Dennis M. Klinman, M.D., Ph.D.
Dr. Klinman co-discovered CpG oligonucleotides (ODN) and demonstrated that they were TLR9 agonists in Man. He pioneered the use of CpG ODN as vaccine adjuvants and immunoprotective agents. He also discovered immunosuppressive ODN and demonstrated their ability to treat/prevent autoimmune and inflammatory diseases. Dr. Klinman’s lab focuses on modifying the innate immune system to alter inflammation and host susceptibility to cancer.
My laboratory is interested in understanding the mechanism by which immunomodulatory DNA alters host susceptibility to cancer, inflammation and infectious diseases. Our research focuses on the ability of immunostimulatory CpG and immunosuppressive TTAGGG oligodeoxynucleotides (ODN) to alter the inflammatory and immune milieu of the host. CpG DNA interacts with toll-like receptor 9 to trigger an innate immune response that improves host resistance to a wide range of infectious microorganisms and tumors. CpG DNA also improves antigen presenting cell function, thereby facilitating the development of an adaptive immune response when co-administered with vaccines encoding pathogen or tumor specific antigens. In contrast, suppressive ODN down-regulate inflammatory responses, delaying the onset and reducing the severity of autoimmune and pro-inflammatory syndromes.
My laboratory has been studying the mechanism of action and therapeutic potential of CpG and suppressive ODN for the past decade. We contributed to the initial discovery of CpG ODN and their immunomodulatory properties, the identification of TLR 9 as the receptor for CpG DNA, the finding that CpG ODN improved host resistance to pathogen and tumor challenge, and the ability of these molecules to act as immune adjuvants, boosting and accelerating the response to therapeutic and prophylactic vaccines. Our studies of suppressive ODN included the discovery of the key TTAGGG motif, the molecular mechanism by which suppressive ODN block T cell responses, and their ability to prevent/treat multiple autoimmune and inflammatory diseases in animal models. We hold numerous licensed patents relating to CpG and suppressive ODN, and our pre-clinical studies examining the immunomodulatory activity and safety of these agents form the basis for a number of ongoing phase I, II and III clinical trials.
Ongoing studies focus on furthering our understanding of the immunomodulatory activity of CpG and suppressive ODN, especially when combined with other immune response modifiers. This includes nalyzing the ability of CpG ODN (alone and in combination with other TLR ligands and small molecule immune potentiators) to accelerate and magnify the protective immune response elicited by vaccines targeting infectious pathogens and tumors. We've identified novel adjuvant combinations/ formulations that significantly improve vaccine-specific immunity, and are pursuing strategies to boost their activity further.
At a more basic level, my lab is interested in the receptors that contribute to the recognition of CpG and suppressive DNA. We will pursue our recent finding that CXCL16 plays a key role in the recognition, uptake, and intracellular localization of 'D' class CpG ODN. We will also evaluate whether other scavenger receptors participate in the recognition of immunomodulatory DNA. To gain a broader perspective on the impact of CpG and suppression ODN on host immunity, we will continue studies using microarray technology to examine the kinetics and magnitude with which genes are activated following exposure to these agents. By correlating the up-regulation of specific genes with the host's subsequent immune responses, we hope to identify genetic markers predictive of clinically effective treatments.
Selected Key Publications
Sequential immunizations with rgp120s from independent isolates of human immunodeficiency virus type 1 induce the preferential expansion of broadly crossreactive B cells.J Exp Med. 173: 881, 1991. [ Journal Article ]
- Nature. 374: 546, 1995. [ Journal Article ]
CpG motifs present in bacterial DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma.Proc Natl Acad Sci USA. 93: 2879, 1996. [ Journal Article ]
- J Immunol. 166: 2372, 2001. [ Journal Article ]
Intratumoral injection of CpG oligonucleotides induces the differentiation and reduces the immunosuppressive activity of myeloid-derived suppressor cells.J Immunol. 188: 1592, 2012. [ Journal Article ]
Dr. Klinman received his MD/PhD from the University of Pennsylvania, and completed his fellowship training in Rheumatology at the National Institute of Arthritis, NIH. He headed the Section of Viral Immunology at the Center for Biologics Evaluation and Research of the FDA before joining the Laboratory of Experimental Immunology of the National Cancer Institute as chief of the Immunoregulation Group. He has authored over 300 peer reviewed articles, received of the FDA's 'Outstanding Scientist of the Year' Award, the 'Outstanding Achievement Award In Biology' from the Washington Academy of Science, and 'Meritorious', 'Outstanding' and 'Distinguished' Service Medals from the Public Health Service, among other honors.
|Christian Bode M.D.||Research Collaborator|
|Emilie Goguet Ph.D.||Postdoctoral Fellow (Visiting)|
|Begum Horuluoglu MSc.||Predoctoral Fellow (Visiting)|
|Neslihan Kayraklioglu M.D.||Postdoctoral Fellow (Visiting)|
|Folkert W Steinhagen M.D.||Research Collaborator|
|Debra Tross-Currie||Research Biologist|