title: Sterile inflammation induced by Carbopol elicits robust adaptive immune responses in the absence of pathogen-associated molecular patterns.
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.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. Electronic address: Kate.Gartlan@qimrberghofer.edu.au.
authors.forename: Kate H
authors.initials: KH
authors.lastname: Gartlan
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: George
authors.initials: G
authors.lastname: Krashias
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Wegmann
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: William R
authors.initials: WR
authors.lastname: Hillson
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Scherer
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Greenberg
authors.affiliation: Department of Immunobiology, Yale University, New Haven, CT 06519-1612, USA.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Eisenbarth
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Amin E
authors.initials: AE
authors.lastname: Moghaddam
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Quentin J
authors.initials: QJ
authors.lastname: Sattentau
mesh_terms: D000180:Acrylic Resins / Q000494:pharmacology*; D056704:Adaptive Immunity; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D002460:Cell Line; D018925:Chemokines / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G; D007249:Inflammation / Q000276:immunology*; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000069452:Pathogen-Associated Molecular Pattern Molecules; D010587:Phagocytosis; D018417:Th1 Cells / Q000276:immunology
chemical_list: D000180:Acrylic Resins; D000276:Adjuvants, Immunologic; D018925:Chemokines; D016207:Cytokines; D007074:Immunoglobulin G; D000069452:Pathogen-Associated Molecular Pattern Molecules; C006912:carboxypolymethylene
keywords: Antibodies; HIV-1; Polyanionic carbomer; Th1 immune responses; Vaccine adjuvant