Mucosal SIgA Enhancement: Development of Safe and Effective Mucosal Adjuvants and Mucosal Antigen Delivery Vehicles

  • Jun Kunisawa
  • Jerry R. McGhee
  • Hiroshi Kiyono

The respiratory and digestive tracts represent major entry routes for pathogenic microorganisms from the lumen into an almost sterile environment of the body. Several physical and biological barriers associated with the innate immune system protect these sites from invasion and help to maintain mucosal homeostasis. The first physical defense line is a barrier structure made up of epithelial cells (ECs) joined firmly by tight junction proteins with brush-border microvilli and a dense layer of mucin (Berkes et al., 2003). Antimicrobial peptides such as defensins and type II phospholipase A2 produced by ECs and Paneth cells are additional molecules preventing the attachment and penetration of pathogenic microorganisms into mucosal tissues (Selsted and Ouellette, 2005).


Cholera Toxin Systemic Immune Response Adjuvant Activity Modify Vaccinia Virus Ankara Mucosal Vaccine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Agren, L., Sverremark, E., Ekman, L., Schon, K., Lowenadler, B., Fernandez, C., and Lycke, N. (2000). The ADP-ribosylating CTA1-DD adjuvant enhances T cell-dependent and independent responses by direct action on B cells involving anti-apoptotic Bcl-2- and germinal center-promoting effects. J. Immunol. 164:6276–6286.PubMedGoogle Scholar
  2. Agren, L. C., Ekman, L., Lowenadler, B., and Lycke, N. Y. (1997). Genetically engineered nontoxic vaccine adjuvant that combines B cell targeting with immunomodulation by cholera toxin A1 subunit. J. Immunol. 158:3936–3946.PubMedGoogle Scholar
  3. Agren, L. C., Ekman, L., Lowenadler, B., Nedrud, J. G., and Lycke, N. Y. (1999). Adjuvanticity of the cholera toxin A1-based gene fusion protein, CTA1-DD, is critically dependent on the ADP-ribosyltransferase and Ig-binding activity. J. Immunol. 162:2432–2440.PubMedGoogle Scholar
  4. Akira, S., and Takeda, K. (2004). Toll-like receptor signalling. Nat. Rev. Immunol. 4:499–511.PubMedGoogle Scholar
  5. Aman, A. T., Fraser, S., Merritt, E. A., Rodigherio, C., Kenny, M., Ahn, M., Hol, W. G., Williams, N. A., Lencer, W. I., and Hirst, T. R. (2001). A mutant cholera toxin B subunit that binds GM1-ganglioside but lacks immunomodulatory or toxic activity. Proc. Natl. Acad. Sci. USA 98:8536–8541.PubMedGoogle Scholar
  6. Andino, R., Silvera, D., Suggett, S. D., Achacoso, P. L., Miller, C. J., Baltimore, D., and Feinberg, M. B. (1994). Engineering poliovirus as a vaccine vector for the expression of diverse antigens. Science 265:1448–1451.PubMedGoogle Scholar
  7. Aramaki, Y., Tomizawa, H., Hara, T., Yachi, K., Kikuchi, H., and Tsuchiya, S. (1993). Stability of liposomes in vitro and their uptake by rat Peyer’s patches following oral administration. Pharm. Res. 10:1228–1231.PubMedGoogle Scholar
  8. Arulanandam, B. P., Lynch, J. M., Briles, D. E., Hollingshead, S., and Metzger, D. W. (2001). Intranasal vaccination with pneumococcal surface protein A and interleukin-12 augments antibody-mediated opsonization and protective immunity against Streptococcus pneumoniae infection. Infect. Immun. 69:6718–6724.PubMedGoogle Scholar
  9. Arulanandam, B. P., O’Toole, M., and Metzger, D. W. (1999). Intranasal interleukin-12 is a powerful adjuvant for protective mucosal immunity. J. Infect. Dis. 180:940–949.PubMedGoogle Scholar
  10. Babiuk, L. A., and Tikoo, S. K. (2000). Adenoviruses as vectors for delivering vaccines to mucosal surfaces. J. Biotechnol. 83:105–113.PubMedGoogle Scholar
  11. Baldridge, J. R., McGowan, P., Evans, J. T., Cluff, C., Mossman, S., Johnson, D., and Persing, D. (2004). Taking a Toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents. Expert. Opin. Biol. Ther. 4:1129–1138.PubMedGoogle Scholar
  12. Baldridge, J. R., Yorgensen, Y., Ward, J. R., and Ulrich, J. T. (2000). Monophosphoryl lipid A enhances mucosal and systemic immunity to vaccine antigens following intranasal administration. Vaccine 18:2416–2425.PubMedGoogle Scholar
  13. Bangham, A. D., Horne, R. W., Glauert, A. M., Dingle, J. T., and Lucy, J. A. (1962). Action of saponin on biological cell membranes. Nature 196:952–955.PubMedGoogle Scholar
  14. Barchfeld, G. L., Hessler, A. L., Chen, M., Pizza, M., Rappuoli, R., and Van Nest, G. A. (1999). The adjuvants MF59 and LT-K63 enhance the mucosal and systemic immunogenicity of subunit influenza vaccine administered intranasally in mice. Vaccine 17:695–704.PubMedGoogle Scholar
  15. Barouch, D. H., and Nabel, G. J. (2005). Adenovirus vector-based vaccines for human immunodeficiency virus type 1. Hum. Gene Ther. 16:149–156.PubMedGoogle Scholar
  16. Barry, E. M., Gomez-Duarte, O., Chatfield, S., Rappuoli, R., Pizza, M., Losonsky, G., Galen, J., and Levine, M. M. (1996). Expression and immunogenicity of pertussis toxin S1 subunit-tetanus toxin fragment C fusions in Salmonella typhi vaccine strain CVD 908. Infect. Immun. 64:4172–4181.PubMedGoogle Scholar
  17. Basler, C. F., and Garcia-Sastre, A. (2002). Viruses and the type I interferon antiviral system: induction and evasion. Int. Rev. Immunol. 21:305–337.PubMedGoogle Scholar
  18. Baudry, B., Fasano, A., Ketley, J., and Kaper, J. B. (1992). Cloning of a gene (zot) encoding a new toxin produced by Vibrio cholerae. Infect. Immun. 60:428–434.PubMedGoogle Scholar
  19. Ben-Ahmeida, E. T., Potter, C. W., Gregoriadis, G., Adithan, C., and Jennings, R. (1994). IgG subclass response and protection against challenge following immunisation of mice with various influenza A vaccines. J. Med. Microbiol. 40:261–269.PubMedGoogle Scholar
  20. Berkes, J., Viswanathan, V. K., Savkovic, S. D., and Hecht, G. (2003). Intestinal epithelial responses to enteric pathogens: Effects on the tight junction barrier, ion transport, and inflammation. Gut 52:439–451.PubMedGoogle Scholar
  21. Berland, R., and Wortis, H. H. (2002). Origins and functions of B-1 cells with notes on the role of CD5. Annu. Rev. Immunol. 20:253–300.PubMedGoogle Scholar
  22. Bertley, F. M., Kozlowski, P. A., Wang, S. W., Chappelle, J., Patel, J., Sonuyi, O., Mazzara, G., Montefiori, D., Carville, A., Mansfield, K. G., and Aldovini, A. (2004). Control of simian/human immunodeficiency virus viremia and disease progression after IL-2-augmented DNA-modified vaccinia virus Ankara nasal vaccination in nonhuman primates. J. Immunol. 172:3745–3757.PubMedGoogle Scholar
  23. Boismenu, R., Feng, L., Xia, Y. Y., Chang, J. C., and Havran, W. L. (1996). Chemokine expression by intraepithelial gamma delta T cells. Implications for the recruitment of inflammatory cells to damaged epithelia. J. Immunol. 157:985–992.PubMedGoogle Scholar
  24. Bone, H., Eckholdt, S., and Williams, N. A. (2002). Modulation of B lymphocyte signalling by the B subunit of Escherichia coli heat-labile enterotoxin. Int. Immunol. 14:647–658.PubMedGoogle Scholar
  25. Borsutzky, S., Fiorelli, V., Ebensen, T., Tripiciano, A., Rharbaoui, F., Scoglio, A., Link, C., Nappi, F., Morr, M., Butto, S., Cafaro, A., Muhlradt, P. F., Ensoli, B., and Guzman, C. A. (2003). Efficient mucosal delivery of the HIV-1 Tat protein using the synthetic lipopeptide MALP-2 as adjuvant. Eur. J. Immunol. 33:1548–1556.PubMedGoogle Scholar
  26. Borsutzky, S., Kretschmer, K., Becker, P. D., Muhlradt, P. F., Kirschning, C. J., Weiss, S., and Guzman, C. A. (2005). The mucosal adjuvant macrophage-activating lipopeptide-2 directly stimulates B lymphocytes via the TLR2 without the need of accessory cells. J. Immunol. 174:6308–6313.PubMedGoogle Scholar
  27. Bos, N. A., Cebra, J. J., and Kroese, F. G. (2000). B-1 cells and the intestinal microflora. Curr. Topics Microbiol. Immunol. 252:211–220.Google Scholar
  28. Bowen, J. C., Nair, S. K., Reddy, R., and Rouse, B. T. (1994). Cholera toxin acts as a potent adjuvant for the induction of cytotoxic T-lymphocyte responses with non-replicating antigens. Immunology 81:338–342.PubMedGoogle Scholar
  29. Bowman, C. C., and Clements, J. D. (2001). Differential biological and adjuvant activities of cholera toxin and Escherichia coli heat-labile enterotoxin hybrids. Infect. Immun. 69:1528–1535.PubMedGoogle Scholar
  30. Boyaka, P. N., Marinaro, M., Jackson, R. J., Menon, S., Kiyono, H., Jirillo, E., and McGhee, J. R. (1999). IL-12 is an effective adjuvant for induction of mucosal immunity. J. Immunol. 162:122–128.PubMedGoogle Scholar
  31. Boyaka, P. N., Ohmura, M., Fujihashi, K., Koga, T., Yamamoto, M., Kweon, M. N., Takeda, Y., Jackson, R. J., Kiyono, H., Yuki, Y., and McGhee, J. R. (2003). Chimeras of labile toxin one and cholera toxin retain mucosal adjuvanticity and direct Th cell subsets via their B subunit. J. Immunol. 170:454–462.PubMedGoogle Scholar
  32. Bradney, C. P., Sempowski, G. D., Liao, H. X., Haynes, B. F., and Staats, H. F. (2002). Cytokines as adjuvants for the induction of anti-human immunodeficiency virus peptide immunoglobulin G (IgG) and IgA antibodies in serum and mucosal secretions after nasal immunization. J. Virol. 76:517–524.PubMedGoogle Scholar
  33. Brandtzaeg, P., and Johansen, F. E. (2005). Mucosal B cells: phenotypic characteristics, transcriptional regulation, and homing properties. Immunol. Rev. 206:32–63.PubMedGoogle Scholar
  34. Braun, M. C., He, J., Wu, C. Y., and Kelsall, B. L. (1999). Cholera toxin suppresses interleukin (IL)-12 production and IL-12 receptor beta1 and beta2 chain expression. J. Exp. Med. 189:541–552.PubMedGoogle Scholar
  35. Cardenas-Freytag, L., Cheng, E., Mayeux, P., Domer, J. E., and Clements, J. D. (1999). Effectiveness of a vaccine composed of heat-killed Candida albicans and a novel mucosal adjuvant, LT(R192G), against systemic candidiasis. Infect. Immun. 67:826–833.PubMedGoogle Scholar
  36. Chatfield, S. N., Charles, I. G., Makoff, A. J., Oxer, M. D., Dougan, G., Pickard, D., Slater, D., and Fairweather, N. F. (1992). Use of the nirB promoter to direct the stable expression of heterologous antigens in Salmonella oral vaccine strains: development of a single-dose oral tetanus vaccine. Biotechnology (N Y) 10:888–892.Google Scholar
  37. Chen, H., and Langer, R. (1997). Magnetically-responsive polymerized liposomes as potential oral delivery vehicles. Pharm. Res. 14:537–540.PubMedGoogle Scholar
  38. Chen, H., Torchilin, V., and Langer, R. (1996). Lectin-bearing polymerized liposomes as potential oral vaccine carriers. Pharm. Res. 13:1378–1383.PubMedGoogle Scholar
  39. Cheroutre, H. (2005). IELs: Enforcing law and order in the court of the intestinal epithelium. Immunol. Rev. 206:114–131.PubMedGoogle Scholar
  40. Chong, C., Friberg, M., and Clements, J. D. (1998). LT(R192G), a non-toxic mutant of the heat-labile enterotoxin of Escherichia coli, elicits enhanced humoral and cellular immune responses associated with protection against lethal oral challenge with Salmonella spp. Vaccine 16:732–740.PubMedGoogle Scholar
  41. Chu, R. S., McCool, T., Greenspan, N. S., Schreiber, J. R., and Harding, C. V. (2000). CpG oligodeoxynucleotides act as adjuvants for pneumococcal polysaccharide–protein conjugate vaccines and enhance antipolysaccharide immunoglobulin G2a (IgG2a) and IgG3 antibodies. Infect. Immun. 68:1450–1456.PubMedGoogle Scholar
  42. Clark, M. A., Blair, H., Liang, L., Brey, R. N., Brayden, D., and Hirst, B. H. (2001a). Targeting polymerised liposome vaccine carriers to intestinal M cells. Vaccine 20:208–217.PubMedGoogle Scholar
  43. Clark, M. A., Hirst, B. H., and Jepson, M. A. (1998). M-cell surface beta1 integrin expression and invasin-mediated targeting of Yersinia pseudotuberculosis to mouse Peyer’s patch M cells. Infect. Immun. 66:1237–1243.PubMedGoogle Scholar
  44. Clark, M. A., Jepson, M. A., and Hirst, B. H. (2001b). Exploiting M cells for drug and vaccine delivery. Adv. Drug Deliv. Rev. 50:81–106.PubMedGoogle Scholar
  45. Cong, Y., Oliver, A. O., and Elson, C. O. (2001). Effects of cholera toxin on macrophage production of co-stimulatory cytokines. Eur. J. Immunol. 31:64–71.PubMedGoogle Scholar
  46. Cong, Y., Weaver, C. T., and Elson, C. O. (1997). The mucosal adjuvanticity of cholera toxin involves enhancement of costimulatory activity by selective up-regulation of B7.2 expression. J. Immunol. 159:5301–5308.PubMedGoogle Scholar
  47. Crotty, S., and Andino, R. (2004). Poliovirus vaccine strains as mucosal vaccine vectors and their potential use to develop an AIDS vaccine. Adv. Drug Deliv. Rev. 56:835–852.PubMedGoogle Scholar
  48. Curtiss, R., 3rd (2005). Antigen delivery systems II: Development of live recombinant attenuated bacterial antigen and DNA vaccine delivery vector vaccines. In: Mestecky, J., Bienenstock, J., Lamm, M. E., Storober, W., and McGhee, J. R. (eds.), Mucosal Immunology, Academic Press, San Diego, pp. 1009–1037.Google Scholar
  49. Curtiss, R., 3rd, and Kelly, S. M. (1987). Salmonella typhimurium deletion mutants lacking adenylate cyclase and cyclic AMP receptor protein are avirulent and immunogenic. Infect. Immun. 55:3035–3043.PubMedGoogle Scholar
  50. Darji, A., Guzman, C. A., Gerstel, B., Wachholz, P., Timmis, K. N., Wehland, J., Chakraborty, T., and Weiss, S. (1997). Oral somatic transgene vaccination using attenuated S. typhimurium. Cell 91:765–775.Google Scholar
  51. de Haan, L., Verweij, W. R., Feil, I. K., Lijnema, T. H., Hol, W. G., Agsteribbe, E., and Wilschut, J. (1996). 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. 64:5413–5416.PubMedGoogle Scholar
  52. De Magistris, M. T., Pizza, M., Douce, G., Ghiara, P., Dougan, G., and Rappuoli, R. (1998). Adjuvant effect of non-toxic mutants of E. coli heat-labile enterotoxin following intranasal, oral and intravaginal immunization. Dev. Biol. Stand. 92:123–126.PubMedGoogle Scholar
  53. Dickinson, B. L., and Clements, J. D. (1995). Dissociation of Escherichia coli heat-labile enterotoxin adjuvanticity from ADP-ribosyltransferase activity. Infect. Immun. 63:1617–1623.PubMedGoogle Scholar
  54. Dietrich, G., Spreng, S., Favre, D., Viret, J. F., and Guzman, C. A. (2003). Live attenuated bacteria as vectors to deliver plasmid DNA vaccines. Curr. Opin. Mol. Ther. 5:10–19.PubMedGoogle Scholar
  55. Dilloo, D., Bacon, K., Holden, W., Zhong, W., Burdach, S., Zlotnik, A., and Brenner, M. (1996). Combined chemokine and cytokine gene transfer enhances antitumor immunity. Nat. Med. 2:1090–1095.PubMedGoogle Scholar
  56. Doherty, T. M., Olsen, A. W., van Pinxteren, L., and Andersen, P. (2002). Oral vaccination with subunit vaccines protects animals against aerosol infection with Mycobacterium tuberculosis. Infect. Immun. 70:3111–3121.PubMedGoogle Scholar
  57. Douce, G., Turcotte, C., Cropley, I., Roberts, M., Pizza, M., Domenghini, M., Rappuoli, R., and Dougan, G. (1995). Mutants of Escherichia coli heat-labile toxin lacking ADP-ribosyltransferase activity act as nontoxic, mucosal adjuvants. Proc. Natl. Acad. Sci. USA 92:1644–1648.PubMedGoogle Scholar
  58. Dougan, G., Maskell, D., Pickard, D., and Hormaeche, C. (1987). Isolation of stable aroA mutants of Salmonella typhi Ty2: Properties and preliminary characterisation in mice. Mol. Gen. Genet. 207:402–405.PubMedGoogle Scholar
  59. Dramsi, S., Lebrun, M., and Cossart, P. (1996). Molecular and genetic determinants involved in invasion of mammalian cells by Listeria monocytogenes. Curr. Topics Microbiol. Immunol. 209:61–77.Google Scholar
  60. Drexler, I., Staib, C., and Sutter, G. (2004). Modified vaccinia virus Ankara as antigen delivery system: how can we best use its potential? Curr. Opin. Biotechnol. 15:506–512.PubMedGoogle Scholar
  61. Dubois, B., Goubier, A., Joubert, G., and Kaiserlian, D. (2005). Oral tolerance and regulation of mucosal immunity. Cell. Mol. Life Sci. 62:1322–1332.PubMedGoogle Scholar
  62. Duckett, N. S., Olmos, S., Durrant, D. M., and Metzger, D. W. (2005). Intranasal interleukin-12 treatment for protection against respiratory infection with the Francisella tularensis live vaccine strain. Infect. Immun. 73:2306–2311.PubMedGoogle Scholar
  63. Dumais, N., Patrick, A., Moss, R. B., Davis, H. L., and Rosenthal, K. L. (2002). Mucosal immunization with inactivated human immunodeficiency virus plus CpG oligodeoxynucleotides induces genital immune responses and protection against intravaginal challenge. J. Infect. Dis. 186:1098–1105.PubMedGoogle Scholar
  64. Duverger, A., Jackson, R. J., van Ginkel, F. W., Fischer, R., Tafaro, A., Leppla, S. H., Fujihashi, K., Kiyono, H., McGhee, J. R., and Boyaka, P. N. (2006). Bacillus anthracis edema toxin acts as an adjuvant for mucosal immune responses to nasally administered vaccine antigens. J. Immunol. 176:1776–1783.PubMedGoogle Scholar
  65. Ertl, H. C., and Xiang, Z. (1996). Novel vaccine approaches. J. Immunol. 156:3579–3582.PubMedGoogle Scholar
  66. Evans, J. T., Cluff, C. W., Johnson, D. A., Lacy, M. J., Persing, D. H., and Baldridge, J. R. (2003). Enhancement of antigen-specific immunity via the TLR4 ligands MPL adjuvant and Ribi.529. Expert. Rev. Vaccines 2:219–229.PubMedGoogle Scholar
  67. Everest, P., Frankel, G., Li, J., Lund, P., Chatfield, S., and Dougan, G. (1995). Expression of LacZ from the htrA, nirB and groE promoters in a Salmonella vaccine strain: influence of growth in mammalian cells. FEMS Microbiol. Lett. 126:97–101.PubMedGoogle Scholar
  68. Fagarasan, S., Shinkura, R., Kamata, T., Nogaki, F., Ikuta, K., Tashiro, K., and Honjo, T. (2000). Alymphoplasia (aly)-type nuclear factor kappaB-inducing kinase (NIK) causes defects in secondary lymphoid tissue chemokine receptor signaling and homing of peritoneal cells to the gut-associated lymphatic tissue system. J. Exp. Med. 191:1477–1486.PubMedGoogle Scholar
  69. Fasano, A., Baudry, B., Pumplin, D. W., Wasserman, S. S., Tall, B. D., Ketley, J. M., and Kaper, J. B. (1991). Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions. Proc. Natl. Acad. Sci. USA 88:5242–5246.PubMedGoogle Scholar
  70. Fayad, R., Zhang, H., Quinn, D., Huang, Y., and Qiao, L. (2004). Oral administration with papillomavirus pseudovirus encoding IL-2 fully restores mucosal and systemic immune responses to vaccinations in aged mice. J. Immunol. 173:2692–2698.PubMedGoogle Scholar
  71. Feng, Y., Jadhav, A. P., Rodighiero, C., Fujinaga, Y., Kirchhausen, T., and Lencer, W. I. (2004). Retrograde transport of cholera toxin from the plasma membrane to the endoplasmic reticulum requires the trans-Golgi network but not the Golgi apparatus in Exo2-treated cells. EMBO Rep. 5:596–601.PubMedGoogle Scholar
  72. Fooks, A. R. (2000). Development of oral vaccines for human use. Curr. Opin. Mol. Ther. 2:80–86.PubMedGoogle Scholar
  73. Forrest, J. C., and Dermody, T. S. (2003). Reovirus receptors and pathogenesis. J. Virol. 77:9109–9115.PubMedGoogle Scholar
  74. Foster, N., Clark, M. A., Jepson, M. A., and Hirst, B. H. (1998). Ulex europaeus 1 lectin targets microspheres to mouse Peyer’s patch M-cells in vivo. Vaccine 16:536–541.Google Scholar
  75. Foster, N., and Hirst, B. H. (2005). Exploiting receptor biology for oral vaccination with biodegradable particulates. Adv. Drug Deliv. Rev. 57:431–450.PubMedGoogle Scholar
  76. Fraser, S. A., de Haan, L., Hearn, A. R., Bone, H. K., Salmond, R. J., Rivett, A. J., Williams, N. A., and Hirst, T. R. (2003). Mutant Escherichia coli heat-labile toxin B subunit that separates toxoid-mediated signaling and immunomodulatory action from trafficking and delivery functions. Infect. Immun. 71:1527–1537.PubMedGoogle Scholar
  77. Fujihashi, K., Koga, T., van Ginkel, F. W., Hagiwara, Y., and McGhee, J. R. (2002). A dilemma for mucosal vaccination: Efficacy versus toxicity using enterotoxin-based adjuvants. Vaccine 20:2431–2438.PubMedGoogle Scholar
  78. Fukuta, S., Magnani, J. L., Twiddy, E. M., Holmes, R. K., and Ginsburg, V. (1988). Comparison of the carbohydrate-binding specificities of cholera toxin and Escherichia coli heat-labile enterotoxins LTh-I, LT-IIa, and LT-IIb. Infect. Immun. 56:1748–1753.PubMedGoogle Scholar
  79. Furrie, E., Smith, R. E., Turner, M. W., Strobel, S., and Mowat, A. M. (2002). Induction of local innate immune responses and modulation of antigen uptake as mechanisms underlying the mucosal adjuvant properties of immune stimulating complexes (ISCOMS). Vaccine 20:2254–2262.PubMedGoogle Scholar
  80. Galen, J. E., and Levine, M. M. (2001). Can a ‘flawless’ live vector vaccine strain be engineered? Trends Microbiol. 9:372–376.PubMedGoogle Scholar
  81. Gallichan, W. S., Woolstencroft, R. N., Guarasci, T., McCluskie, M. J., Davis, H. L., and Rosenthal, K. L. (2001). Intranasal immunization with CpG oligodeoxynucleotides as an adjuvant dramatically increases IgA and protection against herpes simplex virus-2 in the genital tract. J. Immunol. 166:3451–3457.PubMedGoogle Scholar
  82. Germanier, R., and Furer, E. (1971). Immunity in experimental salmonellosis. II. Basis for the avirulence and protective capacity of gal E mutants of Salmonella typhimurium. Infect. Immun. 4:663–673.PubMedGoogle Scholar
  83. Giannasca, P. J., Giannasca, K. T., Falk, P., Gordon, J. I., and Neutra, M. R. (1994). Regional differences in glycoconjugates of intestinal M cells in mice: Potential targets for mucosal vaccines. Am. J. Physiol. 267:G1108–G1121.PubMedGoogle Scholar
  84. Gomez-Duarte, O. G., Galen, J., Chatfield, S. N., Rappuoli, R., Eidels, L., and Levine, M. M. (1995). Expression of fragment C of tetanus toxin fused to a carboxyl-terminal fragment of diphtheria toxin in Salmonella typhi CVD 908 vaccine strain. Vaccine 13:1596–1602.PubMedGoogle Scholar
  85. Gomez-Roman, V. R., and Robert-Guroff, M. (2003). Adenoviruses as vectors for HIV vaccines. AIDS Rev. 5:178–185.PubMedGoogle Scholar
  86. Grillot-Courvalin, C., Goussard, S., Huetz, F., Ojcius, D. M., and Courvalin, P. (1998). Functional gene transfer from intracellular bacteria to mammalian cells. Nat. Biotechnol. 16:862–866.PubMedGoogle Scholar
  87. Guy-Grand, D., and Vassalli, P. (2002). Gut intraepithelial lymphocyte development. Curr. Opin. Immunol. 14:255–259.PubMedGoogle Scholar
  88. Hagiwara, Y., Kawamura, Y. I., Kataoka, K., Rahima, B., Jackson, R. J., Komase, K., Dohi, T., Boyaka, P. N., Takeda, Y., Kiyono, H., McGhee, J. R., and Fujihashi, K. (2006). A second generation of double mutant cholera toxin adjuvants: Enhanced immunity without intracellular trafficking. J. Immunol. 177:3045–3054.PubMedGoogle Scholar
  89. Haile, M., and Kallenius, G. (2005). Recent developments in tuberculosis vaccines. Curr. Opin. Infect. Dis. 18:211–215.PubMedGoogle Scholar
  90. Halpern, M. S., and Koshland, M. E. (1970). Noval subunit in secretory IgA. Nature 228:1276–1278.PubMedGoogle Scholar
  91. Hamada, H., Hiroi, T., Nishiyama, Y., Takahashi, H., Masunaga, Y., Hachimura, S., Kaminogawa, S., Takahashi-Iwanaga, H., Iwanaga, T., Kiyono, H., Yamamoto, H., and Ishikawa, H. (2002). Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. J. Immunol. 168:57–64.PubMedGoogle Scholar
  92. Han, M., Watarai, S., Kobayashi, K., and Yasuda, T. (1997). Application of liposomes for development of oral vaccines: study of in vitro stability of liposomes and antibody response to antigen associated with liposomes after oral immunization. J. Vet. Med. Sci. 59:1109–1114.PubMedGoogle Scholar
  93. Harandi, A. M., and Holmgren, J. (2004). CpG DNA as a potent inducer of mucosal immunity: Implications for immunoprophylaxis and immunotherapy of mucosal infections. Curr. Opin. Invest. Drugs 5:141–145.Google Scholar
  94. Hartmann, G., and Krieg, A. M. (2000). Mechanism and function of a newly identified CpG DNA motif in human primary B cells. J. Immunol. 164:944–953.PubMedGoogle Scholar
  95. Haynes, L., and Eaton, S. M. (2005). The effect of age on the cognate function of CD4+ T cells. Immunol. Rev. 205:220–228.PubMedGoogle Scholar
  96. Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., and Akira, S. (2000). A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745.PubMedGoogle Scholar
  97. Higgins, L. M., Lambkin, I., Donnelly, G., Byrne, D., Wilson, C., Dee, J., Smith, M., and O’Mahony, D. J. (2004). In vivo phage display to identify M cell-targeting ligands. Pharm. Res. 21:695–705.PubMedGoogle Scholar
  98. Hiroi, T., Yanagita, M., Iijima, H., Iwatani, K., Yoshida, T., Takatsu, K., and Kiyono, H. (1999). Deficiency of IL-5 receptor alpha-chain selectively influences the development of the common mucosal immune system independent IgA-producing B-1 cell in mucosa-associated tissues. J. Immunol. 162:821–828.PubMedGoogle Scholar
  99. Hiroi, T., Yanagita, M., Ohta, N., Sakaue, G., and Kiyono, H. (2000). IL-15 and IL-15 receptor selectively regulate differentiation of common mucosal immune system-independent B-1 cells for IgA responses. J. Immunol. 165:4329–4337.PubMedGoogle Scholar
  100. Hohmann, E. L., Oletta, C. A., Killeen, K. P., and Miller, S. I. (1996). phoP/phoQ-deleted Salmonella typhi (Ty800) is a safe and immunogenic single-dose typhoid fever vaccine in volunteers. J. Infect. Dis. 173:1408–1414.PubMedGoogle Scholar
  101. Hohmann, E. L., Oletta, C. A., Loomis, W. P., and Miller, S. I. (1995). Macrophage-inducible expression of a model antigen in Salmonella typhimurium enhances immunogenicity. Proc. Natl. Acad. Sci. USA 92:2904–2908.PubMedGoogle Scholar
  102. Hoiseth, S. K., and Stocker, B. A. (1981). Aromatic-dependent Salmonella typhimurium are non-virulent and effective as live vaccines. Nature 291:238–239.PubMedGoogle Scholar
  103. Hone, D. M., DeVico, A. L., Fouts, T. R., Onyabe, D. Y., Agwale, S. M., Wambebe, C. O., Blattner, W. A., Gallo, R. C., and Lewis, G. K. (2002). Development of vaccination strategies that elicit broadly neutralizing antibodies against human immunodeficiency virus type 1 in both the mucosal and systemic immune compartments. J. Hum. Virol. 5:17–23.PubMedGoogle Scholar
  104. Hone, D. M., Tacket, C. O., Harris, A. M., Kay, B., Losonsky, G., and Levine, M. M. (1992). Evaluation in volunteers of a candidate live oral attenuated Salmonella typhi vector vaccine. J. Clin. Invest. 90:412–420.PubMedGoogle Scholar
  105. Horner, A. A., Datta, S. K., Takabayashi, K., Belyakov, I. M., Hayashi, T., Cinman, N., Nguyen, M. D., Van Uden, J. H., Berzofsky, J. A., Richman, D. D., and Raz, E. (2001). Immunostimulatory DNA-based vaccines elicit multifaceted immune responses against HIV at systemic and mucosal sites. J. Immunol. 167:1584–1591.PubMedGoogle Scholar
  106. Hornquist, E., Grdic, D., Mak, T., and Lycke, N. (1996). CD8-deficient mice exhibit augmented mucosal immune responses and intact adjuvant effects to cholera toxin. Immunology 87:220–229.PubMedGoogle Scholar
  107. Hu, K. F., Elvander, M., Merza, M., Akerblom, L., Brandenburg, A., and Morein, B. (1998). The immunostimulating complex (ISCOM) is an efficient mucosal delivery system for respiratory syncytial virus (RSV) envelope antigens inducing high local and systemic antibody responses. Clin. Exp. Immunol. 113:235–243.PubMedGoogle Scholar
  108. Hu, K. F., Lovgren-Bengtsson, K., and Morein, B. (2001). Immunostimulating complexes (ISCOMs) for nasal vaccination. Adv. Drug Deliv. Rev. 51:149–159.PubMedGoogle Scholar
  109. Hutchings, C. L., Gilbert, S. C., Hill, A. V., and Moore, A. C. (2005). Novel protein and poxvirus-based vaccine combinations for simultaneous induction of humoral and cell-mediated immunity. J. Immunol. 175:599–606.PubMedGoogle Scholar
  110. Ichinohe, T., Watanabe, I., Ito, S., Fujii, H., Moriyama, M., Tamura, S., Takahashi, H., Sawa, H., Chiba, J., Kurata, T., Sata, T., and Hasegawa, H. (2005). Synthetic double-stranded RNA poly(I:C) combined with mucosal vaccine protects against influenza virus infection. J. Virol. 79:2910–2919.PubMedGoogle Scholar
  111. Isaka, M., Komiya, T., Takahashi, M., Yasuda, Y., Taniguchi, T., Zhao, Y., Matano, K., Matsui, H., Maeyama, J., Morokuma, K., Ohkuma, K., Goto, N., and Tochikubo, K. (2004). Recombinant cholera toxin B subunit (rCTB) as a mucosal adjuvant enhances induction of diphtheria and tetanus antitoxin antibodies in mice by intranasal administration with diphtheria-pertussis-tetanus (DPT) combination vaccine. Vaccine 22:3061–3068.PubMedGoogle Scholar
  112. Isomura, I., Yasuda, Y., Tsujimura, K., Takahashi, T., Tochikubo, K., and Morita, A. (2005). Recombinant cholera toxin B subunit activates dendritic cells and enhances antitumor immunity. Microbiol. Immunol. 49:79–87.PubMedGoogle Scholar
  113. Iwasaki, A., and Medzhitov, R. (2004). Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5:987–995.PubMedGoogle Scholar
  114. Iwata, M., Hirakiyama, A., Eshima, Y., Kagechika, H., Kato, C., and Song, S. Y. (2004). Retinoic acid imprints gut-homing specificity on T cells. Immunity 21:527–538.PubMedGoogle Scholar
  115. Jain, S. L., Barone, K. S., and Michael, J. G. (1996). Activation patterns of murine T cells after oral administration of an enterocoated soluble antigen. Cell. Immunol. 167:170–175.PubMedGoogle Scholar
  116. Jang, M. H., Kweon, M. N., Iwatani, K., Yamamoto, M., Terahara, K., Sasakawa, C., Suzuki, T., Nochi, T., Yokota, Y., Rennert, P. D., Hiroi, T., Tamagawa, H., Iijima, H., Kunisawa, J., Yuki, Y., and Kiyono, H. (2004). Intestinal villous M cells: An antigen entry site in the mucosal epithelium. Proc. Natl. Acad. Sci. USA 101:6110–6115.PubMedGoogle Scholar
  117. Jepson, M. A., Clark, M. A., and Hirst, B. H. (2004). M cell targeting by lectins: A strategy for mucosal vaccination and drug delivery. Adv. Drug Deliv. Rev. 56:511–525.PubMedGoogle Scholar
  118. Jiang, W., Baker, H. J., and Smith, B. F. (2003). Mucosal immunization with helicobacter, CpG DNA, and cholera toxin is protective. Infect. Immun. 71:40–46.PubMedGoogle Scholar
  119. Johansson-Lindbom, B., Svensson, M., Wurbel, M. A., Malissen, B., Marquez, G., and Agace, W. (2003). Selective generation of gut tropic T cells in gut-associated lymphoid tissue (GALT): Requirement for GALT dendritic cells and adjuvant. J. Exp. Med. 198:963–969.PubMedGoogle Scholar
  120. Johnson, K., Charles, I., Dougan, G., Pickard, D., O’Gaora, P., Costa, G., Ali, T., Miller, I., and Hormaeche, C. (1991). The role of a stress-response protein in Salmonella typhimurium virulence. Mol. Microbiol. 5:401–407.PubMedGoogle Scholar
  121. Kaetzel, C. S. (2005). The polymeric immunoglobulin receptor: Bridging innate and adaptive immune responses at mucosal surfaces. Immunol. Rev. 206:83–99.PubMedGoogle Scholar
  122. Kaetzel, C. S., Robinson, J. K., Chintalacharuvu, K. R., Vaerman, J. P., and Lamm, M. E. (1991). The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: A local defense function for IgA. Proc. Natl. Acad. Sci. USA 88:8796–8800.PubMedGoogle Scholar
  123. Karem, K. L., Bowen, J., Kuklin, N., and Rouse, B. T. (1997). Protective immunity against herpes simplex virus (HSV) type 1 following oral administration of recombinant Salmonella typhimurium vaccine strains expressing HSV antigens. J. Gen. Virol. 78(Pt. 2):427–434.PubMedGoogle Scholar
  124. Karlsson, G. B., and Liljestrom, P. (2003). Live viral vectors: Semliki Forest virus. Methods Mol. Med. 87:69–82.PubMedGoogle Scholar
  125. Kazanji, M., Laurent, F., and Pery, P. (1994). Immune responses and protective effect in mice vaccinated orally with surface sporozoite protein of Eimeria falciformis in ISCOMs. Vaccine 12:798–804.PubMedGoogle Scholar
  126. Kelsall, B. L., and Leon, F. (2005). Involvement of intestinal dendritic cells in oral tolerance, immunity to pathogens, and inflammatory bowel disease. Immunol. Rev. 206:132–148.PubMedGoogle Scholar
  127. Kensil, C. R., Patel, U., Lennick, M., and Marciani, D. (1991). Separation and characterization of saponins with adjuvant activity from Quillaja saponaria Molina cortex. J. Immunol. 146:431–437.PubMedGoogle Scholar
  128. Khromykh, A. A. (2000). Replicon-based vectors of positive strand RNA viruses. Curr. Opin. Mol. Ther. 2:555–569.PubMedGoogle Scholar
  129. Kiyono, H., and Fukuyama, S. (2004). NALT- versus Peyer’s-patch-mediated mucosal immunity. Nat. Rev. Immunol. 4PubMedGoogle Scholar
  130. Kiyono, H., Michalek, S. M., Mosteller, L. M., Torii, M., Hamada, S., and McGhee, J. R. (1982). Enhancement of murine immune responses to orally administered haptenated Streptococcus mutans. Scand. J. Immunol. 16:455–463.PubMedGoogle Scholar
  131. Kobayashi, R., Kohda, T., Kataoka, K., Ihara, H., Kozaki, S., Pascual, D. W., Staats, H. F., Kiyono, H., McGhee, J. R., and Fujihashi, K. (2005). A novel neurotoxoid vaccine prevents mucosal botulism. J. Immunol. 174:2190–2195.PubMedGoogle Scholar
  132. Kovanen, P. E., and Leonard, W. J. (2004). Cytokines and immunodeficiency diseases: critical roles of the gamma(c)-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways. Immunol. Rev. 202:67–83.PubMedGoogle Scholar
  133. Krieg, A. M., Yi, A. K., Matson, S., Waldschmidt, T. J., Bishop, G. A., Teasdale, R., Koretzky, G. A., and Klinman, D. M. (1995). CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–549.PubMedGoogle Scholar
  134. Kunisawa, J., Fukuyama, S., and Kiyono, H. (2005). Mucosa-associated lymphoid tissues in aerodigestive tract: Their shared and divergent traits and their importance to the orchestration of the mucosal immune system. Curr. Mol. Med. 5:557–572.PubMedGoogle Scholar
  135. Kunisawa, J., and Kiyono, H. (2005). A marvel of mucosal T cells and secretory antibodies for the creation of first lines of defense. Cell. Mol. Life Sci. 62:1308–1321.PubMedGoogle Scholar
  136. Kunisawa, J., Nakagawa, S., and Mayumi, T. (2001a). Pharmacotherapy by intracellular delivery of drugs using fusogenic liposomes: Application to vaccine development. Adv. Drug Deliv. Rev. 52:177–186.PubMedGoogle Scholar
  137. Kunisawa, J., Nakanishi, T., Takahashi, I., Okudaira, A., Tsutsumi, Y., Katayama, K., Nakagawa, S., Kiyono, H., and Mayumi, T. (2001b). Sendai virus fusion protein mediates simultaneous induction of MHC class I/II-dependent mucosal and systemic immune responses via the nasopharyngeal-associated lymphoreticular tissue immune system. J. Immunol. 167:1406–1412.PubMedGoogle Scholar
  138. Kunisawa, J., Okudaira, A., Tsutsumi, Y., Takahashi, I., Nakanishi, T., Kiyono, H., and Mayumi, T. (2000). Characterization of mucoadhesive microspheres for the induction of mucosal and systemic immune responses. Vaccine 19:589–594.PubMedGoogle Scholar
  139. Kunisawa, J., and Shastri, N. (2003). The group II chaperonin TRiC protects proteolytic intermediates from degradation in the MHC class I antigen processing pathway. Mol. Cell 12:565–576.PubMedGoogle Scholar
  140. Kunisawa, J., Takahashi, I., Okudaira, A., Hiroi, T., Katayama, K., Ariyama, T., Tsutsumi, Y., Nakagawa, S., Kiyono, H., and Mayumi, T. (2002). Lack of antigen-specific immune responses in anti-IL-7 receptor alpha chain antibody-treated Peyer’s patch-null mice following intestinal immunization with microencapsulated antigen. Eur. J. Immunol. 32:2347–2355.PubMedGoogle Scholar
  141. Kunkel, E. J., Kim, C. H., Lazarus, N. H., Vierra, M. A., Soler, D., Bowman, E. P., and Butcher, E. C. (2003). CCR10 expression is a common feature of circulating and mucosal epithelial tissue IgA Ab-secreting cells. J. Clin. Invest. 111:1001–1010.PubMedGoogle Scholar
  142. Kweon, M. N., Yamamoto, M., Watanabe, F., Tamura, S., Van Ginkel, F. W., Miyauchi, A., Takagi, H., Takeda, Y., Hamabata, T., Fujihashi, K., McGhee, J. R., and Kiyono, H. (2002). A nontoxic chimeric enterotoxin adjuvant induces protective immunity in both mucosal and systemic compartments with reduced IgE antibodies. J. Infect. Dis. 186:1261–1269.PubMedGoogle Scholar
  143. Lambkin, I., Pinilla, C., Hamashin, C., Spindler, L., Russell, S., Schink, A., Moya-Castro, R., Allicotti, G., Higgins, L., Smith, M., Dee, J., Wilson, C., Houghten, R., and O’Mahony, D. (2003). Toward targeted oral vaccine delivery systems: Selection of lectin mimetics from combinatorial libraries. Pharm. Res. 20:1258–1266.PubMedGoogle Scholar
  144. Lambkin, R., Oxford, J. S., Bossuyt, S., Mann, A., Metcalfe, I. C., Herzog, C., Viret, J. F., and Gluck, R. (2004). Strong local and systemic protective immunity induced in the ferret model by an intranasal virosome-formulated influenza subunit vaccine. Vaccine 22:4390–4396.PubMedGoogle Scholar
  145. Lee, J., Mo, J. H., Katakura, K., Alkalay, I., Rucker, A. N., Liu, Y. T., Lee, H. K., Shen, C., Cojocaru, G., Shenouda, S., Kagnoff, M., Eckmann, L., Ben-Neriah, Y., and Raz, E. (2006). Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nature Cell Biol. 8:1327–1336.PubMedGoogle Scholar
  146. Lee, S., Gierynska, M., Eo, S. K., Kuklin, N., and Rouse, B. T. (2003). Influence of DNA encoding cytokines on systemic and mucosal immunity following genetic vaccination against herpes simplex virus. Microbes Infect. 5:571–578.PubMedGoogle Scholar
  147. Lencer, W. I., Moe, S., Rufo, P. A., and Madara, J. L. (1995). Transcytosis of cholera toxin subunits across model human intestinal epithelia. Proc. Natl. Acad. Sci. USA 92:10, 094–10, 098.Google Scholar
  148. Lencer, W. I., and Tsai, B. (2003). The intracellular voyage of cholera toxin: Going retro. Trends Biochem. Sci. 28:639–645.PubMedGoogle Scholar
  149. Levine, M. M., Galen, J., Barry, E., Noriega, F., Tacket, C., Sztein, M., Chatfield, S., Dougan, G., Losonsky, G., and Kotloff, K. (1997). Attenuated Salmonella typhi and Shigella as live oral vaccines and as live vectors. Behring. Inst. Mitt. 120–123.Google Scholar
  150. Lillard, J. W., Jr., Boyaka, P. N., Chertov, O., Oppenheim, J. J., and McGhee, J. R. (1999a). Mechanisms for induction of acquired host immunity by neutrophil peptide defensins. Proc. Natl. Acad. Sci. USA 96:651–656.PubMedGoogle Scholar
  151. Lillard, J. W., Jr., Boyaka, P. N., Hedrick, J. A., Zlotnik, A., and McGhee, J. R. (1999b). Lymphotactin acts as an innate mucosal adjuvant. J. Immunol. 162:1959–1965.PubMedGoogle Scholar
  152. Lillard, J. W., Jr., Boyaka, P. N., Taub, D. D., and McGhee, J. R. (2001). RANTES potentiates antigen-specific mucosal immune responses. J. Immunol. 166:162–169.PubMedGoogle Scholar
  153. Lillard, J. W., Jr., Singh, U. P., Boyaka, P. N., Singh, S., Taub, D. D., and McGhee, J. R. (2003). MIP-1alpha and MIP-1beta differentially mediate mucosal and systemic adaptive immunity. Blood 101:807–814.PubMedGoogle Scholar
  154. Lindsay, D. S., Parton, R., and Wardlaw, A. C. (1994). Adjuvant effect of pertussis toxin on the production of anti-ovalbumin IgE in mice and lack of direct correlation between PCA and ELISA. Int. Arch. Allergy Immunol. 105:281–288.PubMedGoogle Scholar
  155. Lundstrom, K. (2002). Alphavirus-based vaccines. Curr. Opin. Mol. Ther. 4:28–34.PubMedGoogle Scholar
  156. Lundstrom, K. (2003a). Alphavirus vectors for vaccine production and gene therapy. Expert. Rev. Vaccines 2:447–459.PubMedGoogle Scholar
  157. Lundstrom, K. (2003b). Semliki Forest virus vectors for gene therapy. Expert Opin. Biol. Ther. 3:771–777.PubMedGoogle Scholar
  158. Lycke, N. (2004). ADP-ribosylating bacterial enzymes for the targeted control of mucosal tolerance and immunity. Ann. NY Acad. Sci. 1029:193–208.PubMedGoogle Scholar
  159. Lycke, N. (2005). Targeted vaccine adjuvants based on modified cholera toxin. Curr. Mol. Med. 5:591–597.PubMedGoogle Scholar
  160. Lycke, N., and Holmgren, J. (1986). Strong adjuvant properties of cholera toxin on gut mucosal immune responses to orally presented antigens. Immunology 59:301–308.PubMedGoogle Scholar
  161. Lycke, N. Y. (1993). Cholera toxin promotes B cell isotype switching by two different mechanisms. cAMP induction augments germ-line Ig H-chain RNA transcripts whereas membrane ganglioside GM1-receptor binding enhances later events in differentiation. J. Immunol. 150:4810–4821.PubMedGoogle Scholar
  162. Mackett, M., Smith, G. L., and Moss, B. (1984). General method for production and selection of infectious vaccinia virus recombinants expressing foreign genes. J. Virol. 49:857–864.PubMedGoogle Scholar
  163. Macpherson, A. J., Gatto, D., Sainsbury, E., Harriman, G. R., Hengartner, H., and Zinkernagel, R. M. (2000). A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288:2222–2226.PubMedGoogle Scholar
  164. Maddaloni, M., Staats, H. F., Mierzejewska, D., Hoyt, T., Robinson, A., Callis, G., Kozaki, S., Kiyono, H., McGhee, J. R., Fujihashi, K., and Pascual, D. W. (2006). Mucosal vaccine targeting improves onset of mucosal and systemic immunity to botulinum neurotoxin A. J. Immunol. 177:5524–5532.PubMedGoogle Scholar
  165. Manocha, M., Pal, P. C., Chitralekha, K. T., Thomas, B. E., Tripathi, V., Gupta, S. D., Paranjape, R., Kulkarni, S., and Rao, D. N. (2005). Enhanced mucosal and systemic immune response with intranasal immunization of mice with HIV peptides entrapped in PLG microparticles in combination with Ulex europaeus-I lectin as M cell target. Vaccine 23:5599–5617.PubMedGoogle Scholar
  166. Marchetti, M., Rossi, M., Giannelli, V., Giuliani, M. M., Pizza, M., Censini, S., Covacci, A., Massari, P., Pagliaccia, C., Manetti, R., Telford, J. L., Douce, G., Dougan, G., Rappuoli, R., and Ghiara, P. (1998). Protection against Helicobacter pylori infection in mice by intragastric vaccination with H. pylori antigens is achieved using a non-toxic mutant of E. coli heat-labile enterotoxin (LT) as adjuvant. Vaccine 16:33–37.PubMedGoogle Scholar
  167. Marinaro, M., Boyaka, P. N., Jackson, R. J., Finkelman, F. D., Kiyono, H., Jirillo, E., and McGhee, J. R. (1999a). Use of intranasal IL-12 to target predominantly Th1 responses to nasal and Th2 responses to oral vaccines given with cholera toxin. J. Immunol. 162:114–121.PubMedGoogle Scholar
  168. Marinaro, M., Di Tommaso, A., Uzzau, S., Fasano, A., and De Magistris, M. T. (1999b). Zonula occludens toxin is a powerful mucosal adjuvant for intranasally delivered antigens. Infect. Immun. 67:1287–1291.PubMedGoogle Scholar
  169. Marinaro, M., Fasano, A., and De Magistris, M. T. (2003). Zonula occludens toxin acts as an adjuvant through different mucosal routes and induces protective immune responses. Infect. Immun. 71:1897–1902.PubMedGoogle Scholar
  170. Martin, M., Michalek, S. M., and Katz, J. (2003). Role of innate immune factors in the adjuvant activity of monophosphoryl lipid A. Infect. Immun. 71:2498–2507.PubMedGoogle Scholar
  171. McCluskie, M. J., and Davis, H. L. (2000). Oral, intrarectal and intranasal immunizations using CpG and non-CpG oligodeoxynucleotides as adjuvants. Vaccine 19:413–422.PubMedGoogle Scholar
  172. McGhee, J. R., Fujihashi, K., Beagley, K. W., and Kiyono, H. (1991). Role of interleukin-6 in human and mouse mucosal IgA plasma cell responses. Immunol. Res. 10:418–422.PubMedGoogle Scholar
  173. Mestecky, J., Zikan, J., and Butler, W. T. (1971). Immunoglobulin M and secretory immunoglobulin A: Presence of a common polypeptide chain different from light chains. Science 171:1163–1165.PubMedGoogle Scholar
  174. Mikloska, Z., Ruckholdt, M., Ghadiminejad, I., Dunckley, H., Denis, M., and Cunningham, A. L. (2000). Monophosphoryl lipid A and QS21 increase CD8 T lymphocyte cytotoxicity to herpes simplex virus-2 infected cell proteins 4 and 27 through IFN-gamma and IL-12 production. J. Immunol. 164:5167–5176.PubMedGoogle Scholar
  175. Mizuguchi, H., Kay, M. A., and Hayakawa, T. (2001). Approaches for generating recombinant adenovirus vectors. Adv. Drug Deliv. Rev. 52:165–176.PubMedGoogle Scholar
  176. Mohamedi, S. A., Brewer, J. M., Alexander, J., Heath, A. W., and Jennings, R. (2000). Antibody responses, cytokine levels and protection of mice immunised with HSV-2 antigens formulated into NISV or ISCOM delivery systems. Vaccine 18:2083–2094.PubMedGoogle Scholar
  177. Moldoveanu, Z., Novak, M., Huang, W. Q., Gilley, R. M., Staas, J. K., Schafer, D., Compans, R. W., and Mestecky, J. (1993). Oral immunization with influenza virus in biodegradable microspheres. J. Infect. Dis. 167:84–90.PubMedGoogle Scholar
  178. Mora, J. R., Bono, M. R., Manjunath, N., Weninger, W., Cavanagh, L. L., Rosemblatt, M., and Von Andrian, U. H. (2003). Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature 424:88–93.PubMedGoogle Scholar
  179. Morris, C. B., Cheng, E., Thanawastien, A., Cardenas-Freytag, L., and Clements, J. D. (2000). Effectiveness of intranasal immunization with HIV-gp160 and an HIV-1 env CTL epitope peptide (E7) in combination with the mucosal adjuvant LT(R192G). Vaccine 18:1944–1951.PubMedGoogle Scholar
  180. Mowat, A. M., Donachie, A. M., Reid, G., and Jarrett, O. (1991). Immune-stimulating complexes containing Quil A and protein antigen prime class I MHC-restricted T lymphocytes in vivo and are immunogenic by the oral route. Immunology 72:317–322.PubMedGoogle Scholar
  181. Nashar, T. O., Webb, H. M., Eaglestone, S., Williams, N. A., and Hirst, T. R. (1996). Potent immunogenicity of the B subunits of Escherichia coli heat-labile enterotoxin: Receptor binding is essential and induces differential modulation of lymphocyte subsets. Proc. Natl. Acad. Sci. USA 93:226–230.PubMedGoogle Scholar
  182. Nawar, H. F., Arce, S., Russell, M. W., and Connell, T. D. (2007). Mutants of type II heat-labile enterotoxin LT-IIa with altered ganglioside-binding activities and diminished toxicity are potent mucosal adjuvants. Infect. Immun. 75:621–633.PubMedGoogle Scholar
  183. Neutra, M. R., Mantis, N. J., and Kraehenbuhl, J. P. (2001). Collaboration of epithelial cells with organized mucosal lymphoid tissues. Nat. Immunol. 2:1004–1009.PubMedGoogle Scholar
  184. Niess, J. H., Brand, S., Gu, X., Landsman, L., Jung, S., McCormick, B. A., Vyas, J. M., Boes, M., Ploegh, H. L., Fox, J. G., Littman, D. R., and Reinecker, H. C. (2005). CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307:254–258.PubMedGoogle Scholar
  185. Oh, S., Berzofsky, J. A., Burke, D. S., Waldmann, T. A., and Perera, L. P. (2003). Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity. Proc. Natl. Acad. Sci. USA 100:3392–3397.PubMedGoogle Scholar
  186. O’Hagan, D. T., and Singh, M. (2003). Microparticles as vaccine adjuvants and delivery systems. Expert. Rev. Vaccines 2:269–283.PubMedGoogle Scholar
  187. Ohmura, M., Yamamoto, M., Kiyono, H., Fujihashi, K., Takeda, Y., and McGhee, J. R. (2001). Highly purified mutant E112K of cholera toxin elicits protective lung mucosal immunity to diphtheria toxin. Vaccine 20:756–762.PubMedGoogle Scholar
  188. Ohmura, M., Yamamoto, M., Tomiyama-Miyaji, C., Yuki, Y., Takeda, Y., and Kiyono, H. (2005). Nontoxic Shiga toxin derivatives from Escherichia coli possess adjuvant activity for the augmentation of antigen-specific immune responses via dendritic cell activation. Infect. Immun. 73:4088–4097.PubMedGoogle Scholar
  189. Ohmura-Hoshino, M., Yamamoto, M., Yuki, Y., Takeda, Y., and Kiyono, H. (2004). Non-toxic Stx derivatives from Escherichia coli possess adjuvant activity for mucosal immunity. Vaccine 22:3751–3761.PubMedGoogle Scholar
  190. Okada, H., and Toguchi, H. (1995). Biodegradable microspheres in drug delivery. Crit. Rev. Ther. Drug Carrier Syst. 12:1–99.PubMedGoogle Scholar
  191. Okada, J., Cohen, S., and Langer, R. (1995). In vitro evaluation of polymerized liposomes as an oral drug delivery system. Pharm. Res. 12:576–582.PubMedGoogle Scholar
  192. O’Neal, C. M., Clements, J. D., Estes, M. K., and Conner, M. E. (1998). Rotavirus 2/6 viruslike particles administered intranasally with cholera toxin, Escherichia coli heat-labile toxin (LT), and LT-R192G induce protection from rotavirus challenge. J. Virol. 72:3390–3393.PubMedGoogle Scholar
  193. Ourmanov, I., Brown, C. R., Moss, B., Carroll, M., Wyatt, L., Pletneva, L., Goldstein, S., Venzon, D., and Hirsch, V. M. (2000). Comparative efficacy of recombinant modified vaccinia virus Ankara expressing simian immunodeficiency virus (SIV) Gag-Pol and/or Env in macaques challenged with pathogenic SIV. J. Virol. 74:2740–2751.PubMedGoogle Scholar
  194. Paoletti, E. (1996). Applications of pox virus vectors to vaccination: an update. Proc. Natl. Acad. Sci. USA 93:11349–11353.PubMedGoogle Scholar
  195. Partidos, C. D., Pizza, M., Rappuoli, R., and Steward, M. W. (1996). The adjuvant effect of a non-toxic mutant of heat-labile enterotoxin of Escherichia coli for the induction of measles virus-specific CTL responses after intranasal co-immunization with a synthetic peptide. Immunology 89:483–487.PubMedGoogle Scholar
  196. Peppoloni, S., Ruggiero, P., Contorni, M., Morandi, M., Pizza, M., Rappuoli, R., Podda, A., and Del Giudice, G. (2003). Mutants of the Escherichia coli heat-labile enterotoxin as safe and strong adjuvants for intranasal delivery of vaccines. Expert. Rev. Vaccines 2:285–293.PubMedGoogle Scholar
  197. Pinczewski, J., Zhao, J., Malkevitch, N., Patterson, L. J., Aldrich, K., Alvord, W. G., and Robert-Guroff, M. (2005). Enhanced immunity and protective efficacy against SIVmac251 intrarectal challenge following ad-SIV priming by multiple mucosal routes and gp120 boosting in MPL-SE. Viral Immunol. 18:236–243.PubMedGoogle Scholar
  198. Pizza, M., Giuliani, M. M., Fontana, M. R., Douce, G., Dougan, G., and Rappuoli, R. (2000). LTK63 and LTR72, two mucosal adjuvants ready for clinical trials. Int. J. Med. Microbiol. 290:455–461.PubMedGoogle Scholar
  199. Poltorak, A., He, X., Smirnova, I., Liu, M. Y., Van Huffel, C., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., Freudenberg, M., Ricciardi-Castagnoli, P., Layton, B., and Beutler, B. (1998). Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088.PubMedGoogle Scholar
  200. Porter, D. C., Ansardi, D. C., Choi, W. S., and Morrow, C. D. (1993). Encapsidation of genetically engineered poliovirus minireplicons which express human immunodeficiency virus type 1 Gag and Pol proteins upon infection. J. Virol. 67:3712–3719.PubMedGoogle Scholar
  201. Proietti, E., Bracci, L., Puzelli, S., Di Pucchio, T., Sestili, P., De Vincenzi, E., Venditti, M., Capone, I., Seif, I., De Maeyer, E., Tough, D., Donatelli, I., and Belardelli, F. (2002). Type I IFN as a natural adjuvant for a protective immune response: lessons from the influenza vaccine model. J. Immunol. 169:375–383.PubMedGoogle Scholar
  202. Rappuoli, R., Douce, G., Dougan, G., and Pizza, M. (1995). Genetic detoxification of bacterial toxins: A new approach to vaccine development. Int. Arch. Allergy Immunol. 108:327–333.PubMedGoogle Scholar
  203. Rappuoli, R., Pizza, M., Douce, G., and Dougan, G. (1999). Structure and mucosal adjuvanticity of cholera and Escherichia coli heat-labile enterotoxins. Immunol. Today 20:493–500.PubMedGoogle Scholar
  204. Rescigno, M., Urbano, M., Valzasina, B., Francolini, M., Rotta, G., Bonasio, R., Granucci, F., Kraehenbuhl, J. P., and Ricciardi-Castagnoli, P. (2001). Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat. Immunol. 2:361–367.PubMedGoogle Scholar
  205. Rharbaoui, F., Drabner, B., Borsutzky, S., Winckler, U., Morr, M., Ensoli, B., Muhlradt, P. F., and Guzman, C. A. (2002). The Mycoplasma-derived lipopeptide MALP-2 is a potent mucosal adjuvant. Eur. J. Immunol. 32:2857–2865.PubMedGoogle Scholar
  206. Rharbaoui, F., Westendorf, A., Link, C., Felk, S., Buer, J., Gunzer, M., and Guzman, C. A. (2004). The mycoplasma-derived macrophage-activating 2-kilodalton lipopeptide triggers global immune activation on nasal mucosa-associated lymphoid tissues. Infect. Immun. 72:6978–6986.PubMedGoogle Scholar
  207. Rimmelzwaan, G. F., Baars, M., van Beek, R., van Amerongen, G., Lovgren-Bengtsson, K., Claas, E. C., and Osterhaus, A. D. (1997). Induction of protective immunity against influenza virus in a macaque model: Comparison of conventional and iscom vaccines. J. Gen. Virol. 78(Pt. 4):757–765.PubMedGoogle Scholar
  208. Roberts, M., Bacon, A., Rappuoli, R., Pizza, M., Cropley, I., Douce, G., Dougan, G., Marinaro, M., McGhee, J., and Chatfield, S. (1995). A mutant pertussis toxin molecule that lacks ADP-ribosyltransferase activity, PT-9K/129G, is an effective mucosal adjuvant for intranasally delivered proteins. Infect. Immun. 63:2100–2108.PubMedGoogle Scholar
  209. Saito, T., Deskin, R. W., Casola, A., Haeberle, H., Olszewska, B., Ernst, P. B., Alam, R., Ogra, P. L., and Garofalo, R. (1997). Respiratory syncytial virus induces selective production of the chemokine RANTES by upper airway epithelial cells. J. Infect. Dis. 175:497–504.PubMedGoogle Scholar
  210. Sakaue, G., Hiroi, T., Nakagawa, Y., Someya, K., Iwatani, K., Sawa, Y., Takahashi, H., Honda, M., Kunisawa, J., and Kiyono, H. (2003). HIV mucosal vaccine: nasal immunization with gp160-encapsulated hemagglutinating virus of Japan-liposome induces antigen-specific CTLs and neutralizing antibody responses. J. Immunol. 170:495–502.PubMedGoogle Scholar
  211. Sanders, M. T., Brown, L. E., Deliyannis, G., and Pearse, M. J. (2005). ISCOM-based vaccines: The second decade. Immunol. Cell. Biol. 83:119–128.PubMedGoogle Scholar
  212. Santosuosso, M., McCormick, S., and Xing, Z. (2005). Adenoviral vectors for mucosal vaccination against infectious diseases. Viral Immunol. 18:283–291.PubMedGoogle Scholar
  213. Sato, A., and Iwasaki, A. (2005). Peyer’s patch dendritic cells as regulators of mucosal adaptive immunity. Cell. Mol. Life Sci. 62:1333–1338.PubMedGoogle Scholar
  214. Sauter, S. L., Rahman, A., and Muralidhar, G. (2005). Non-replicating viral vector-based AIDS vaccines: Interplay between viral vectors and the immune system. Curr. HIV Res. 3:157–181.PubMedGoogle Scholar
  215. Schmitz, A., Herrgen, H., Winkeler, A., and Herzog, V. (2000). Cholera toxin is exported from microsomes by the Sec61p complex. J. Cell. Biol. 148:1203–1212.PubMedGoogle Scholar
  216. Selsted, M. E., and Ouellette, A. J. (2005). Mammalian defensins in the antimicrobial immune response. Nat. Immunol. 6:551–557.PubMedGoogle Scholar
  217. Shastri, N., Cardinaud, S., Schwab, S. R., Serwold, T., and Kunisawa, J. (2005). All the peptides that fit: The beginning, the middle, and the end of the MHC class I antigen processing pathway. Immunol. Rev. 207:31–41.PubMedGoogle Scholar
  218. Shikina, T., Hiroi, T., Iwatani, K., Jang, M. H., Fukuyama, S., Tamura, M., Kubo, T., Ishikawa, H., and Kiyono, H. (2004). IgA class switch occurs in the organized nasopharynx- and gut-associated lymphoid tissue, but not in the diffuse lamina propria of airways and gut. J. Immunol. 172:6259–6264.PubMedGoogle Scholar
  219. Shimoda, M., Nakamura, T., Takahashi, Y., Asanuma, H., Tamura, S., Kurata, T., Mizuochi, T., Azuma, N., Kanno, C., and Takemori, T. (2001). Isotype-specific selection of high affinity memory B cells in nasal-associated lymphoid tissue. J. Exp. Med. 194:1597–1607.PubMedGoogle Scholar
  220. Shreedhar, V. K., Kelsall, B. L., and Neutra, M. R. (2003). Cholera toxin induces migration of dendritic cells from the subepithelial dome region to T- and B-cell areas of Peyer’s patches. Infect. Immun. 71:504–509.PubMedGoogle Scholar
  221. Sicinski, P., Rowinski, J., Warchol, J. B., Jarzabek, Z., Gut, W., Szczygiel, B., Bielecki, K., and Koch, G. (1990). Poliovirus type 1 enters the human host through intestinal M cells. Gastroenterology 98:56–58.PubMedGoogle Scholar
  222. Silla, S., Fallarino, F., Boon, T., and Uyttenhove, C. (1999). Enhancement by IL-12 of the cytolytic T lymphocyte (CTL) response of mice immunized with tumor-specific peptides in an adjuvant containing QS21 and MPL. Eur. Cytokine Netw. 10:181–190.PubMedGoogle Scholar
  223. Simmons, C. P., Mastroeni, P., Fowler, R., Ghaem-maghami, M., Lycke, N., Pizza, M., Rappuoli, R., and Dougan, G. (1999). MHC class I-restricted cytotoxic lymphocyte responses induced by enterotoxin-based mucosal adjuvants. J. Immunol. 163:6502–6510.PubMedGoogle Scholar
  224. Simms, J. R., Heath, A. W., and Jennings, R. (2000). Use of herpes simplex virus (HSV) type 1 ISCOMS 703 vaccine for prophylactic and therapeutic treatment of primary and recurrent HSV-2 infection in guinea pigs. J. Infect. Dis. 181:1240–1248.PubMedGoogle Scholar
  225. Somavarapu, S., Bramwell, V. W., and Alpar, H. O. (2003). Oral plasmid DNA delivery systems for genetic immunisation. J. Drug Target 11:547–553.PubMedGoogle Scholar
  226. Soriani, M., Bailey, L., and Hirst, T. R. (2002). Contribution of the ADP-ribosylating and receptor-binding properties of cholera-like enterotoxins in modulating cytokine secretion by human intestinal epithelial cells. Microbiology 148:667–676.PubMedGoogle Scholar
  227. Spangler, B. D. (1992). Structure and function of cholera toxin and the related Escherichia coli heat-labile enterotoxin. Microbiol. Rev. 56:622–647.PubMedGoogle Scholar
  228. Staats, H. F., and Ennis, F. A., Jr. (1999). IL-1 is an effective adjuvant for mucosal and systemic immune responses when coadministered with protein immunogens. J. Immunol. 162:6141–6147.PubMedGoogle Scholar
  229. Stagg, A. J., Kamm, M. A., and Knight, S. C. (2002). Intestinal dendritic cells increase T cell expression of alpha4beta7 integrin. Eur. J. Immunol. 32:1445–1454.PubMedGoogle Scholar
  230. Stickl, H., Hochstein-Mintzel, V., Mayr, A., Huber, H. C., Schafer, H., and Holzner, A. (1974). [MVA vaccination against smallpox: Clinical tests with an attenuated live vaccinia virus strain (MVA) (author’s transl)]. Dtsch. Med. Wochenschr. 99:2386–2392.PubMedGoogle Scholar
  231. Sun, J. B., Holmgren, J., and Czerkinsky, C. (1994). Cholera toxin B subunit: An efficient transmucosal carrier-delivery system for induction of peripheral immunological tolerance. Proc. Natl. Acad. Sci. USA 91:10, 795–10, 799.Google Scholar
  232. Tabata, Y., Inoue, Y., and Ikada, Y. (1996). Size effect on systemic and mucosal immune responses induced by oral administration of biodegradable microspheres. Vaccine 14:1677–1685.PubMedGoogle Scholar
  233. Tacket, C. O., Kelly, S. M., Schodel, F., Losonsky, G., Nataro, J. P., Edelman, R., Levine, M. M., and Curtiss, R., 3rd (1997a). Safety and immunogenicity in humans of an attenuated Salmonella typhi vaccine vector strain expressing plasmid-encoded hepatitis B antigens stabilized by the Asd-balanced lethal vector system. Infect. Immun. 65:3381–3385.PubMedGoogle Scholar
  234. Tacket, C. O., Sztein, M. B., Losonsky, G. A., Wasserman, S. S., Nataro, J. P., Edelman, R., Pickard, D., Dougan, G., Chatfield, S. N., and Levine, M. M. (1997b). Safety of live oral Salmonella typhi vaccine strains with deletions in htrA and aroC aroD and immune response in humans. Infect. Immun. 65:452–456.PubMedGoogle Scholar
  235. Takahashi, H., Takeshita, T., Morein, B., Putney, S., Germain, R. N., and Berzofsky, J. A. (1990). Induction of CD8+ cytotoxic T cells by immunization with purified HIV-1 envelope protein in ISCOMs. Nature 344:873–875.PubMedGoogle Scholar
  236. Takahashi, I., Marinaro, M., Kiyono, H., Jackson, R. J., Nakagawa, I., Fujihashi, K., Hamada, S., Clements, J. D., Bost, K. L., and McGhee, J. R. (1996). Mechanisms for mucosal immunogenicity and adjuvancy of Escherichia coli labile enterotoxin. J. Infect. Dis. 173:627–635.PubMedGoogle Scholar
  237. Takata, S., Ohtani, O., and Watanabe, Y. (2000). Lectin binding patterns in rat nasal-associated lymphoid tissue (NALT) and the influence of various types of lectin on particle uptake in NALT. Arch. Histol. Cytol. 63:305–312.PubMedGoogle Scholar
  238. Takatsu, K., Tominaga, A., Harada, N., Mita, S., Matsumoto, M., Takahashi, T., Kikuchi, Y., and Yamaguchi, N. (1988). T cell-replacing factor (TRF)/interleukin 5 (IL-5): molecular and functional properties. Immunol. Rev. 102:107–135.PubMedGoogle Scholar
  239. Tartaglia, J., Perkus, M. E., Taylor, J., Norton, E. K., Audonnet, J. C., Cox, W. I., Davis, S. W., van der Hoeven, J., Meignier, B., Riviere, M., et al. (1992). NYVAC: A highly attenuated strain of vaccinia virus. Virology 188:217–232.PubMedGoogle Scholar
  240. Thapar, M. A., Parr, E. L., and Parr, M. B. (1990). Secretory immune responses in mouse vaginal fluid after pelvic, parenteral or vaginal immunization. Immunology 70:121–125.PubMedGoogle Scholar
  241. Toka, F. N., and Rouse, B. T. (2005). Mucosal application of plasmid-encoded IL-15 sustains a highly protective anti-Herpes simplex virus immunity. J. Leuk. Biol. 78:178–186.Google Scholar
  242. Ugozzoli, M., O’Hagan, D. T., and Ott, G. S. (1998). Intranasal immunization of mice with herpes simplex virus type 2 recombinant gD2: The effect of adjuvants on mucosal and serum antibody responses. Immunology 93:563–571.PubMedGoogle Scholar
  243. Vajdy, M., Srivastava, I., Polo, J., Donnelly, J., O’Hagan, D., and Singh, M. (2004). Mucosal adjuvants and delivery systems for protein-, DNA- and RNA-based vaccines. Immunol. Cell. Biol. 82:617–627.PubMedGoogle Scholar
  244. van Heyningen, S. (1977). Cholera toxin. Biol. Rev. Camb. Phil. Soc. 52:509.Google Scholar
  245. van Pinxteren, L. A., Bruce, M. G., Campbell, I., Wood, A., Clarke, C. J., Bellman, A., Morein, B., and Snodgrass, D. R. (1999). Effect of oral rotavirus/iscom vaccines on immune responses in gnotobiotic lambs. Vet. Immunol. Immunopathol. 71:53–67.PubMedGoogle Scholar
  246. Vogel, K., Kantor, J., Wood, L., Rivera, R., and Schlom, J. (1998). Oral immunization with enterocoated microbeads induces antigen-specific cytolytic T-cell responses. Cell. Immunol. 190:61–67.PubMedGoogle Scholar
  247. Wang, X., Hone, D. M., Haddad, A., Shata, M. T., and Pascual, D. W. (2003). M cell DNA vaccination for CTL immunity to HIV. J. Immunol. 171:4717–4725.PubMedGoogle Scholar
  248. Wang, X., Kochetkova, I., Haddad, A., Hoyt, T., Hone, D. M., and Pascual, D. W. (2005). Transgene vaccination using Ulex europaeus agglutinin I (UEA-1) for targeted mucosal immunization against HIV-1 envelope. Vaccine 23:3836–3842.PubMedGoogle Scholar
  249. Watanabe, I., Hagiwara, Y., Kadowaki, S. E., Yoshikawa, T., Komase, K., Aizawa, C., Kiyono, H., Takeda, Y., McGhee, J. R., Chiba, J., Sata, T., Kurata, T., and Tamura, S. (2002). Characterization of protective immune responses induced by nasal influenza vaccine containing mutant cholera toxin as a safe adjuvant (CT112K). Vaccine 20:3443–3455.PubMedGoogle Scholar
  250. Wierzbicki, A., Kiszka, I., Kaneko, H., Kmieciak, D., Wasik, T. J., Gzyl, J., Kaneko, Y., and Kozbor, D. (2002). Immunization strategies to augment oral vaccination with DNA and viral vectors expressing HIV envelope glycoprotein. Vaccine 20:1295–1307.PubMedGoogle Scholar
  251. Williams, N. A., Hirst, T. R., and Nashar, T. O. (1999). Immune modulation by the cholera-like enterotoxins: From adjuvant to therapeutic. Immunol. Today 20:95–101.PubMedGoogle Scholar
  252. Woo, P. C., Wong, L. P., Zheng, B. J., and Yuen, K. Y. (2001). Unique immunogenicity of hepatitis B virus DNA vaccine presented by live-attenuated Salmonella typhimurium. Vaccine 19:2945–2954.PubMedGoogle Scholar
  253. Woof, J. M., and Mestecky, J. (2005). Mucosal immunoglobulins. Immunol. Rev. 206:64–82.PubMedGoogle Scholar
  254. Wu, S., Pascual, D. W., Lewis, G. K., and Hone, D. M. (1997). Induction of mucosal and systemic responses against human immunodeficiency virus type 1 glycoprotein 120 in mice after oral immunization with a single dose of a Salmonella-HIV vector. AIDS Res. Hum. Retroviruses 13:1187–1194.PubMedGoogle Scholar
  255. Wu, Y., Wang, X., Csencsits, K. L., Haddad, A., Walters, N., and Pascual, D. W. (2001). M cell-targeted DNA vaccination. Proc. Natl. Acad. Sci. USA 98:9318–9323.PubMedGoogle Scholar
  256. Wyatt, L. S., Shors, S. T., Murphy, B. R., and Moss, B. (1996). Development of a replication-deficient recombinant vaccinia virus vaccine effective against parainfluenza virus 3 infection in an animal model. Vaccine 14:1451–1458.PubMedGoogle Scholar
  257. Xin, K. Q., Hamajima, K., Sasaki, S., Tsuji, T., Watabe, S., Okada, E., and Okuda, K. (1999). IL-15 expression plasmid enhances cell-mediated immunity induced by an HIV-1 DNA vaccine. Vaccine 17:858–866.PubMedGoogle Scholar
  258. Xu-Amano, J., Kiyono, H., Jackson, R. J., Staats, H. F., Fujihashi, K., Burrows, P. D., Elson, C. O., Pillai, S., and McGhee, J. R. (1993). 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.PubMedGoogle Scholar
  259. Yamamoto, M., Briles, D. E., Yamamoto, S., Ohmura, M., Kiyono, H., and McGhee, J. R. (1998). A nontoxic adjuvant for mucosal immunity to pneumococcal surface protein A. J. Immunol. 161:4115–4121.PubMedGoogle Scholar
  260. Yamamoto, M., Kiyono, H., Yamamoto, S., Batanero, E., Kweon, M. N., Otake, S., Azuma, M., Takeda, Y., and McGhee, J. R. (1999). Direct effects on antigen-presenting cells and T lymphocytes explain the adjuvanticity of a nontoxic cholera toxin mutant. J. Immunol. 162:7015–7021.PubMedGoogle Scholar
  261. Yamamoto, M., McGhee, J. R., Hagiwara, Y., Otake, S., and Kiyono, H. (2001). Genetically manipulated bacterial toxin as a new generation mucosal adjuvant. Scand. J. Immunol. 53:211–217.PubMedGoogle Scholar
  262. Yamamoto, M., Rennert, P., McGhee, J. R., Kweon, M. N., Yamamoto, S., Dohi, T., Otake, S., Bluethmann, H., Fujihashi, K., and Kiyono, H. (2000). Alternate mucosal immune system: Organized Peyer’s patches are not required for IgA responses in the gastrointestinal tract. J. Immunol. 164:5184–5191.PubMedGoogle Scholar
  263. Yamamoto, S., Kiyono, H., Yamamoto, M., Imaoka, K., Fujihashi, K., Van Ginkel, F. W., Noda, M., Takeda, Y., and McGhee, J. R. (1997a). A nontoxic mutant of cholera toxin elicits Th2-type responses for enhanced mucosal immunity. Proc. Natl. Acad. Sci. USA 94:5267–5272.PubMedGoogle Scholar
  264. Yamamoto, S., Takeda, Y., Yamamoto, M., Kurazono, H., Imaoka, K., Yamamoto, M., Fujihashi, K., Noda, M., Kiyono, H., and McGhee, J. R. (1997b). Mutants in the ADP-ribosyltransferase cleft of cholera toxin lack diarrheagenicity but retain adjuvanticity. J. Exp. Med. 185:1203–1210.PubMedGoogle Scholar
  265. Yang, S. K., Eckmann, L., Panja, A., and Kagnoff, M. F. (1997). Differential and regulated expression of C-X-C, C-C, and C-chemokines by human colon epithelial cells. Gastroenterology 113:1214–1223.PubMedGoogle Scholar
  266. Yoshino, N., Lu, F. X., Fujihashi, K., Hagiwara, Y., Kataoka, K., Lu, D., Hirst, L., Honda, M., van Ginkel, F. W., Takeda, Y., Miller, C. J., Kiyono, H., and McGhee, J. R. (2004). A novel adjuvant for mucosal immunity to HIV-1 gp120 in nonhuman primates. J. Immunol. 173:6850–6857.PubMedGoogle Scholar
  267. Zho, F., and Neutra, M. R. (2002). Antigen delivery to mucosa-associated lymphoid tissues using liposomes as a carrier. Biosci. Rep. 22:355–369.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Jun Kunisawa
    • 1
  • Jerry R. McGhee
    • 2
  • Hiroshi Kiyono
    • 1
  1. 1.Division of Mucosal Immunology, Department of Microbiology and ImmunologyThe University of TokyoJapan
  2. 2.Departments of Oral Biology and Microbiology, The Immunobiology Vaccine CenUniversity of Alabama at BirminghamBirminghamUSA

Personalised recommendations