Abstract
Carbopol is a polyanionic carbomer used in man for topical application and drug delivery purposes. However parenteral administration of Carbopol in animal models results in systemic adjuvant activity including strong pro-inflammatory type-1 T-cell (Th1) polarization. Here we investigated potential pathways of immune activation by Carbopol by comparison with other well-characterized adjuvants. Carbopol administration triggered rapid and robust leukocyte recruitment, pro-inflammatory cytokine secretion and antigen capture largely by inflammatory monocytes. The induction of antigen specific Th1 cells by Carbopol was found to occur via a non-canonical pathway, independent of MyD88/TRIF signaling and in the absence of pattern-recognition-receptor (PRR) activation typically associated with Th1/Ig2a induction. Using multispectral fluorescence imaging (Imagestream) and electron microscopy we demonstrated that phagocytic uptake of Carbopol particles followed by entry into the phagosomal/lysosomal pathway elicited conformational changes to the polymer and reactive oxygen species (ROS) production. We therefore conclude that Carbopol may mediate its adjuvant activity via novel mechanisms of antigen presenting cell activation and Th1 induction, leading to enhanced IgG2a responses independent of microbial pattern recognition.
Highlights
Adjuvants are essential components of vaccines in which the vaccine antigen lacks robust intrinsic immunogenicity, such as those composed of recombinant or purified subunits of pathogens, or tumor antigens that may require tolerance to be broken
To investigate the potential mode of action of Carbopol, we compared early innate immune responses induced by Carbopol with those induced by Alhydrogel, which elicits a strong Th2/IgG1-associated immune bias [24]
We demonstrate that Carbopol adjuvant activity is accompanied by potent innate immune activation, comprising chemokine and pro-inflammatory cytokine secretion associated with rapid leukocyte recruitment and antigen uptake
Summary
Adjuvants are essential components of vaccines in which the vaccine antigen lacks robust intrinsic immunogenicity, such as those composed of recombinant or purified subunits of pathogens, or tumor antigens that may require tolerance to be broken. In recent years the adjuvant field has made breakthroughs in understanding underlying mechanisms of adjuvant activity, with the discovery of multiple pattern recognition pathways triggering innate and adaptive immune activation [1,2] This has led to the discovery of numerous molecules with adjuvant activity that stimulate the immune system via defined pathways, including those triggered by toll-like receptors (TLRs) [1,2], the NLRP3 inflammasome [3,4] and IRF3 [5,6]. Some of these molecules have made their way into clinical trials and have considerable promise in vaccine development. Other potential modes of adjuvant action are hypothesized to include less specific activities such as the ‘depot’ effect by which the adjuvant sequesters antigen and releases it into the system over time, and local tissue damage resulting in release of intracellular inflammatory mediators such as ATP, nucleic acids, uric acid, IL-25 and IL-33 [6,10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
