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Bystander suppression of experimental arthritis by nasal administration of a heat shock protein peptide.

AbstractOBJECTIVES:
Mucosal immune therapy with disease-inducing antigens is an effective way to prevent experimental arthritis, but in humans these antigens are unknown. In juvenile idiopathic arthritis, however, T cell recognition of a so-called bystander antigen, heat shock protein 60 (HSP60), is associated with a good prognosis. Recently epitopes derived from HSP60, a microbial peptide (p1) and its self-homologue (p2) were reported to induce tolerogenic T cell responses in vitro in patients with arthritis. A study was undertaken to determine whether mucosal administration of these bystander epitopes can be similarly effective in suppressing arthritis.
METHODS:
Rats were treated nasally with p1, p2 or phosphate-buffered saline before arthritis induction. Arthritis scores were assessed and peptide-specific proliferative responses, phenotypic analysis, cytokine production and in vitro suppressive capacity of cells were measured in lymph nodes and spleens. CD4 spleen T cells from p1- or p2-treated rats were adoptively transferred into naïve rats that were subsequently injected with complete Freund's adjuvant for arthritis induction.
RESULTS:
Nasal administration of p1 prevented experimental arthritis whereas treatment with the self-homologue p2 did not. Adoptive transfer of CD4 T cells protected against experimental arthritis. Treatment with p1 increased peptide-specific and self-crossreactive interferon γ (IFNγ) production. Tumour necrosis factor α (TNFα) levels were reduced at the site of inflammation. Forkhead box P3 (FoxP3) expression remained stable but the suppressive capacity of T regulatory cells in p1-treated rats was enhanced.
CONCLUSION:
p1 immune therapy induces a population of CD4 T cells with reduced TNFα and increased peptide-specific IFNγ production at the site of inflammation. This population expresses FoxP3 and has potent suppressive capacity which, upon transfer, protects against arthritis. The bystander epitope p1 may therefore be a suitable candidate for antigen-specific immunotherapy in arthritis.
AuthorsEvelien Zonneveld-Huijssoon, Sarah T A Roord, Wilco de Jager, Mark Klein, Salvatore Albani, Stephen M Anderton, Wietse Kuis, Femke van Wijk, Berent J Prakken
JournalAnnals of the rheumatic diseases (Ann Rheum Dis) Vol. 70 Issue 12 Pg. 2199-206 (Dec 2011) ISSN: 1468-2060 [Electronic] England
PMID21914624 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Chaperonin 60
  • Cytokines
  • Epitopes, T-Lymphocyte
  • Inflammation Mediators
  • Peptide Fragments
  • Freund's Adjuvant
Topics
  • Administration, Intranasal
  • Animals
  • Arthritis, Experimental (immunology, prevention & control)
  • Bystander Effect (immunology)
  • CD4-Positive T-Lymphocytes (transplantation)
  • Chaperonin 60 (administration & dosage, immunology, therapeutic use)
  • Cytokines (biosynthesis)
  • Epitopes, T-Lymphocyte (administration & dosage, immunology, therapeutic use)
  • Freund's Adjuvant
  • Immunity, Mucosal
  • Immunotherapy, Adoptive (methods)
  • Inflammation Mediators (metabolism)
  • Lymphocyte Activation (immunology)
  • Male
  • Peptide Fragments (administration & dosage, immunology, therapeutic use)
  • Rats
  • Rats, Inbred Lew
  • Spleen (immunology)
  • T-Lymphocytes (immunology)
  • T-Lymphocytes, Regulatory (immunology)

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