title: Retinoic acid and polyriboinosinic:polyribocytidylic acid stimulate robust anti-tetanus antibody production while differentially regulating type 1/type 2 cytokines and lymphocyte populations.
abstract: Retinoic acid (RA), a bioactive retinoid, and polyriboinosinic:polyribocytidylic acid (PIC) are known to promote immunity in vitamin A-deficient animals. In this study, we hypothesized that RA, PIC, and the combination can provide significant immunoadjuvant activity even in the vitamin A-adequate state. Six-week-old C57BL/6 mice were immunized with tetanus toxoid (TT) and treated with RA and/or PIC at priming in three independent studies of short and long duration. RA and PIC differentially regulated both primary and secondary anti-TT IgG isotypes, whereas the combination of RA + PIC stimulated the highest level of anti-TT IgG production and, concomitantly, a ratio of IgG1 to IgG2a similar to that of the control group. The regulation of Ab response was strongly associated with type 1/type 2 cytokine gene expression. Whereas RA reduced type 1 cytokines (IFN-gamma and IL-12), PIC enhanced both type 1 and type 2 cytokines (IL-4 and IL-12) and cytokine-related transcription factors. Despite the presence of PIC, the IL-4:IFN-gamma ratio was significantly elevated by RA. In addition, RA and/or PIC modulated NK/NKT cell populations and the level of expression of the costimulatory molecules CD80/CD86, evident 3 days after priming. Notably, the NKT:NK and CD80:CD86 ratios were correlated with the IL-4:IFN-gamma ratio, indicative of multiple converging modes of regulation. Overall, RA, PIC, and RA + PIC rapidly and differentially shaped the anti-tetanus Ig response. The robust, durable, and proportionate increase in all anti-TT IgG isotypes induced by RA + PIC suggests that this combination is promising as a means to enhance the Ab response to TT and similar vaccines.
authors.affiliation: Integrative Biosciences Nutritional Sciences Program, Department of Nutritional Sciences, and Huck Institute for the Life Sciences, Pennsylvania State University, University Park, PA 16801, USA.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Ma
authors.forename: Qiuyan
authors.initials: Q
authors.lastname: Chen
authors.forename: A Catharine
authors.initials: AC
authors.lastname: Ross
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004338:Drug Combinations; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D007117:Immunization, Secondary; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011119:Polynucleotides / Q000008:administration & dosage / Q000276:immunology*; D013745:Tetanus Toxoid / Q000008:administration & dosage / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014212:Tretinoin / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D016207:Cytokines; D004338:Drug Combinations; D011119:Polynucleotides; D013745:Tetanus Toxoid; C049667:poly(rI).poly(dC); D014212:Tretinoin