Combination of Intensive Chemotherapy and Anticancer Vaccines in the Treatment of Human Malignancies: The Hematological Experience
Figure 2
The immunostimulatory effect of TLR9 ligation by CpG oligonucleotides. (a) TLR9 is normally activated by nonmethylated CpG dinucleotides (DNA motifs). In vaccination therapy TLR9 can be activated by synthetic oligodeoxynucleotides (ODN) containing CpG motifs (CPG ODN), these molecules can be linked to antigenic peptides (Ag CpG ODN). This complex is endocytosed by dendritic cells (DC); the antigen is then presented and CpG ODN enhances the accessory cell function of the dendritic cells [105–107]. (b) Binding of CpG ODN by TLR9+ dendritic cells initiates signal transduction through members of the IL-1 receptor-associated kinase (IRAK) family, mitogen activated kinases (MAPK) or Interferon (IFN) regulatory factors. These events lead to activation of nuclear factor kappa B (NFB) transcription factors with increased cytokine release and expression of costimulatory molecules [108]. (c) Inhibitory control mechanisms of CpG-mediated immune activation seem to include induction of IL-10, cyclooxygenase-2 (COX-2), NO synthase 2 (NOS-2) and prostaglandin E2 (PGE2). Intravenous administration of CpG ODN to mice induce splenic expression of the enzyme indoleamine 2,3-dioxygenase (IDO) that is an enzyme associated generation of regulatory T cells (Treg) and thereby inhibition of Th1 cells, cytotoxic T cells (Tc cells) and B cells [108].
