Synthetic oligonucleotides (ODN) expressing multiple TTAGGG motifs patterned after the repetitive 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. Results from my group show that systemically administered Sup ODN alter the host immune milieu and can be harnessed to reduce susceptibility to inflammation- induced cancer. The initial focus of this research examined the effect of Sup ODN in the DMBA/TPA model of skin carcinogenesis. We found that Sup ODN significantly reduced both the number of mice that develop DMBA/TPA dependent papillomas and the number of papillomas/animal in this murine model of inflammation-associated tumorigenesis. To confirm and extend that finding, we initiated studies in a completely different model system of inflammation-promoted tumorigenesis. First, we demonstrated that Sup ODN were effective in preventing/treating the life-threatening pulmonary inflammation caused by silicosis (a disease that affects many miners in the US and abroad). Epidemiologic studies of such miners suggest that the inflammation induced by silica particles (as well as asbestos and coal dust) increases their susceptibility to lung cancer induced by exposure to cigarette smoke. This led us to develop a novel model in which exposure to silica dust plus NNK (a major carcinogen present in cigarette smoke) increases the risk of lung cancer in mice. We've now shown that Sup ODN can be used to significantly reduce silicotic inflammation, and that this returns susceptibility to NNK-induced lung cancer to background levels. To clarify the mechanism by which Sup ODN inhibit tumor development, various measures of inflammation were examined. In both models studied, leukocyte infiltration and the production of pro-inflammatory cytokines and chemokines were significantly reduced whereas control ODN had no significant effect. We are extending these studies to include other agents that cause pulmonary inflammation and disease. We are also using microarray technology to identify the genes and regulatory networks triggered by suppressive ODN. These microarray studies indicate that very large numbers of genes are rapidly down-regulated following the administration of suppressive ODN. Most recently we extended this research to evaluating the effect of Sup ODN in murine models of chronic obstructive pulmonary disease (COPD) and ischemic stroke. In both of those diseases, inflammation increases the severity and extends the duration of pathology. Our findings demonstrate that treatment with Sup ODN effectively reduced inflammation and significantly reduce the severity of both these disease states. We hypothesize that chronic treatment with Sup ODN will be needed to reduce host susceptibility to cancer. Unfortunately, ODN therapy is typically administered parenterally making it difficult to envision long-term human studies/therapy. We've therefore initiated a study to determine if ODN could be delivered orally and retain their activity. Multiple studies of local (GI) and systemic immunity were performed. Results indicate that orally delivered ODN have their primary effect on immune cells in the gut and very little effect systemically. Moreover, encapsulating the ODN to prevent degradation in the stomach has no significant effect on their uptake or activity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010853-11
Application #
9556391
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Steinhagen, Folkert; Zillinger, Thomas; Peukert, Konrad et al. (2018) Suppressive oligodeoxynucleotides containing TTAGGG motifs inhibit cGAS activation in human monocytes. Eur J Immunol 48:605-611
Scheiermann, Julia; Klinman, Dennis M (2016) Suppressive oligonucleotides inhibit inflammation in a murine model of mechanical ventilator induced lung injury. J Thorac Dis 8:2434-2443
Bayik, Defne; Gursel, Ihsan; Klinman, Dennis M (2016) Structure, mechanism and therapeutic utility of immunosuppressive oligonucleotides. Pharmacol Res 105:216-25
Klinman, Dennis M; Sato, Takashi; Shimosato, Takeshi (2016) Use of nanoparticles to deliver immunomodulatory oligonucleotides. Wiley Interdiscip Rev Nanomed Nanobiotechnol 8:631-7
Zhao, Jing; Mou, Yongshan; Bernstock, Joshua D et al. (2015) Synthetic Oligodeoxynucleotides Containing Multiple Telemeric TTAGGG Motifs Suppress Inflammasome Activity in Macrophages Subjected to Oxygen and Glucose Deprivation and Reduce Ischemic Brain Injury in Stroke-Prone Spontaneously Hypertensive Rats. PLoS One 10:e0140772
Klinman, Dennis M (2015) Therapeutic implications of orally delivered immunomodulatory oligonucleotides. Mol Ther 23:222-3
Wandu, Wambui S; Tan, Cuiyan; Ogbeifun, Osato et al. (2015) Leucine-Rich Repeat Kinase 2 (Lrrk2) Deficiency Diminishes the Development of Experimental Autoimmune Uveitis (EAU) and the Adaptive Immune Response. PLoS One 10:e0128906
Bode, Christian; Kinjo, Takeshi; Alvord, W Gregory et al. (2014) Suppressive oligodeoxynucleotides reduce lung cancer susceptibility in mice with silicosis. Carcinogenesis 35:1078-83
Shimada, Masaru; Yoshizaki, Shinji; Ichino, Motohide et al. (2014) Apoptosis of antigen-specific CTLs contributes to low immune response in gut-associated lymphoid tissue post vaccination. Vaccine 32:5198-205
Takahashi, Ryohei; Sato, Takashi; Klinman, Dennis M et al. (2013) Suppressive oligodeoxynucleotides synergistically enhance antiproliferative effects of anticancer drugs in A549 human lung cancer cells. Int J Oncol 42:429-36

Showing the most recent 10 out of 19 publications