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Expert Review of Vaccines Volume 8, 2009 - Issue 9
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Special Focus Issues: DNA Vaccines - Review

Dendritic cell-targeting DNA-based mucosal adjuvants for the development of mucosal vaccines

Kosuke Kataoka Department of Preventive Dentistry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504, Japan. [email protected]
&
Kohtaro Fujihashi Departments of Pediatric Dentistry and Microbiology, The Immunobiology Vaccine Center, The University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA. [email protected]
Pages 1183-1193 | Published online: 09 Jan 2014

  • Fujihashi K, Prosper BN, McGhee JR. Host defenses at mucosal surfaces. In: Clinical Immunology (Third Edition). Rich RT, Fleisher TA, Shearer WT et al. (Eds). Mosby Elsevier, PA, USA 287–304 (2008).
  • Kiyono H, Kunisawa J, McGhee JR, Mestecky J. The mucosal immune system. In: Fundamental Immunology (Fifth Edition). Paul WE (Ed.). Lippincott Williams & Wilkins, PA, USA 983–1030 (2008).
  • Dubin PJ, Kolls JK. Th17 cytokines and mucosal immunity. Immunol. Rev.226, 160–171 (2008).
  • Fuss IJ, Strober W. The role of IL-13 and NK T cells in experimental and human ulcerative colitis. Mucosal Immunol.1(Suppl. 1), S31–S33 (2008).
  • Kitani A, Xu L. Regulatory T cells and the induction of IL-17. Mucosal Immunol.1(Suppl. 1), S43–S46 (2008).
  • Maloy KJ, Kullberg MC. IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol.1(5), 339–349 (2008).
  • Cerutti A, Qiao X, He B. Plasmacytoid dendritic cells and the regulation of immunoglobulin heavy chain class switching. Immunol. Cell Biol.83(5), 554–562 (2005).
  • Fleeton M, Contractor N, Leon F et al. Involvement of dendritic cell subsets in the induction of oral tolerance and immunity. Ann. NY Acad. Sci.1029, 60–65 (2004).
  • Litinskiy MB, Nardelli B, Hilbert DM et al. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat. Immunol.3(9), 822–829 (2002).
  • Irache JM, Salman HH, Gamazo C, Espuelas S. Mannose-targeted systems for the delivery of therapeutics. Expert Opin. Drug Deliv.5(6), 703–724 (2008).
  • Salman HH, Gamazo C, Agueros M, Irache JM. Bioadhesive capacity and immunoadjuvant properties of thiamine-coated nanoparticles. Vaccine25(48), 8123–8132 (2007).
  • Xu-Amano J, Kiyono H, Jackson RJ et al. Helper T cell subsets for immunoglobulin A responses: oral immunization with tetanus toxoid and cholera toxin as adjuvant selectively induces Th2 cells in mucosa associated tissues. J. Exp. Med.178, 1309–1320 (1993).
  • Dickinson BL, Clements JD. Dissociation of Escherichia coli heat-labile enterotoxin adjuvanticity from ADP-ribosyltransferase activity. Infect. Immun.63(5), 1617–1623 (1995).
  • Douce G, Turcotte C, Cropley I et al. Mutants of Escherichia coli heat-labile toxin lacking ADP-ribosyltransferase activity act as nontoxic, mucosal adjuvants. Proc. Natl Acad. Sci. USA92(5), 1644–1648 (1995).
  • Hagiwara Y, McGhee JR, Fujihashi K et al. Protective mucosal immunity in aging is associated with functional CD4+ T cells in nasopharyngeal-associated lymphoreticular tissue. J. Immunol.170, 1754–1762 (2003).
  • Marinaro M, Staats HF, Hiroi T et al. Mucosal adjuvant effect of cholera toxin in mice results from induction of T helper 2 (Th2) cells and IL-4. J. Immunol.155, 4621–4629 (1995).
  • Yamamoto S, Kiyono H, Yamamoto M et al. A nontoxic mutant of cholera toxin elicits Th2-type responses for enhanced mucosal immunity. Proc. Natl Acad. Sci. USA94(10), 5267–5272 (1997).
  • Yamamoto S, Takeda Y, Yamamoto M et al. Mutants in the ADP-ribosyltransferase cleft of cholera toxin lack diarrheagenicity but retain adjuvanticity. J. Exp. Med.185(7), 1203–1210 (1997).
  • Takahashi I, Marinaro M, Kiyono H et al. Mechanisms for mucosal immunogenicity and adjuvancy of Escherichia coli labile enterotoxin. J. Infect. Dis.173(3), 627–635 (1996).
  • de Haan L, Verweij WR, Feil IK et al. Mutants of the Escherichia coli heat-labile enterotoxin with reduced ADP-ribosylation activity or no activity retain the immunogenic properties of the native holotoxin. Infect. Immun.64(12), 5413–5416 (1996).
  • Douce G, Fontana M, Pizza M, Rappuoli R, Dougan G. Intranasal immunogenicity and adjuvanticity of site-directed mutant derivatives of cholera toxin. Infect. Immun.65(7), 2821–2828 (1997).
  • Fontana MR, Manetti R, Giannelli V et al. Construction of nontoxic derivatives of cholera toxin and characterization of the immunological response against the A subunit. Infect. Immun.63(6), 2356–2360 (1995).
  • Giuliani MM, Del Giudice G, Giannelli V et al. Mucosal adjuvanticity and immunogenicity of LTR72, a novel mutant of Escherichia coli heat-labile enterotoxin with partial knockout of ADP-ribosyltransferase activity. J. Exp. Med.187(7), 1123–1132 (1998).
  • Lycke N, Tsuji T, Holmgren J. The adjuvant effect of Vibrio cholerae and Escherichia coli heat-labile enterotoxins is linked to their ADP-ribosyltransferase activity. Eur. J. Immunol.22(9), 2277–2281 (1992).
  • Di Tommaso A, Saletti G, Pizza M et al. Induction of antigen-specific antibodies in vaginal secretions by using a nontoxic mutant of heat-labile enterotoxin as a mucosal adjuvant. Infect. Immun.64(3), 974–979 (1996).
  • Pizza M, Fontana MR, Giuliani MM et al. A genetically detoxified derivative of heat-labile Escherichia coli enterotoxin induces neutralizing antibodies against the A subunit. J. Exp. Med.180(6), 2147–2153 (1994).
  • Hagiwara Y, Kawamura YI, Kataoka K et al. A second generation of double mutant cholera toxin adjuvants: enhanced immunity without intracellular trafficking. J. Immunol.177(5), 3045–3054 (2006).
  • Marinaro M, Boyaka PN, Jackson RJ et al. Use of intranasal IL-12 to target predominantly Th1 responses to nasal and Th2 responses to oral vaccines given with cholera toxin. J. Immunol.162(1), 114–121 (1999).
  • Boyaka PN, Marinaro M, Jackson RJ et al. IL-12 is an effective adjuvant for induction of mucosal immunity. J. Immunol.162(1), 122–128 (1999).
  • Arulanandam BP, O’Toole M, Metzger DW. Intranasal interleukin-12 is a powerful adjuvant for protective mucosal immunity. J. Infect. Dis.180(4), 940–949 (1999).
  • Lynch JM, Briles DE, Metzger DW. Increased protection against pneumococcal disease by mucosal administration of conjugate vaccine plus interleukin-12. Infect. Immun.71(8), 4780–4788 (2003).
  • Marinaro M, Boyaka PN, Finkelman FD et al. Oral but not parenteral interleukin (IL)-12 redirects T helper 2 (Th2)-type responses to an oral vaccine without altering mucosal IgA responses. J. Exp. Med.185(3), 415–427 (1997).
  • Staats HF, Ennis FA Jr. IL-1 is an effective adjuvant for mucosal and systemic immune responses when coadministered with protein immunogens. J. Immunol.162(10), 6141–6147 (1999).
  • Lillard JW Jr, Boyaka PN, Chertov O, Oppenheim JJ, McGhee JR. Mechanisms for induction of acquired host immunity by neutrophil peptide defensins. Proc. Natl Acad. Sci. USA96, 651–656 (1999).
  • Lillard JW Jr, Boyaka PN, Hedrick JA, Zlotnik A, McGhee JR. Lymphotactin acts as an innate mucosal adjuvant. J. Immunol.162(4), 1959–1965 (1999).
  • Borthwick NJ, Akbar AN, MacCormac LP et al. Selective migration of highly differentiated primed T cells, defined by low expression of CD45RB, across human umbilical vein endothelial cells: effects of viral infection on transmigration. Immunology90(2), 272–280 (1997).
  • Kelsall BL, Strober W. Distinct populations of dendritic cells are present in the subepithelial dome and T cell regions of the murine Peyer’s patch. J. Exp. Med.183, 237–247 (1996).
  • Iwasaki A, Kelsall BL. Localization of distinct Peyer’s patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3α, MIP-3β and secondary lymphoid organ chemokine. J. Exp. Med.191, 1381–1394 (2000).
  • Bernstein JM. Waldeyer’s ring and otitis media: the nasopharyngeal tonsil and otitis media. Int. J. Pediatr. Otorhinolaryngol.49(Suppl. 1), S127–S132 (1999).
  • McWilliam AS, Napoli S, Marsh AM et al. Dendritic cells are recruited into the airway epithelium during the inflammatory response to a broad spectrum of stimuli. J. Exp. Med.184, 2429–2432 (1996).
  • Stumbles PA, Thomas, JA, Pimm CL et al. Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity. J. Exp. Med.188, 2019–2031 (1998).
  • Facchetti F, Candiago, E, Vermi W. Plasmacytoid monocytes express IL-3-receptor a and differentiate into dendritic cells. Histopathology35, 88–89 (1999).
  • Grouard G, Rissoan MC, Filgueira L, Durand I, Banchereau J, Liu YJ. The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3 and CD40-ligand. J. Exp. Med.185, 1101–1111 (1997).
  • Siegal FP, Kadowaki N, Shodell M et al. The nature of the principal type 1 interferon-producing cells in human blood. Science284, 1835–1837 (1999).
  • Perussia B, Fanning V, Trinchieri G. A leukocyte subset bearing HLA-DR antigens is responsible for in vitro a interferon production in response to viruses. Nat. Immun. Cell Growth Regul.4, 120–137 (1985).
  • Kadowaki N, Antonenko S, Liu Y-J. Distinct CpG DNA and polyinosinic–polycytidylic acid double-stranded RNA, respectively, stimulate CD11c- type 2 dendritic cell precursors and CD11c+ dendritic cells to produce type I IFN. J. Immunol.166, 2291–2295 (2001).
  • Rissoan MC, Soumelis V, Kadowaki N et al. Reciprocal control of T helper cell and dendritic cell differentiation. Science283, 1183–1186 (1999).
  • Starr SE, Bandyopadhyay S, Shanmugam V et al. Morphological and functional differences between HLA-DR+ peripheral blood dendritic cells and HLA-DR+ IFN-α producing cells. Adv. Exp. Med. Biol.329, 173–178 (1993).
  • Dubois B, Bridon JM, Fayette J et al. Dendritic cells directly modulate B cell growth and differentiation. J. Leukoc. Biol.66, 224–230 (1999).
  • Zitvogel L. Dendritic and natural killer cells cooperate in the control/switch of innate immunity. J. Exp. Med.195(3), F9–F14 (2002).
  • Liu Y-J. Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell106, 259–262 (2001).
  • Bjorck P. Isolation and characterization of plasmacytoid dendritic cells from Flt3 ligand and granulocyte–macrophage colony-stimulating factor-treated mice. Blood98, 3520–3526 (2001).
  • Asseli-Patureln C, Boonstra A, Dalod M et al. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat. Immunol.2, 1144–1150 (2001).
  • Nakano H, Yanagita M, Gunn MD. CD11c+B220+Gr-1+ cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. J. Exp. Med.194, 1171–1178 (2001).
  • Manfra DJ, Chen SC, Jensen KK, Fine JS, Wiekowski MT, Lira SA. Conditional expression of murine flt3 ligand leads to expansion of multiple dendritic cell subsets in peripheral blood and tissues of transgenic mice. J. Immunol.170, 2843–2852 (2003).
  • Gilliet M, Boonstra A, Paturel C et al. The development of murine plasmacytoid dendritic cell precursors is differentially regulated by FLT3-ligand and granulocyte/macrophage colony-stimulating factor. J. Exp. Med.195, 953–958 (2002).
  • Brawand P, Fitzpatrick DR, Greenfield BW, Brasel K, Maliszewski CR, De Smedt T. Murine plasmacytoid pre-dendritic cells generated from Flt3 ligand-supplemented bone marrow cultures are immature APCs. J. Immunol.169, 6711–6719 (2002).
  • Bilsborough J, George, TC, Norment A, Viney JL. Mucosal CD8a+ DC, with a plasmacytoid phenotype, induce differentiation and support function of T cells with regulatory properties. Immunology108, 481–492 (2003).
  • Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature392(6673), 245–252 (1998).
  • Steinman RM. The dendritic cell system and its role in immunogenicity. Annu. Rev. Immunol.9, 271–296 (1991).
  • Puengtomwatanakul S, Sirisinha S. Impaired biliary secretion of immunoglobulin A in vitamin A-deficient rats. Proc. Soc. Exp. Biol. Med.182(4), 437–442 (1986).
  • Sirisinha S, Darip MD, Moongkarndi P, Ongsakul M, Lamb AJ. Impaired local immune response in vitamin A-deficient rats. Clin. Exp. Immunol.40(1), 127–135 (1980).
  • Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY. Retinoic acid imprints gut-homing specificity on T cells. Immunity21(4), 527–538 (2004).
  • McGhee JR, Kunisawa J, Kiyono H. Gut lymphocyte migration: we are halfway ‘home’. Trends Immunol.28(4), 150–153 (2007).
  • Mora JR, Iwata M, Eksteen B et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science314(5802), 1157–1160 (2006).
  • Coombes JL, Siddiqui KR, Arancibia-Carcamo CV et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med.204(8), 1757–1764 (2007).
  • Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat. Immunol.8(10), 1086–1094 (2007).
  • Mucida D, Park Y, Kim G et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science317(5835), 256–260 (2007).
  • Sun CM, Hall JA, Blank RB et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med.204(8), 1775–1785 (2007).
  • Uematsu S, Fujimoto K, Jang MH et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat. Immunol.9(7), 769–776 (2008).
  • Cardon LR, Burge C, Clayton DA, Karlin S. Pervasive CpG suppression in animal mitochondrial genomes. Proc. Natl Acad. Sci. USA91(9), 3799–3803 (1994).
  • Razin A, Friedman J. DNA methylation and its possible biological roles. Prog. Nucleic Acid Res. Mol. Biol.25, 33–52 (1981).
  • Hemmi H, Takeuchi O, Kawai T et al. A Toll-like receptor recognizes bacterial DNA. Nature408(6813), 740–745 (2000).
  • Klinman DM. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat. Rev. Immunol.4(4), 249–258 (2004).
  • Wagner H. Bacterial CpG DNA activates immune cells to signal infectious danger. Adv. Immunol.73, 329–368 (1999).
  • Klinman DM, Yi AK, Beaucage SL, Conover J, Krieg AM. CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon γ. Proc. Natl Acad. Sci. USA93(7), 2879–2883 (1996).
  • Krieg AM, Yi AK, Matson S et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature374(6522), 546–549 (1995).
  • Yamamoto S, Yamamoto T, Kataoka T, Kuramoto E, Yano O, Tokunaga T. Unique palindromic sequences in synthetic oligonucleotides are required to induce IFN and augment IFN-mediated natural killer activity. J. Immunol.148(12), 4072–4076 (1992).
  • Zimmermann S, Egeter O, Hausmann S et al. CpG oligodeoxynucleotides trigger protective and curative Th1 responses in lethal murine leishmaniasis. J. Immunol.160(8), 3627–3630 (1998).
  • Jahrsdorfer B, Weiner GJ. CpG oligodeoxynucleotides for immune stimulation in cancer immunotherapy. Curr. Opin Investig. Drugs4(6), 686–690 (2003).
  • Kline JN, Waldschmidt TJ, Businga TR et al. Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J. Immunol.160(6), 2555–2559 (1998).
  • Klinman DM, Barnhart KM, Conover J. CpG motifs as immune adjuvants. Vaccine17(1), 19–25 (1999).
  • Klinman DM. Therapeutic applications of CpG-containing oligodeoxynucleotides. Antisense Nucleic Acid Drug Dev.8(2), 181–184 (1998).
  • Brazolot Millan CL, Weeratna R, Krieg AM, Siegrist CA, Davis HL. CpG DNA can induce strong Th1 humoral and cell-mediated immune responses against hepatitis B surface antigen in young mice. Proc. Natl Acad. Sci. USA95(26), 15553–15558 (1998).
  • Davis HL, Weeratna R, Waldschmidt TJ, Tygrett L, Schorr J, Krieg AM. CpG DNA is a potent enhancer of specific immunity in mice immunized with recombinant hepatitis B surface antigen. J. Immunol.160(2), 870–876 (1998).
  • Eastcott JW, Holmberg CJ, Dewhirst FE, Esch TR, Smith DJ, Taubman MA. Oligonucleotide containing CpG motifs enhances immune response to mucosally or systemically administered tetanus toxoid. Vaccine19(13–14), 1636–1642 (2001).
  • Kovarik J, Bozzotti P, Love-Homan L et al. CpG oligodeoxynucleotides can circumvent the Th2 polarization of neonatal responses to vaccines but may fail to fully redirect Th2 responses established by neonatal priming. J. Immunol.162(3), 1611–1617 (1999).
  • McCluskie MJ, Davis HL. CpG DNA is a potent enhancer of systemic and mucosal immune responses against hepatitis B surface antigen with intranasal administration to mice. J. Immunol.161(9), 4463–4466 (1998).
  • Moldoveanu Z, Love-Homan L, Huang WQ, Krieg AM. CpG DNA, a novel immune enhancer for systemic and mucosal immunization with influenza virus. Vaccine16(11–12), 1216–1224 (1998).
  • McCluskie MJ, Weeratna RD, Krieg AM, Davis HL. CpG DNA is an effective oral adjuvant to protein antigens in mice. Vaccine19(7–8), 950–957 (2000).
  • Weeratna RD, Brazolot Millan CL, McCluskie MJ, Davis HL. CpG ODN can re-direct the Th bias of established Th2 immune responses in adult and young mice. FEMS Immunol. Med. Microbiol.32(1), 65–71 (2001).
  • Yi AK, Yoon JG, Yeo SJ, Hong SC, English BK, Krieg AM. Role of mitogen-activated protein kinases in CpG DNA-mediated IL-10 and IL-12 production: central role of extracellular signal-regulated kinase in the negative feedback loop of the CpG DNA-mediated Th1 response. J. Immunol.168(9), 4711–4720 (2002).
  • Boyaka PN, Tafaro A, Fischer R, Leppla SH, Fujihashi K, McGhee JR. Effective mucosal immunity to anthrax: neutralizing antibodies and Th cell responses following nasal immunization with protective antigen. J. Immunol.170(11), 5636–5643 (2003).
  • Kitani A, Fuss IJ, Nakamura K, Schwartz OM, Usui T, Strober W. Treatment of experimental (trinitrobenzene sulfonic acid) colitis by intranasal administration of transforming growth factor (TGF)-β1 plasmid: TGF-β1-mediated suppression of T helper cell type 1 response occurs by interleukin (IL)-10 induction and IL-12 receptor β2 chain downregulation. J. Exp. Med.192(1), 41–52 (2000).
  • Fukuiwa T, Sekine S, Kobayashi R et al. A combination of Flt3 ligand cDNA and CpG ODN as nasal adjuvant elicits NALT dendritic cells for prolonged mucosal immunity. Vaccine26(37), 4849–4859 (2008).
  • Hino A, Fukuyama S, Kataoka K, Kweon MN, Fujihashi K, Kiyono H. Nasal IL-12p70 DNA prevents and treats intestinal allergic diarrhea. J. Immunol.174(11), 7423–7432 (2005).
  • Kataoka K, McGhee JR, Kobayashi R, Fujihashi K, Shizukuishi S, Fujihashi K. Nasal Flt3 ligand cDNA elicits CD11c+ CD8+ dendritic cells for enhanced mucosal immunity. J. Immunol.172, 3612–3619 (2004).
  • Wang X, Zhang X, Kang Y et al. Interleukin-15 enhance DNA vaccine elicited mucosal and systemic immunity against foot and mouth disease virus. Vaccine26(40), 5135–5144 (2008).
  • Yamanaka H, Hoyt T, Yang X et al. A nasal interleukin-12 DNA vaccine coexpressing Yersinia pestis F1-V fusion protein confers protection against pneumonic plague. Infect. Immun.76(10), 4564–4573 (2008).
  • Kutzler MA, Robinson TM, Chattergoon MA et al. Coimmunization with an optimized IL-15 plasmid results in enhanced function and longevity of CD8 T cells that are partially independent of CD4 T cell help. J. Immunol.175(1), 112–123 (2005).
  • Brasel K, McKenna HJ, Morrissey PJ et al. Hematologic effects of flt3 ligand in vivo in mice. Blood88, 2004–2012 (1996).
  • Maraskovsky E, Brasel K, Teepe M et al. Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J. Exp. Med.184, 1953–1962 (1996).
  • Viney JL, Mowat AM, O’Malley JM, Williamson E, Fanger NA. Expanding dendritic cells in vivo enhances the induction of oral tolerance. J. Immunol.160, 5815–5825 (1998).
  • Williamson E, Westrich GM, Viney JL. Modulating dendritic cells to optimize mucosal immunization protocols. J. Immunol.163, 3668–3675 (1999).
  • Pisarev VM, Parajuli P, Mosley RL et al. Flt3 ligand enhances the immunogenicity of a gag-based HIV-1 vaccine. Int. J. Immunopharmacol.22(11), 865–876 (2000).
  • Baca-Estrada ME, Ewen C, Mahony D, Babiuk LA, Wilkie D, Foldvari M. The haemopoietic growth factor, Flt3L, alters the immune response induced by transcutaneous immunization. Immunology107, 69–76 (2002).
  • Hung CF, Hsu KF, Cheng WF et al. Enhancement of DNA vaccine potency by linkage of antigen gene to a gene encoding the extracellular domain of Fms-like tyrosine kinase 3-ligand. Cancer Res.61, 1080–1088 (2001).
  • Moore AC, Kong WP, Chakrabarti BK, Nabel GJ. Effects of antigen and genetic adjuvants on immune responses to human immunodeficiency virus DNA vaccines in mice. J. Virol.76, 243–250 (2002).
  • Field M, Rao MC, Chang EB. Intestinal electrolyte transport and diarrheal disease (1). N. Engl. J. Med.321, 800–806 (1989).
  • Gill DM, King CA. The mechanism of action of cholera toxin in pigeon erythrocyte lysates. J. Biol. Chem.250, 6424–6432 (1975).
  • Reiss CS, Plakhov IV, Komatsu T. Viral replication in olfactory receptor neurons and entry into the olfactory bulb and brain. Ann. NY Acad. Sci.855, 751–761 (1998).
  • Babic N, Klupp B, Brack A, Mettenleiter TC, Ugolini G, Flamand A. Deletion of glycoprotein gE reduces the propagation of pseudorabies virus in the nervous system of mice after intranasal inoculation. Virology219(1), 279–284 (1996).
  • van Ginkel FW, Jackson RJ, Yuki Y, McGhee JR. The mucosal adjuvant cholera toxin redirects vaccine proteins into olfactory tissues. J. Immunol.165, 4778–4782 (2000).
  • van Ginkel FW, Jackson RJ, Yoshino N et al. Enterotoxin-based mucosal adjuvants alter antigen trafficking and induce inflammatory responses in the nasal tract. Infect. Immun.73(10), 6892–6902 (2005).
  • van Ginkel FW, McGhee JR, Watt JM, Campos-Torres A, Parish LA, Briles DE. Pneumococcal carriage results in ganglioside-mediated olfactory tissue infection. Proc. Natl Acad. Sci. USA100(24), 14363–14367 (2003).
  • Yoshino N, Lu FX, Fujihashi K et al. A novel adjuvant for mucosal immunity to HIV-1 gp120 in nonhuman primates. J. Immunol.173(11), 6850–6857 (2004).
  • Mancini P, Santi PA. Localization of the GM1 ganglioside in the vestibular system using cholera toxin. Hear. Res.64(2), 151–165 (1993).
  • de Fijter JW, Eijgenraam JW, Braam CA et al. Deficient IgA1 immune response to nasal cholera toxin subunit B in primary IgA nephropathy. Kidney Int.50(3), 952–961 (1996).
  • Mutsch M, Zhou W, Rhodes P et al. Use of the inactivated intranasal influenza vaccine and the risk of Bell’s palsy in Switzerland. N. Engl. J. Med.350(9), 896–903 (2004).
  • Cuburu N, Kweon MN, Song JH et al. Sublingual immunization induces broad-based systemic and mucosal immune responses in mice. Vaccine25(51), 8598–8610 (2007).
  • Huang CF, Wu TC, Chu YH, Hwang KS, Wang CC, Peng HJ. Effect of neonatal sublingual vaccination with native or denatured ovalbumin and adjuvant CpG or cholera toxin on systemic and mucosal immunity in mice. Scand. J. Immunol.68(5), 502–510 (2008).
  • Song JH, Nguyen HH, Cuburu N et al. Sublingual vaccination with influenza virus protects mice against lethal viral infection. Proc. Natl Acad. Sci. USA105(5), 1644–1649 (2008).
  • Sun JB, Flach CF, Czerkinsky C, Holmgren J. B lymphocytes promote expansion of regulatory T cells in oral tolerance: powerful induction by antigen coupled to cholera toxin B subunit. J. Immunol.181(12), 8278–8287 (2008).
  • Song JH, Kim JI, Kwon HJ et al. CCR7-CCL19/CCL21-regulated dendritic cells are responsible for effectiveness of sublingual vaccination. J. Immunol.182(11), 6851–6860 (2009).

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