Activation of adjuvant core response genes by the novel adjuvant PCEP

Abstract

Adjuvants are critical components of many vaccines but their mechanisms of action are often poorly understood. Understanding the mechanisms of adjuvant activity is critical in defining how innate immunity influenced adaptive immunity. We investigated the capacity of a novel adjuvant, poly[di(sodiumcarboxylatoethylphenoxy)phosphazene] (PCEP), to induce innate immune responses at the site of injection. PCEP induced time-dependent changes in the gene expression of many "adjuvant core response genes" including cytokines, chemokines, innate immune receptors, interferon-induced genes, adhesion molecules and antigen-presentation genes. In addition, PCEP triggered local production of cytokines and the chemokine CCL-2 as indicated by ELISA. Interestingly, PCEP up-regulated the gene expression of the inflammasome receptor, Nlrp3, and induced the production of pro-inflammatory cytokines IL-1β, and IL-18 at the site of injection. Secretion of these cytokines is predominantly a result of activation of the inflammasome, a multi-protein complex that activates caspase-1, leading to the processing and secretion of proinflammatory cytokines. These results suggest that PCEP may modulate antigen-specific immune responses by strongly activating early innate immune responses and promoting a strong immuno-stimulatory environment at the site of injection.