Skip to main content
SpringerLink
Log in

Nasal administration of arthritis-related T cell epitopes of heat shock protein 60 as a promising way for immunotherapy in chronic arthritis

  • Published:
Biotherapy

Abstract

Adjuvant Arthritis (AA) can be induced in Lewis rats by immunisation with mycobacterial antigens. The disease can be passively transferred with T cell clone A2b, which recognises the 180–188 amino acid sequence in mycobacterial heat shock protein 60 (hsp60) and which crossreacts with crude cartilage proteoglycans. We succeeded to induce peripheral tolerance to this AA-associated T cell epitope following nasal administration of a peptide containing this epitope (mycobacterial hsp60 176–190). In rats treated nasally with 176–190 and immunised with mycobacterial hsp60, proliferative responses to 176–190 were reduced. AA was inhibited nasally with 176–190 treated rats and not in rats nasally treated with a control mycobacterial hsp60 peptide (211–225). Moreover, nasal 176–190 led to similar arthritis protective effects in a non-microbially induced experimental arthritis (avridine induced arthritis).

In a subsequent study we tried to prevent and to treat AA through nasal administration of mycobacterial hsp60 peptide 180–188 and a peptide analogue of 180–188, 180–188L183->A (Alanine 183), which has been shown to have an increased MHC-binding affinity for rat RT1 B1 and an increased capacity to inhibit the proliferative A2b responsein vitro.

We found that nasal administration of 180–188 had a moderate arthritis suppressive effect in AA, whereas its analogue peptide Alanine 183, had a strong suppressive effect. This strong arthritis suppressive effect was only partly due to the higher MHC-binding affinity for rat RT1 B1. Furthermore, it was possible to passively transfer nasal Alanine 183 induced disease protection. The present findings may in our view offer novel prospects for immunotherapy through nasal administration of (analogue) peptides, with a mimicry relationship with joint specific cartilage proteoglycan epitopes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Brandtzaeg P. History of oral tolerance. Ann. NY Acad. Sc. 1996; 778: 1–27.

    Article  CAS  Google Scholar 

  2. Higgins PJ, Weiner HL. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein and its fragments. J. Immunol. 1988; 140: 440–5.

    PubMed  CAS  Google Scholar 

  3. Weiner HL, Friedman A, Miller A, et al. Oral tolerance: Immunologic mechanisms and treatment of animal and human organ specific autoimmune diseases by oral administration of autoantigens. Ann. Rev. Immunol. 1994; 12: 809–37.

    Article  CAS  Google Scholar 

  4. Staines NA, Harper N, Ward FJ, Thompson HSG, Bansal S. Arthritis: animal models of oral tolerance. Ann. NY. Acad. Sc. 1996; 778: 297–305.

    Article  CAS  Google Scholar 

  5. Neurath MF, Fuss I, Kelsall BL, Presky DH, Waegell W, Strober W. Experimental granulomatous colitis in mice is abrogated by induction of TGF-β-mediated oral tolerance. J. Exp. Med. 1996; 183: 2605–26.

    Article  PubMed  CAS  Google Scholar 

  6. Zhang JA, Davidson L, Eisenbarth G, Weiner HL. Suppression of diabetes in NOD mice by oral administration of porcine insulin. Proc. Natl. Acad. Sci. USA 1991; 88: 10252–56.

    Article  PubMed  CAS  Google Scholar 

  7. Nussenblatt RB, Caspi RR, Mahdi R, et al. Inhibition of S-antigen induced experimental autoimmune uveoretinitis by oral induction of tolerance with S-antigen. J. Immunol. 1990; 144: 1689–95.

    PubMed  CAS  Google Scholar 

  8. Martin R, McFarland HF, McFarlin DE. Immunological aspects of demyelinating diseases. Ann. Rev. Immunol. 1992; 10: 153–87.

    Article  CAS  Google Scholar 

  9. Lider O, Santos LMB, Lee CSY, Higgins PJ, Weiner HL. Suppression of experimental allergic autoimmune encephalomyelitis by oral administration of myelin basic protein II. Suppression of disease and in vitro immune responses is mediated by antigen specific CD8+ cells. J. Immunol. 1989; 142: 440–5.

    Google Scholar 

  10. Miller A, Lider O, Roberts MB, Sporn MB, Weiner HL. Suppressor T cells generated by oral tolerance to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factorβ after antigen-specific triggering. Proc. Natl. Acad. Sci. USA 1992; 89: 421–5.

    Article  PubMed  CAS  Google Scholar 

  11. Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL. Regulatory T Cell Clones Induced by Oral Tolerance: Suppression of Autoimmune Encephalomyelitis. Science 1994; 265: 1237–40.

    Article  PubMed  CAS  Google Scholar 

  12. Miller A, Lider O, Weiner HL. Antigen-driven bystander suppression following oral administration of antigens. J. Exp. Med. 1991; 174: 791–8.

    Article  PubMed  CAS  Google Scholar 

  13. Miller A, Al-Sabbagh A, Santos LMB, Prabhu Das M, Weiner HL. Epitopes of Myelin Basic Protein that Trigger TGF-β Release after Oral Tolerization Are Distinct from Encephalitogenic Epitopes and Mediate Epitope-Driven Bystander Suppression. J. Immunol. 1993; 151: 7307–15.

    PubMed  CAS  Google Scholar 

  14. Chen Y, Inobe J, Marks R, Gonnella P, Kuchroo VK, Weiner HL. Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature 1995; 376: 177–80.

    Article  PubMed  CAS  Google Scholar 

  15. Whitacre CC, Gienapp II, Orosz CG, Bitar D. Oral tolerance in experimental autoimmune encephalomyelitis. III. Evidence for clonal anergy. J. Immunol. 1991; 23: 935–42.

    Google Scholar 

  16. Melamed D, Friedman A. Direct evidence for anergy in T-lymphocytes tolerized by oral administration of ovalbumin. Eur. J. Immunol. 1993; 23: 1–10.

    Article  Google Scholar 

  17. Friedman A, Weiner HL. Induction of anergy or active suppression following oral tolerance is determined by antigen dosage. Proc. Natl. Acad. Sci. USA 1994; 91: 6688–92.

    Article  PubMed  CAS  Google Scholar 

  18. Critchfield JM, Racke MK, Zunicka-Pflucker JC, et al. T Cell Deletion in High Antigen Dose Therapy of Autoimmune Encephalomyelitis. Science 1994; 263: 1139–42.

    Article  PubMed  CAS  Google Scholar 

  19. Chen Y, Inobe J, Kuchroo VK, Baron JL, Janeway CA, Weiner HL. Oral tolerance in myelin basic protein T-cell receptor transgenic mice: suppression of autoimmune encephalomyelitis and dose-dependent induction of regulatory cells. Proc. Natl. Acad. Sci. USA 1996; 93: 388–91.

    Article  PubMed  CAS  Google Scholar 

  20. Weiner HL, Mackin GA, Matsui M, et al. Double-Blind Pilot Trial of Oral Tolerization with Myelin Antigens in Multiple Sclerosis. Science 1993; 259: 1321–24.

    Article  PubMed  CAS  Google Scholar 

  21. Trentham DE, Dynesius-Trentham RA, Orav JE, et al. Effects of oral administration of type II Collagen on Rheumatoid Arthritis. Science 1993; 261: 1727–30.

    Article  PubMed  CAS  Google Scholar 

  22. Parker D, Turk JL. Delay in the development of the allergic response to metals following intratracheal instillation. Int. Archs. Allergy Appl. Immun. 1978; 57: 289–93.

    CAS  Google Scholar 

  23. Al-Sabbagh A, Nelson PA, Akselband Y, Sobel RA, Weiner HL. Antigen-driven peripheral immune tolerance:suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis by aerosol administration of myelin basic protein or type II collagen. Cell. Immunol. 1996; 171: 111–9.

    Article  PubMed  CAS  Google Scholar 

  24. van Halteren AG, van der Cammen AG, Cooper D, Savelkoul HF, Kraal G, Holt PG. Regulation of antigen-specific IgE, IgG1, and mast cell responses to ingested allergen by mucosal tolerance induction. J. Immunol. 1997; 159: 3009–15.

    PubMed  Google Scholar 

  25. McMenamin C, Pimm CL, McKersey M, Holt PG. Regulation of IgE responses to inhaled antigen in mice by antigen specificγδ T cells. Science 1994; 265: 1869–71.

    Article  PubMed  CAS  Google Scholar 

  26. Prakken BJ, van der Zee R, Anderton SM, van Kooten PJS, Kuis W, Van Eden W. Peptide induced nasal tolerance for a mycobacterial hsp60 T cell epitope in rats suppresses both adjuvant arthritis and non-microbially induced experimental arthritis. Proc. Natl. Acad. Sci. USA 1997; 94: 3284–89.

    Article  PubMed  CAS  Google Scholar 

  27. Harrison LC, Dempsey-Collier M, Kramer DR, Takahashi K. Aerosol insulin induces regulatory CD8γδ T cells that prevent murine insulin-dependent diabetes. J. Exp. Med. 1997; 184: 2167–74.

    Article  Google Scholar 

  28. Sedgwick JD, Holt PG. Induction of IgE-secreting cells and IgE isotype-specific suppressor T cells in the respiratory lymph nodes of rats in response to antigen inhalation. Cell Immunol. 1985; 94: 182–94.

    Article  PubMed  CAS  Google Scholar 

  29. Holt PG, Sedgwick JD. Suppression of IgE responses following inhalation of antigen. Immunol. Today 1987; 8: 14–6.

    Article  Google Scholar 

  30. Hoyne GF, Askonas BA, Hetzel C, Thomas WR, Lamb JR. Regulation of house dust mite responses by intransally administered peptide: transient activation of CD4+ T cells precedes the activation of tolerance in vivo. Intern. Immunol. 1996; 8: 335–42.

    Article  CAS  Google Scholar 

  31. Metzler B, Wraith DC. Inhibition of experimental autoimmune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity. Intern. Immunol. 1993; 5: 1159–65.

    Article  CAS  Google Scholar 

  32. Tian Y, Atkinson MA, Clare-Salzler M, et al. Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes. J. Exp. Med. 1996; 183: 1561–67.

    Article  PubMed  CAS  Google Scholar 

  33. Staines NA, Harper N, Ward FJ, Malmström V, Holmdahl R, Bansal S. Mucosal tolerance and suppression of collagen-induced arthritis (CIA) induced by nasal inhalation of synthetic peptide 184–198 of bovine type II collagen (CII) expressing a dominant T cell epitope. Clin. Exp. Immunol. 1996; 103: 368–75.

    Article  PubMed  CAS  Google Scholar 

  34. 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. USA 1996; 93: 956–60.

    Article  PubMed  CAS  Google Scholar 

  35. Melamed D, Fishman-Lobell J, Uni Z, Weiner HL, Friedman A. Peripheral tolerance of Th2 lymphocytes induced by continuous feeding of ovalbumin. Intern. Immunol. 1996; 8: 717–24.

    Article  CAS  Google Scholar 

  36. McMenamin C, Holt PG. The natural immune response to inhaled soluble protein antigens involves major histocompatibility complex (MHC) class I-restricted CD8+ T Cell-mediated but MHC class II-restricted CD4+ T cell-dependent immune deviation resulting in selective suppression of immunoglobulin E production. J. Exp. Med. 1993; 178: 889–99.

    Article  PubMed  CAS  Google Scholar 

  37. Wolvers DAE, van der Cammen AG, Kraal G. Mucosal tolerance is associated with, but independent of, the upregulation of Th2 responses. Immunology 1997; 92: 32833–6.

    Article  Google Scholar 

  38. Wright PF, Murphy BR, Kervina M, Lawrence EM, Phelan MA, Karzon DT. Secretory immunological response after intranasal inactivated influenza A virus vaccinations: evidence for immunoglobulin A memory. Infect. Immun. 1983; 40: 1092–5.

    PubMed  CAS  Google Scholar 

  39. Clements ML, Murphy BR. Development and persistence of local and systemic antibody responses in adults given live attenuated or inactivated influenza A virus. J. Clin. Microbiol. 1997; 23: 66–72.

    Google Scholar 

  40. Waldo FB. Nasal immunization with tetanus toxoid increases the subsequent systemic dimeric IgAl antiboddy response to intramuscular immunization. J. Clin. Lab. Immunol. 1991; 34: 125–9.

    PubMed  CAS  Google Scholar 

  41. Waldo FB, van den Wall Bake AWL, Mestecky J, Husby S. Suppression of the immune response by nasal immunization. Clin. Immunol. Immunopathology 1994; 72: 30–4.

    Article  CAS  Google Scholar 

  42. Pearson CM. Development of arthritis, periarthritis and periostitis in rats giving adjuvant. Proc. Soc. Exp. Biol. Med. 1956; 91: 91–101.

    Google Scholar 

  43. Hogervorst EJM, Wagenaar JPA, Boog CJP, van der Zee R, van Embden JDA, Van Eden W. Adjuvant arthritis and immunity to the mycobacterial 65kDa heat shock protein. Intern. Immunol. 1992; 4: 719–27.

    Article  CAS  Google Scholar 

  44. Whitehouse DJ, Whitehouse MW, Pearson CM. Passive transfer of adjuvant-induced arthritis and allergic encephalomyelitis in rats using thoracic duct lymphocytes. Nature 1969; 224: 1322–26.

    Article  PubMed  CAS  Google Scholar 

  45. Holoshitz J, Naparstek Y, Ben-Nun A, Cohen IR. Lines of T lymphocytes induce or vaccinate against autoimmune arthritis. Science 1983; 219: 56–8.

    Article  PubMed  CAS  Google Scholar 

  46. Cohen IR, Holoshitz J, Van Eden W, Frenkel A. T lymphocyte clones illuminate pathogenesis and affect therapy of experimental arthritis. Arthritis Rheum. 1985; 28: 841–5.

    Article  PubMed  CAS  Google Scholar 

  47. Van Eden W, Holoshitz J, Nevo Z, Frenkel A, Klajman A, Cohen IR. Arthritis induced by a T-lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteoglycans. Proc. Natl. Acad. Sci. USA 1985; 82: 5117–21.

    Article  PubMed  Google Scholar 

  48. Anderton SM, van der Zee R, Noordzij A, Van Eden W. Differential mycobacterial 65-kDa heat shock protein T cell epitope recognition after Adjuvant Arthritis-inducing or protective immunization protocols. J. Immunol. 1994; 152: 3656–64.

    PubMed  CAS  Google Scholar 

  49. Anderton SM, van der Zee R, Prakken ABJ, Noordzij A, Van Eden W. Activation of T-cells recognizing self 60 kDa heat shock protein can protect against experimental arthritis. J. Exp. Med. 1995; 181: 943–52.

    Article  PubMed  CAS  Google Scholar 

  50. Wauben MHM, Boog CJP, van der Zee R, Joosten I, Schlief A, Van Eden W. Disease inhibition by MHC binding peptide analogues of disease-associated epitopes: more than blocking alone. J. Exp. Med. 1992; 176: 667–77.

    Article  PubMed  CAS  Google Scholar 

  51. Joosten I, Wauben MHM, Holewijn MC, et al. Direct binding of autoimmune disease related epitopes to purified Lewis rat MHC class II molecules. Intern. Immunol. 1994; 6: 751–9.

    Article  CAS  Google Scholar 

  52. Sewell KL, Trentham DE. Pathogenesis of rheumatoid arthritis. Lancet 1993; 341: 283–6.

    Article  PubMed  CAS  Google Scholar 

  53. Cassidy JT, Petty RE. Textbook of pediatric rheumatology. New York: Churchill Livingstone Inc., 1990;

    Google Scholar 

  54. Van Eden W, Thole JER, van der Zee R, et al. Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature 1988; 331: 171–3.

    Article  PubMed  Google Scholar 

  55. Goodacre JA, Pearson JP. Human cartilage proteoglycans as T cell autoantigens. Ann. Rheum. Diseases 1992; 51: 1094–97.

    Article  CAS  Google Scholar 

  56. Khoury SJ, Hancock WW, Weiner HL. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with down-regulation of inflammatory cytokines and differential upregulation of transforming growth factorβ, interleukin 4 and prostaglandin E expression in the brain. J. Exp. Med. 1992; 176: 1355–64.

    Article  PubMed  CAS  Google Scholar 

  57. Mannie MD, Rendall SK, Arnold PY, Nardella JP, White GA. Anergy-associated T cell antigen presentation. A mechanism of infectious tolerance in experimental autoimmune encephalomyelitis. J. Immunol. 1996; 157: 1062–70.

    PubMed  CAS  Google Scholar 

  58. Lombardi G, Sidhu S, Batchelor R, Lechler R. Anergic T cells as suppressor cells in vitro. Science 1994; 264: 1587–9.

    Article  PubMed  CAS  Google Scholar 

  59. Cobbold SP, Adams E, Marshall SE, Davies JD, Waldmann H. Mechanisms of peripheral tolerance and suppression induced by monoclonal antibodies to CD4 and CD8. Immunol Rev 1996; 149: 5–33.

    Article  PubMed  CAS  Google Scholar 

  60. Liu GY, Wraith DC. Affinity for class II MHC determines the extend to which soluble peptides tolerize autoreactive T cells in naive and primed adult mice-implications for autoimmunity. Intern. Immunol. 1995; 7: 1255–63.

    Article  CAS  Google Scholar 

  61. Hammer J, Galazzi F, Bono E, et al. Peptide Binding Specificity of HLA-DR4 Molecules: Correlation with Rheumatoid Arthritis Association. J. Exp. Med. 1995; 181: 1847–55.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht, the Netherlands

    Berent Prakken, Marca Wauben, Peter van Kooten, Ruurd van der Zee & Willem van Eden

  2. Department of Medicine, University of California, San Diego, USA

    Berent Prakken

  3. Wilhelmina Children’s Hospital, University Hospital for Children and Youth, Utrecht, the Netherlands

    Berent Prakken & Wietse Kuis

  4. Department of Pathology and Microbiology, School of Medical Sciences, Bristol, United Kingdom

    Steve Anderton

Authors
  1. Berent Prakken
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marca Wauben
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter van Kooten
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Steve Anderton
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ruurd van der Zee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wietse Kuis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Willem van Eden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Berent Prakken.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Prakken, B., Wauben, M., van Kooten, P. et al. Nasal administration of arthritis-related T cell epitopes of heat shock protein 60 as a promising way for immunotherapy in chronic arthritis. Biotherapy 10, 205–211 (1998). https://doi.org/10.1007/BF02678298

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02678298

Key words

Search

Navigation