silica-induced mortality and morbidity. As chronic exposure to silica significantly increases the incidence of lung carcinoma, we plan to evaluate whether suppressive ODN can block silica-induced carcinogenesis. It is hoped that the therapeutic uses of CpG and/or suppressive ODN identified through these research programs can be harnessed to significantly reduce host susceptibility to tumor development and progression.