Review Article | Published:

Mucosal immunity and vaccines

Nature Medicine volume 11, pages S45S53 (2005) | Download Citation

Subjects

Abstract

There is currently great interest in developing mucosal vaccines against a variety of microbial pathogens. Mucosally induced tolerance also seems to be a promising form of immunomodulation for treating certain autoimmune diseases and allergies. Here we review the properties of the mucosal immune system and discuss advances in the development of mucosal vaccines for protection against infections and for treatment of various inflammatory disorders.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. (eds). Mucosal Immunology 3rd edn. (Academic Press, San Diego, 2005).

  2. 2.

    Anatomical basis of tolerance and immunity to intestinal antigens. Nat. Rev. Immunol. 3, 331–341 (2003).

  3. 3.

    & NALT- versus Peyer's-patch-mediated mucosal immunity. Nat. Rev. Immunol. 4, 699–710 (2004).

  4. 4.

    , , , & New gut associated lymphoid tissue “cryptopatches” breed murine intestinal intraepithelial T cell precursors. Immunol. Res. 20, 243–250 (1999).

  5. 5.

    et al. Extrathymic T cell lymphopoiesis: ontogeny and contribution to gut intraepithelial lymphocytes in athymic and euthymic mice. J. Exp. Med. 197, 333–341 (2003).

  6. 6.

    & Gastrointestinal dendritic cells play a role in immunity, tolerance, and disease. Gastroenterology 127, 300–309 (2004).

  7. 7.

    & Freshly isolated Peyer's patch, but not spleen, dendritic cells produce interleukin 10 and induce the differentiation of T helper type 2 cells. J. Exp. Med. 190, 229–239 (1999).

  8. 8.

    , , , & Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004).

  9. 9.

    & Plasma-cell homing. Nat. Rev. Immunol. 3, 822–829 (2003).

  10. 10.

    , , , & Targeting T cell responses by selective chemokine receptor expression. Semin. Immunol. 15, 277–286 (2003).

  11. 11.

    , & Intestinal dendritic cells increase T cell expression of α4β7 integrin. Eur. J. Immunol. 32, 1445–1454 (2002).

  12. 12.

    et al. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424, 88–93 (2003).

  13. 13.

    et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527–538 (2004).

  14. 14.

    et al. Intestinal immune responses in humans. Oral cholera vaccination induces strong intestinal antibody responses, gamma-interferon production, and evokes local immunological memory. J. Clin. Invest. 88, 143–148 (1991).

  15. 15.

    et al. Specific-antibody-secreting cells in the rectums and genital tracts of nonhuman primates following vaccination. Infect. Immun. 66, 5889–5896 (1998).

  16. 16.

    , , & Comparison of the oral, rectal, and vaginal immunization routes for induction of antibodies in rectal and genital tract secretions of women. Infect. Immun. 65, 1387–1394 (1997).

  17. 17.

    , , , & Local and systemic immune responses to rectal administration of recombinant cholera toxin B subunit in humans. Infect. Immun. 69, 4125–4128 (2001).

  18. 18.

    , , , & Comparison of different routes of vaccination for eliciting antibody responses in the human stomach. Vaccine 22, 984–990 (2004).

  19. 19.

    , , , & Nasal and vaginal vaccinations have differential effects on antibody responses in vaginal and cervical secretions in humans. Infect. Immun. 69, 7481–7486 (2001).

  20. 20.

    et al. Specific antibody levels at the cervix during the menstrual cycle of women vaccinated with human papillomavirus 16 virus-like particles. J. Natl. Cancer Inst. 95, 1128–1137 (2003).

  21. 21.

    , & Transcutaneous immunization induces mucosal and systemic immunity: a potent method for targeting immunity to the female reproductive tract. Mol. Immunol. 37, 537–544 (2000).

  22. 22.

    & Innate immunity of the gut: mucosal defense in health and disease. J. Pediatr. Gastroenterol. Nutr. 38, 463–473 (2004).

  23. 23.

    , & Protection against cholera toxin after oral immunization is thymus-dependent and associated with intestinal production of neutralizing IgA antitoxin. Scand. J. Immunol. 25, 413–419 (1987).

  24. 24.

    , , , & Paradoxical IgA immunity in CD4-deficient mice. Lack of cholera toxin-specific protective immunity despite normal gut mucosal IgA differentiation. J. Immunol. 155, 2877–2887 (1995).

  25. 25.

    et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288, 2222–2226 (2000).

  26. 26.

    et al. Restricted IgA repertoire in both B-1 and B-2 cell-derived gut plasmablasts. J. Immunol. 174, 1046–1054 (2005).

  27. 27.

    & Regulation of mucosal B cell immunoglobulin secretion by intestinal epithelial cell-derived cytokines. Cytokine 10, 948–955 (1998).

  28. 28.

    et al. Molecular analysis of B cell differentiation in selective or partial IgA defiency. Clin. Exp. Immunol. 136, 284–290 (2004).

  29. 29.

    et al. Mucosal or targeted lymph node immunization of macaques with a particulate SIVp27 protein elicits virus-specific CTL in the genito-rectal mucosa and draining lymph nodes. J. Immunol. 157, 2521–2527 (1996).

  30. 30.

    et al. Cytokine requirements for induction of systemic and mucosal CTL after nasal immunization. J. Immunol. 167, 5386–5394 (2001).

  31. 31.

    , , , & Transcutaneous immunization induces mucosal CTLs and protective immunity by migration of primed skin dendritic cells. J. Clin. Invest. 113, 998–1007 (2004).

  32. 32.

    & Role of B cells and cytotoxic T lymphocytes in clearance of and immunity to rotavirus infection in mice. J. Virol. 69, 7800–7806 (1995).

  33. 33.

    , , & Transgenic mice lacking class I major histocompatibility complex-restricted T cells have delayed viral clearance and increased mortality after influenza virus challenge. J. Exp. Med. 175, 1143–1145 (1992).

  34. 34.

    , , , & Adoptive transfer of gut intraepithelial lymphocytes protects against murine infection with Toxoplasma gondii. J. Immunol. 158, 5883–5889 (1997).

  35. 35.

    , , & Cholera toxin acts as a potent adjuvant for the induction of cytotoxic T-lymphocyte responses with non-replicating antigens. Immunology 81, 338–342 (1994).

  36. 36.

    et al. Mucosal delivery of a respiratory syncytial virus CTL peptide with enterotoxin-based adjuvants elicits protective, immunopathogenic, and immunoregulatory antiviral CD8+ T cell responses. J. Immunol. 166, 1106–1113 (2001).

  37. 37.

    , , & Genital tract infection with Chlamydia trachomatis fails to induce protective immunity in gamma interferon receptor-deficient mice despite a strong local immunoglobulin A response. Infect. Immun. 65, 1032–1044 (1997).

  38. 38.

    et al. Immunization of mice with urease vaccine affords protection against Helicobacter pylori infection in the absence of antibodies and is mediated by MHC class II-restricted responses. J. Exp. Med. 188, 2277–2288 (1998).

  39. 39.

    , , & Interleukin-12 (IL-12) and IL-18 are important in innate defense against genital herpes simplex virus type 2 infection in mice but are not required for the development of acquired gamma interferon-mediated protective immunity. J. Virol. 75, 6705–6709 (2001).

  40. 40.

    & Oral tolerance. Immunol. Res. 28, 265–284 (2003).

  41. 41.

    , , & Oral tolerance in experimental autoimmune encephalomyelitis. III. Evidence for clonal anergy. J. Immunol. 147, 2155–2163 (1991).

  42. 42.

    et al. Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature 376, 177–180 (1995).

  43. 43.

    & Suppressor T cells for IgE and IgG in Peyer's patches of mice made tolerant by the oral administration of ovalbumin. J. Immunol. 120, 861–865 (1978).

  44. 44.

    , , & Oral administration of the immunodominant B-chain of insulin reduces diabetes in a co-transfer model of diabetes in the NOD mouse and is associated with a switch from Th1 to Th2 cytokines. J. Autoimmun. 10, 339–346 (1997).

  45. 45.

    et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).

  46. 46.

    , , , & Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237–1240 (1994).

  47. 47.

    & CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287–296 (1998).

  48. 48.

    , , , & Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).

  49. 49.

    , & In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro. Proc. Natl Acad. Sci. USA 100, 8886–8891 (2003).

  50. 50.

    , , , & Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J. Exp. Med. 198, 249–258 (2003).

  51. 51.

    et al. Human CD25+ regulatory T cells: two subsets defined by the integrins α4β7 or α4β1 confer distinct suppressive properties upon CD4+ T helper cells. Eur. J. Immunol. 34, 1303–1311 (2004).

  52. 52.

    et al. Role of LAG-3 in regulatory T cells. Immunity 21, 503–513 (2004).

  53. 53.

    , , & Regulation of IgE responses to inhaled antigen in mice by antigen-specific γδ T cells. Science 265, 1869–1871 (1994).

  54. 54.

    & γδ T cells as mediators of mucosal tolerance: the autoimmune diabetes model. Immunol. Rev. 173, 109–119 (2000).

  55. 55.

    Hepatic T cells and liver tolerance. Nat. Rev. Immunol. 3, 51–62 (2003).

  56. 56.

    , & Oral tolerance to nickel requires CD4+ invariant NKT cells for the infectious spread of tolerance and the induction of specific regulatory T cells. J. Immunol. 173, 1043–1050 (2004).

  57. 57.

    , & Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat. Immunol. 2, 725–731 (2001).

  58. 58.

    , & Characteristics of the immune response to poliovirus virion polypeptides after immunization with live or inactivated polio vaccines. J. Infect. Dis. 158, 160–165 (1988).

  59. 59.

    World Health Organization. Cholera vaccines. WHO position paper. Wkly. Epidemiol. Rec. 76, 117–124 (2001).

  60. 60.

    & Oral B subunit killed whole-cell cholera vaccines. in New Generation Vaccines 3rd edn. (ed. Levine, M.M. et al.) 499–510 (Marcel Dekker, New York, 2004).

  61. 61.

    et al. High-level effectiveness of a mass oral cholera vaccination in Beira, Mozambique. N. Engl. J. Med. 352, 757–767 (2005).

  62. 62.

    et al. Herd immunity conferred by killed oral cholera vaccines in Bangladesh. Lancet (in the press).

  63. 63.

    et al. Field trial of a locally produced, killed, oral cholera vaccine in Vietnam. Lancet 349, 231–235 (1997).

  64. 64.

    & Live oral cholera vaccine: from principle to product. Bull. Inst. Pasteur 93, 243–253 (1995).

  65. 65.

    et al. Efficacy trial of single-dose live oral cholera vaccine CVD 103-HgR in North Jakarta, Indonesia, a cholera-endemic area. Vaccine 18, 2399–2410 (2000).

  66. 66.

    et al. Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi. A preliminary report. N. Engl. J. Med. 317, 1101–1104 (1987).

  67. 67.

    et al. Immunogenicity, efficacy and serological correlate of protection of Salmonella typhi Vi capsular polysaccharide vaccine three years after immunization. Vaccine 14, 435–438 (1996).

  68. 68.

    et al. Efficacy trial of Vi polysaccharide vaccine against typhoid fever in Southwestern China. Bull. World Health Organ. 79, 625–631 (2001).

  69. 69.

    et al. Duration of efficacy of Ty21a attenuated Salmonella typhi live oral vaccine. Vaccine 17, S22–S27 (1999).

  70. 70.

    & Microbial-gut interactions in health and disease. Progress in enteric vaccine development. Best Pract. Res. Clin. Gastroenterol. 18, 421–445 (2004).

  71. 71.

    et al. A rotavirus vaccine for prophylaxis of infants against rotavirus gastroenteritis. Pediatr. Infect. Dis. J. 23, S179–S182 (2004).

  72. 72.

    , , , & Safety, immunogenicity and efficacy of intranasal, live attenuated influenza vaccine. Expert Rev. Vaccines 3, 643–654 (2004).

  73. 73.

    , & Influenza virus: immunity and vaccination strategies. Comparison of the immune response to inactivated and live, attenuated influenza vaccines. Scand. J. Immunol. 59, 1–15 (2004).

  74. 74.

    et al. Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Lancet 356, 545–549 (2000).

  75. 75.

    & Therapeutic approaches in multiple sclerosis: lessons from failed and interrupted treatment trials. BioDrugs 16, 183–200 (2002).

  76. 76.

    Can we induce tolerance in rheumatoid arthritis? Curr. Rheumatol. Rep. 3, 64–69 (2001).

  77. 77.

    , , , & Treatment of experimental autoimmune encephalomyelitis by feeding myelin basic protein conjugated to cholera toxin B subunit. Proc. Natl Acad. Sci. USA 93, 7196–7201 (1996).

  78. 78.

    et al. A cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes. Proc. Natl Acad. Sci. USA 94, 4610–4614 (1997).

  79. 79.

    , , , & Treatment of experimental autoimmune arthritis by nasal administration of a type II collagen-cholera toxoid conjugate vaccine. Arthritis Rheum. 42, 1628–1634 (1999).

  80. 80.

    et al. Prevention of mucosally induced uveitis with a HSP60-derived peptide linked to cholera toxin B subunit. Eur. J. Immunol. 33, 224–232 (2003).

  81. 81.

    , , , & Suppression of delayed-type hypersensitivity and IgE antibody responses to ovalbumin by intranasal administration of Escherichia coli heat-labile enterotoxin B subunit-conjugated ovalbumin. Vaccine 15, 225–229 (1997).

  82. 82.

    et al. Oral tolerization with peptide 336–351 linked to cholera toxin B subunit preventing relapses of uveitis in Behcet's disease. Clin. Exp. Immunol. 137, 201–208 (2004).

  83. 83.

    , & Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy 60, 4–12 (2005).

  84. 84.

    et al. Long-lasting effect of sublingual immunotherapy in children with asthma due to house dust mite: a 10-year prospective study. Clin. Exp. Allergy 33, 206–210 (2003).

  85. 85.

    The potential role of allergen-specific sublingual immunotherapy in atopic dermatitis. Am. J. Clin. Dermatol. 5, 281–294 (2004).

  86. 86.

    , , , & Strategies for converting allergens into hypoallergenic vaccine candidates. Methods 32, 313–320 (2004).

  87. 87.

    , , & Mucosal immunisation and adjuvants: a brief overview of recent advances and challenges. Vaccine 21, S89–S95 (2003).

  88. 88.

    , , & Bacteria as DNA vaccine carriers for genetic immunization. Int. J. Med. Microbiol. 294, 319–335 (2004).

  89. 89.

    et al. Mucosal adjuvants and delivery systems for protein-, DNA- and RNA-based vaccines. Immunol. Cell Biol. 82, 617–627 (2004).

  90. 90.

    , , & Papillomavirus pseudovirus: a novel vaccine to induce mucosal and systemic cytotoxic T lymphocyte responses. J. Virol. 75, 10139–10148 (2001).

  91. 91.

    et al. Recombinant Norwalk virus-like particles administered intranasally to mice induce systemic and mucosal (fecal and vaginal) immune responses. J. Virol. 75, 9713–9722 (2001).

  92. 92.

    et al. Chimeric recombinant hepatitis E virus-like particles as an oral vaccine vehicle presenting foreign epitopes. Virology 293, 273–280 (2002).

  93. 93.

    , & Mucosal adjuvants and anti-infection and anti-immunopathology vaccines based on cholera toxin, cholera toxin B subunit and CpG DNA. Expert Rev. Vaccines 2, 205–217 (2003).

  94. 94.

    & Modulation of the immune response by the cholera-like enterotoxins. Curr. Top. Med. Chem. 4, 509–519 (2004).

  95. 95.

    et al. Mucosal vaccines: non-toxic derivatives of LT and CT as mucosal adjuvants. Vaccine 19, 2534–2541 (2001).

  96. 96.

    , & Mutant Escherichia coli heat-labile enterotoxin [LT(R192G)] enhances protective humoral and cellular immune responses to orally administered inactivated influenza vaccine. Vaccine 20, 1019–1029 (2002).

  97. 97.

    , , , & Detoxification of cholera toxin without removal of its immunoadjuvanticity by the addition of (STa-related) peptides to the catalytic subunit. A potential new strategy to generate immunostimulants for vaccination. J. Biol. Chem. 277, 33369–33377 (2002).

  98. 98.

    From toxin to adjuvant: the rational design of a vaccine adjuvant vector, CTA1-DD/ISCOM. Cell. Microbiol. 6, 23–32 (2004).

  99. 99.

    , , & The potential of CpG oligodeoxynucleotides as mucosal adjuvants. Crit. Rev. Immunol. 21, 103–120 (2001).

  100. 100.

    & CpG DNA as a potent inducer of mucosal immunity: implications for immunoprophylaxis and immunotherapy of mucosal infections. Curr. Opin. Investig. Drugs 5, 141–145 (2004).

Download references

Author information

Affiliations

  1. Department of Medical Microbiology & Immunology and Göteborg University Vaccine Research Institute (GUVAX), Göteborg University, SE-405 30 Göteborg, Sweden.

    • Jan Holmgren
  2. INSERM Unité 721, Faculté de Médicine–Pasteur, F-06107 Nice Cedex 02, France.

    • Cecil Czerkinsky

Authors

  1. Search for Jan Holmgren in:

  2. Search for Cecil Czerkinsky in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jan Holmgren.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nm1213