The unmethylated CpG motifs present in bacterial DNA interact with toll-like receptor 9 to trigger a pro-inflammatory immune response. CpG DNA also improves antigen presenting cell function, thereby facilitating the development of adaptive immunity. Over the past several years, my laboratory established that CpG ODN could reduce host susceptibility to infection and allergic inflammation, were effective as vaccine adjuvants, and had a role in the treatment of cancer. We recently demonstrated that they could also accelerate wound repair. These pre-clinical studies suggest that CpG ODN may be used to both treat established diseases and speed wound healing after trauma or (oncologic) surgery. Based in part on this pre-clinical data, a number of phase I through III clinical trials exploring the safety and efficacy of CpG ODN have been initiated. Ongoing pre-clinical research in my lab is designed to identify the optimal therapeutic window for CpG ODN delivery, and examine whether the protective immune responses they elicit can be accelerated and/or magnified by combining them with other immunomodulatory agents (such as additional TLR ligands and small molecule agonistic immune potentiators). One of the model systems used by my lab to examine the adjuvant activity of CpG ODN involves the anthrax vaccine. Recent results in a relevant mouse model indicate that adding CpG ODN to the currently licensed anthrax vaccine (AVA) prolongs the duration over which protective Ab titers are maintained in vivo by more than four-fold, and generates a higher affinity memory B cell population capable of providing protecting against challenge even after Ab production wanes. Additional results suggest that the adjuvant activity of CpG ODN may be further improved through the use of novel formulations or by combining them with additional immune activators. For example, synergistic interactions were observed when CpG ODN were used in combination with poly I:C. Efforts to optimize the therapeutic utility of CpG ODN require a detailed understanding of the cells they activate (both directly and indirectly), their duration of action, and the regulatory pathways involved in mediating these responses. To clarify these issues, we are using microarray technology to identify the genes and networks central to the immune stimulation elicited by CpG ODN. Such experiments are conducted in vitro on highly purified cell subpopulations and in vivo to monitor gene expression under physiologic conditions. Results indicate that significant changes in gene expression are detectable within 15 minutes of ODN administration and persist for at least 9 days. TNFalpha, IL-1beta, IFNgamma and IL-6 were identified as playing key roles in the initial up-regulation of CpG-mediated gene activation (which involves the expression of at least 700 genes). The degree to which individual genes were activated was influenced by an additional set of co-regulatory genes. Three days post ODN administration, the number of up-regulated genes had fallen by >85%. This effect was mediated in part by a group of down-regulators (including MYC, FOS, and SOCS) that actively suppressed CpG-induced gene expression. By correlating changes in the expression of specific genes with the therapeutic efficacy of CpG ODN in vivo, we hope these studies will identify genetic markers predictive of clinically beneficial outcomes.
| Klinman, Dennis M; Tross, Debra (2009) A single-dose combination therapy that both prevents and treats anthrax infection. Vaccine 27:1811-5 |
| Klinman, Dennis M; Klaschik, Sven; Sato, Takashi et al. (2009) CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases. Adv Drug Deliv Rev 61:248-55 |
| Klaschik, Sven; Tross, Debra; Klinman, Dennis M (2009) Inductive and suppressive networks regulate TLR9-dependent gene expression in vivo. J Leukoc Biol 85:788-95 |
