Local and Systemic Effects of Intranodally Injected CpG-C Immunostimulatory-Oligodeoxyribonucleotides in Macaques

Abstract

Immunostimulatory CpG-C oligodeoxyribonucleotides (ISS-ODNs) represent a promising strategy to enhance vaccine efficacy. We have shown that the CpG-C ISS-ODN C274 stimulates macaque blood dendritic cells (DCs) and B cells and augments SIV-specific IFN-γ responses in vitro. To further explore the potential of C274 for future vaccine studies, we assessed the in vivo effects of locally administered C274 (in naive and healthy infected macaques). Costimulatory molecules were marginally increased on DCs and B cells within cells isolated from C274-injected lymph nodes (LNs). However, cells from C274-injected LNs exhibited heightened responsiveness to in vitro culture. This was particularly apparent at the level of CD80 (less so CD86) expression by CD123+ plasmacytoid DCs and was further boosted in the presence of additional C274 in vitro. Notably, cells from C274-injected LNs secreted significantly elevated levels of several cytokines and chemokines upon in vitro culture. This was more pronounced when cells were exposed to additional stimuli in vitro, producing IFN-α, IL-3, IL-6, IL-12, TNF-α, CCL2, CCL3, CCL5, and CXCL8. Following C274 administration in the absence of additional SIV Ag, endogenous IFN-γ secretion was elevated in LN cells of infected animals, but SIV-specific responses were unchanged. Endogenous and SIV-specific responses decreased in blood, before the SIV-specific responses rebounded by 2 wk after C274 treatment. Elevated IFN-α, CCL2, and CCL5 were also detected in the plasma after C274 injection. Thus, locally administered C274 has local and systemic activities, supporting the potential for CpG-C ISS-ODNs to boost immune function to enhance anti-HIV vaccine immunogenicity.

Characterization of Plasmacytoid Dendritic Cells in Bone Marrow of Pig-Tailed Macaques

“…with data from previous reports for macaque and human PBpDCs (2,22,48,49); this result also suggests that BM-pDCs, like PB-pDCs, express TLR-7 and TLR-9, the cognate receptors for single-stranded viral RNA and bacterial DNA with hypomethylated CpG motifs. It is interesting, however, that CD86 levels were consistently lower on BM-pDCs than on PB-pDCs in identically treated cultures.…”

A Novel Cancer Therapy by Skin Delivery of Indoleamine 2,3-Dioxygenase siRNA

“…Another possibility is that the small population of activated dendritic cells alters the properties of resident dendritic cells and other immune cells in lymph nodes. Previous results from Robbiani's group have indicated that single intranodal administration of C274 produced local and systemic effects on lymph node cell functions (45). In conclusion, the skin administration of immune regulatory molecules can induce a systemic antitumor immune response without targeting specific tumor-associated antigens.…”

Impaired Naive and Memory B-Cell Responsiveness to TLR9 Stimulation in Human Immunodeficiency Virus Infection

“…In addition to inducing alpha interferon production from pDCs and enhancing antigen-presenting cell function, these microbial products also regulate memory B-cell homeostasis and antibody production (3,28,29). Studies in humans and in nonhuman primate models indicate that CpG ODN administration can enhance vaccine responsiveness (30,31,33).…”