Regulation of interferon alphabeta induction and dendritic cell function by CpG oligodeoxynucleotides.

摘要

Deoxycytidyl-deoxyguanosine (CpG) oligodeoxynucleotides (ODNs) are single strands of synthetic DNA that mimic bacterial and viral DNA. CpG ODNs are divided into three classes (CpG-A, -B, and -C), which differ in their sequence characteristics and immunomodulatory functions. All three classes signal through TLR9. TLRs and other pattern recognition receptors are under intense therapeutic targeting in attempts to modulate innate and adaptive immune responses with the purpose of treating human immunological disorders. CpG DNA has progressed from successful animal studies to clinical studies in the areas of vaccine adjuvants and therapies for infectious diseases, allergies, asthma, and cancer. The focus of this dissertation is to better understand how CpG ODNs modulate immune function on antigen presenting cells (APCs), particularly murine dendritic cells (DCs). The initial studies examine cross-presentation of particulate Ag by DCs in the presence of CpG ODNs. Cross-presentation plays a major role in driving an adaptive immune response following a pathogenic challenge and gives APCs the ability to activate an adaptive immune response in the absence of self-infection. CpG-B ODNs are not as efficacious as CpG-A and -C ODNs at inducing type-I IFN; however, they are as effective as the other two classes at stimulating MHC-I Ag cross-presentation, a type-I IFN dependent process. These studies also demonstrate that high concentrations of CpG-B selectively inhibit production of type-I IFN induced by other Toll-like receptor (TLR)-9 agonists, as well as other MyD88-dependent and -independent TLR agonists and a non-TLR agonist. The final studies explore the mechanism(s) involved in CpG-B-induced inhibition of type-I IFN and conclude with the possibility that CpG-B, at high (inhibitory) concentrations, may signal via a novel non-TLR9 pathway. Collectively, these studies contribute to a better understanding of how CpG ODNs, particularly CpG-B, modulate DC function in the murine system, offering an additional approach to designing ODN therapies for human use.