Current Diabetes Reports

, Volume 7, Issue 2, pp 91–98 | Cite as

Mucosal exposure to antigen: Cause or cure of type 1 diabetes?

  • Georgia Fousteri
  • Matthias von Herrath
  • Damien Bresson
Article

Abstract

The human gut offers more than 200 m2 of mucosal surface, where direct interactions between the immune system and foreign antigens take place to eliminate pathogens or induce immune tolerance toward food antigens or normal gut flora. Therefore, mucosally administered antigens can induce tolerance under certain circumstances. In autoimmune diabetes, mucosal vaccination with autoantigens elicits some efficacy in restoring tolerance in mice, but it never succeeded in humans. Furthermore, in some instances autoimmunity can be precipitated upon oral or intranasal autoantigen administration. Therefore, it is difficult to predict the effect of mucosal vaccination on autoimmunity and much effort should be put into establishing better assays to reduce the risk for possible adverse events in humans and enable a rapid and smooth translation.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Neutra MR, Mantis NJ, Kraehenbuhl JP: Collaboration of epithelial cells with organized mucosal lymphoid tissues. Nat Immunol 2001, 2:1004–1009.PubMedCrossRefGoogle Scholar
  2. 2.
    von Herrath MG: Design of immune-based interventions in autoimmunity and viral infections—the need for predictive models that integrate time, dose and classes of immune responses. Novartis Found Symp 2001, 239:16–24; discussion 24–30, 45–51.Google Scholar
  3. 3.
    O’shea JJ, Ma A, Lipsky P: Cytokines and autoimmunity. Nat Rev Immunol 2002, 2:37–45.PubMedCrossRefGoogle Scholar
  4. 4.
    Cheroutre H: Starting at the beginning: new perspectives on the biology of mucosal T cells. Annu Rev Immunol 2004, 22:217–246.PubMedCrossRefGoogle Scholar
  5. 5.
    Neutra MR, Kozlowski PA: Mucosal vaccines: the promise and the challenge. Nat Rev Immunol 2006, 6:148–158.PubMedCrossRefGoogle Scholar
  6. 6.
    Faria AM, Weiner HL: Oral tolerance. Immunol Rev 2005, 206:232–259.PubMedCrossRefGoogle Scholar
  7. 7.
    Harrison LC, Hafler DA: Antigen-specific therapy for auto-immune disease. Curr Opin Immunol 2000, 12:704–711.PubMedCrossRefGoogle Scholar
  8. 8.
    Miller JF: Autoantigen-induced deletion of peripheral self-reactive T cells. Int Rev Immunol 1995, 13:107–114.PubMedGoogle Scholar
  9. 9.
    Schwartz RH: Models of T cell anergy: is there a common molecular mechanism? J Exp Med 1996, 184:1–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Ohashi PS, DeFranco AL: Making and breaking tolerance. Curr Opin Immunol 2002, 14:744–759.PubMedCrossRefGoogle Scholar
  11. 11.
    Sakaguchi S, Sakaguchi N, Asano M, et al.: 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 1995, 155:1151–1164.PubMedGoogle Scholar
  12. 12.
    Roncarolo MG, Gregori S, Battaglia M, et al.: Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 2006, 212:28–50.PubMedCrossRefGoogle Scholar
  13. 13.
    Weiner HL: Oral tolerance: immune mechanisms and the generation of Th3-type TGF-beta-secreting regulatory cells. Microbes Infect 2001, 3:947–954.PubMedCrossRefGoogle Scholar
  14. 14.
    Bisikirska B, Colgan J, Luban J, et al.: TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+Tregs. J Clin Invest 2005, 115:2904–2913.PubMedCrossRefGoogle Scholar
  15. 15.
    Cobbold S, Waldmann H: Infectious tolerance. Curr Opin Immunol 1998, 10:518–524.PubMedCrossRefGoogle Scholar
  16. 16.
    Nakayama M, Abiru N, Moriyama H, et al.: Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 2005, 435:220–223.PubMedCrossRefGoogle Scholar
  17. 17.
    Lernmark A, Agardh CD: Immunomodulation with human recombinant autoantigens. Trends Immunol 2005, 26:608–612.PubMedCrossRefGoogle Scholar
  18. 18.
    Bach JF, Koutouzov S, van Endert PM: Are there unique autoantigens triggering autoimmune diseases? Immunol Rev 1998, 164:139–155.PubMedCrossRefGoogle Scholar
  19. 19.
    Tuohy VK, Yu M, Yin L, et al.: The epitope spreading cascade during progression of experimental autoimmune encephalomyelitis and multiple sclerosis. Immunol Rev 1998, 164:93–100.PubMedCrossRefGoogle Scholar
  20. 20.
    Tian J, Gregori S, Adorini L, et al.: The frequency of high avidity T cells determines the hierarchy of determinant spreading. J Immunol 2001, 166:7144–7150.PubMedGoogle Scholar
  21. 21.
    Dai YD, Carayanniotis G, Sercarz E: Antigen processing by autoreactive B cells promotes determinant spreading. Cell Mol Immunol 2005, 2:169–175.PubMedGoogle Scholar
  22. 22.
    Wong FS: Insulin—a primary autoantigen in type 1 diabetes? Trends Mol Med 2005, 11:445–448.PubMedCrossRefGoogle Scholar
  23. 23.
    Oling V, Marttila J, Ilonen J, et al.: GAD65-and proinsulin-specific CD4+ T-cells detected by MHC class II tetramers in peripheral blood of type 1 diabetes patients and at-risk subjects. J Autoimmun 2005, 25:235–243.PubMedCrossRefGoogle Scholar
  24. 24.
    Arif S, Tree TI, Astill TP, et al.: Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest 2004, 113:451–463.PubMedCrossRefGoogle Scholar
  25. 25.
    Zhang ZJ, Davidson L, Eisenbarth G, et al.: Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci U S A 1991, 88:10252–10256.PubMedCrossRefGoogle Scholar
  26. 26.
    Bergerot I, Arreaza GA, Cameron MJ, et al.: Insulin B-chain reactive CD4+ regulatory T-cells induced by oral insulin treatment protect from type 1 diabetes by blocking the cytokine secretion and pancreatic infiltration of diabetogenic effector T-cells. Diabetes 1999, 48:1720–1729.PubMedCrossRefGoogle Scholar
  27. 27.
    Homann D, Dyrberg T, Petersen J, et al.: Insulin in oral immune “tolerance”: a one-amino acid change in the B chain makes the difference. J Immunol 1999, 163:1833–1838.PubMedGoogle Scholar
  28. 28.
    Ma SW, Zhao DL, Yin ZQ, et al.: Transgenic plants expressing autoantigens fed to mice to induce oral immune tolerance. Nat Med 1997, 3:793–796.PubMedCrossRefGoogle Scholar
  29. 29.
    Ma S, Huang Y, Yin Z, et al.: Induction of oral tolerance to prevent diabetes with transgenic plants requires glutamic acid decarboxylase (GAD) and IL-4. Proc Natl Acad Sci U S A 2004, 101:5680–5685.PubMedCrossRefGoogle Scholar
  30. 30.
    Bergerot I, Ploix C, Petersen J, et al.: A cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes. Proc Natl Acad Sci U S A 1997, 94:4610–4614.PubMedCrossRefGoogle Scholar
  31. 31.
    Shreedhar VK, Kelsall BL, Neutra MR: Cholera toxin induces migration of dendritic cells from the subepithelial dome region to T-and B-cell areas of Peyer’s patches. Infect Immun 2003, 71:504–509.PubMedCrossRefGoogle Scholar
  32. 32.
    Ploix C, Bergerot I, Durand A, et al.: Oral administration of cholera toxin B-insulin conjugates protects NOD mice from autoimmune diabetes by inducing CD4+ regulatory T-cells. Diabetes 1999, 48:2150–2156.PubMedCrossRefGoogle Scholar
  33. 33.
    Aspord C, Czerkinsky C, Durand A, et al.: alpha4 integrins and L-selectin differently orchestrate T-cell activity during diabetes prevention following oral administration of CTB-insulin. J Autoimmun 2002, 19:223–232.PubMedCrossRefGoogle Scholar
  34. 34.
    Bellmann K, Kolb H, Rastegar S, et al.: Potential risk of oral insulin with adjuvant for the prevention of Type I diabetes: a protocol effective in NOD mice may exacerbate disease in BB rats. Diabetologia 1998, 41:844–847.PubMedCrossRefGoogle Scholar
  35. 35.
    Blanas E, Carbone FR, Allison J, et al.: Induction of autoimmune diabetes by oral administration of autoantigen. Science 1996, 274:1707–1709.PubMedCrossRefGoogle Scholar
  36. 36.
    Hanninen A, Braakhuis A, Heath WR, et al.: Mucosal antigen primes diabetogenic cytotoxic T-lymphocytes regardless of dose or delivery route. Diabetes 2001, 50:771–775.PubMedCrossRefGoogle Scholar
  37. 37.
    Hanninen A, Martinez NR, Davey GM, et al.: Transient blockade of CD40 ligand dissociates pathogenic from protective mucosal immunity. J Clin Invest 2002, 109:261–267.PubMedCrossRefGoogle Scholar
  38. 38.
    Ke Y, Kapp JA: Oral antigen inhibits priming of CD8+ CTL, CD4+ T cells, and antibody responses while activating CD8+ suppressor T cells. J Immunol 1996, 156:916–921.PubMedGoogle Scholar
  39. 39.
    Garside P, Steel M, Liew FY, et al.: CD4+ but not CD8+ T cells are required for the induction of oral tolerance. Int Immunol 1995, 7:501–504.PubMedCrossRefGoogle Scholar
  40. 40.
    von Herrath MG, Coon B, Wolfe T: Tolerance induction with agonist peptides recognized by autoaggressive lymphocytes is transient: therapeutic potential for type 1 diabetes is limited and depends on time-point of administration, choice of epitope and adjuvant. J Autoimmun 2001, 16:193–199.CrossRefGoogle Scholar
  41. 41.
    von Herrath MG, Dyrberg T, Oldstone MB: Oral insulin treatment suppresses virus-induced antigen-specific destruction of beta cells and prevents autoimmune diabetes in transgenic mice. J Clin Invest 1996, 98:1324–1331.CrossRefGoogle Scholar
  42. 42.
    Bregenholt S, Wang M, Wolfe T, et al.: The cholera toxin B subunit is a mucosal adjuvant for oral tolerance induction in type 1 diabetes. Scand J Immunol 2003, 57:432–438.PubMedCrossRefGoogle Scholar
  43. 43.
    Homann D, Holz A, Bot A, et al.: Autoreactive CD4+ T cells protect from autoimmune diabetes via bystander suppression using the IL-4/Stat6 pathway. Immunity 1999, 11:463–472.PubMedCrossRefGoogle Scholar
  44. 44.
    von Herrath MG, Whitton JL: DNA vaccination to treat autoimmune diabetes. Ann Med 2000, 32:285–292.Google Scholar
  45. 45.
    Li AF, Escher A: Intradermal or oral delivery of GAD-encoding genetic vaccines suppresses type 1 diabetes. DNA Cell Biol 2003, 22:227–232.PubMedCrossRefGoogle Scholar
  46. 46.
    van den Engel NK, an Haack M, Martin S, et al.: Oral DNA vaccination with a plasmid encoding soluble ICAM-1 modulates cytokine expression profiles in nonobese diabetic mice. J Mol Med 2002, 80:301–308.PubMedCrossRefGoogle Scholar
  47. 47.
    Harrison LC, Dempsey-Collier M, Kramer DR, et al.: Aerosol insulin induces regulatory CD8 gamma delta T cells that prevent murine insulin-dependent diabetes. J Exp Med 1996, 184:2167–2174.PubMedCrossRefGoogle Scholar
  48. 48.
    Aspord C, Thivolet C: Nasal administration of CTB-insulin induces active tolerance against autoimmune diabetes in non-obese diabetic (NOD) mice. Clin Exp Immunol 2002, 130:204–211.PubMedCrossRefGoogle Scholar
  49. 49.
    Daniel D, Wegmann DR: Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9–23). Proc Natl Acad Sci U S A 1996, 93:956–960.PubMedCrossRefGoogle Scholar
  50. 50.
    Yuki Y, Hara-Yakoyama C, Guadiz AA, et al.: Production of a recombinant cholera toxin B subunit-insulin B chain peptide hybrid protein by Brevibacillus choshinensis expression system as a nasal vaccine against autoimmune diabetes. Biotechnol Bioeng 2005, 92:803–809.PubMedCrossRefGoogle Scholar
  51. 51.
    Alleva DG, Gaur A, Jin L, et al.: Immunological characterization and therapeutic activity of an altered-peptide ligand, NBI-6024, based on the immunodominant type 1 diabetes autoantigen insulin B-chain (9–23) peptide. Diabetes 2002, 51:2126–2134.PubMedCrossRefGoogle Scholar
  52. 52.
    Chen W, Bergerot I, Elliott JF, et al.: Evidence that a peptide spanning the B-C junction of proinsulin is an early Autoantigen epitope in the pathogenesis of type 1 diabetes. J Immunol 2001, 167:4926–4935.PubMedGoogle Scholar
  53. 53.
    Martinez NR, Augstein P, Moustakas AK, et al.: Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide. J Clin Invest 2003, 111:1365–1371.PubMedCrossRefGoogle Scholar
  54. 54.
    Every AL, Kramer DR, Mannering SI, et al.: Intranasal vaccination with proinsulin DNA induces regulatory CD4+ T cells that prevent experimental autoimmune diabetes. J Immunol 2006, 176:4608–4615.PubMedGoogle Scholar
  55. 55.
    Tian J, Clare-Salzler M, Herschenfeld A, et al.: Modulating autoimmune responses to GAD inhibits disease progression and prolongs islet graft survival in diabetes-prone mice. Nat Med 1996, 2:1348–1353.PubMedCrossRefGoogle Scholar
  56. 56.
    Bresson D, Togher L, Rodrigo E, et al.: Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs. J Clin Invest 2006, 116:1371–1381.PubMedCrossRefGoogle Scholar
  57. 57.
    Ostroukhova M, Seguin-Devaux C, Oriss TB, et al.: Tolerance induced by inhaled antigen involves CD4(+) T cells expressing membrane-bound TGF-beta and FOXP3. J Clin Invest 2004, 114:28–38.PubMedCrossRefGoogle Scholar
  58. 58.
    Sherry NA, Tsai EB, Herold KC: Natural history of beta-cell function in type 1 diabetes. Diabetes 2005, 54(suppl 2):S32–S39.PubMedCrossRefGoogle Scholar
  59. 59.
    Sosenko JM, Palmer JP, Greenbaum CJ, et al.: Patterns of metabolic progression to type 1 diabetes in the Diabetes Prevention Trial-Type 1. Diabetes Care 2006, 29:643–649.PubMedCrossRefGoogle Scholar
  60. 60.
    Skyler JS, Krischer JP, Wolfsdorf J, et al.: Effects of oral insulin in relatives of patients with type 1 diabetes: the Diabetes Prevention Trial—Type 1. Diabetes Care 2005, 28:1068–1076.PubMedCrossRefGoogle Scholar
  61. 61.
    Pozzilli P, Pitocco D, Visalli N, et al.: No effect of oral insulin on residual beta-cell function in recent-onset type I diabetes (the IMDIAB VII). IMDIAB Group. Diabetologia 2000, 43:1000–1004.PubMedCrossRefGoogle Scholar
  62. 62.
    Chaillous L, Lefevre H, Thivolet C, et al.: Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Diabete Insuline Orale group. Lancet 2000, 356:545–549.PubMedCrossRefGoogle Scholar
  63. 63.
    Harrison LC, Honeyman MC, Steele CE, et al.: Pancreatic beta-cell function and immune responses to insulin after administration of intranasal insulin to humans at risk for type 1 diabetes. Diabetes Care 2004, 27:2348–2355.PubMedCrossRefGoogle Scholar
  64. 64.
    Metzler B, Wraith DC: Inhibition of experimental auto-immune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity. Int Immunol 1993, 5:1159–1165.PubMedCrossRefGoogle Scholar
  65. 65.
    Kupila A, Sipila J, Keskinen P, et al.: Intranasally administered insulin intended for prevention of type 1 diabetes—a safety study in healthy adults. Diabetes Metab Res Rev 2003, 19:415–420.PubMedCrossRefGoogle Scholar
  66. 66.
    Liu E, Moriyama H, Abiru N, et al.: Anti-peptide autoantibodies and fatal anaphylaxis in NOD mice in response to insulin self-peptides B:9–23 and B:13–23. J Clin Invest 2002, 110:1021–1027.PubMedCrossRefGoogle Scholar
  67. 67.
    Bielekova B, Goodwin B, Richert N, et al.: Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med 2000, 6:1167–1175.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group LLC 2007

Authors and Affiliations

  • Georgia Fousteri
    • 1
  • Matthias von Herrath
  • Damien Bresson
  1. 1.Department of Developmental Immunology 3La Jolla Institute for Allergy and ImmunologyLa JollaUSA

Personalised recommendations