The route of administration of an immunodominant peptide derived from heat-shock protein 65 dramatically affects disease outcome in pristane-induced arthritis.
Previous studies have shown that immunization of mice with an immunodominant epitope from heat-shock protein 65 (hsp 65) (amino acids 261-271) can protect from the development of pristane-induced arthritis (PIA) and this protection is mediated by an antigen-specific T helper type 2 (Th2) cytokine response. Here we confirm these findings and show that frequent intranasal administration of this peptide exacerbates disease. In naive mice given peptide intranasally an antigen-specific T-cell population is systemically activated similar to that induced by peptide immunization in incomplete Freund's adjuvant. Thus, a paradox exists whereby apparently similar peptide-specific populations are either associated with protection from, or exacerbation of, PIA. However, comparison of cytokine profiles reveals differences between these two cell populations. Peptide inhalation induces the production of Th1-type cytokines (interferon-gamma) whereas intraperitoneal immunization leads to the production of Th2-type cytokines (interleukin-4, interleukin-5 and interleukin-10) by splenic T cells upon stimulation with peptide. Thus, for the application of nasal 'tolerance' in clinical medicine, it is important to identify antigens and dosing regimes that counteract but do not activate adverse immune responses.
Francis
J N
JN
Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, and Peptide Therapeutics Ltd, Cambridge, UK.
Lamont
A G
AG
Thompson
S J
SJ
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D001426:Bacterial Proteins; D002455:Cell Division; D002478:Cells, Cultured; D018834:Chaperonin 60; D018833:Chaperonins / Q000008:administration & dosage* / Q000627:therapeutic use; D016207:Cytokines / Q000096:biosynthesis*; D018450:Disease Progression; D000939:Epitopes / Q000008:administration & dosage; D007166:Immunosuppressive Agents; D007167:Immunotherapy / Q000379:methods*; D007274:Injections, Intraperitoneal; D007322:Instillation, Drug; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D051379:Mice; D008808:Mice, Inbred CBA; D013601:T-Lymphocytes / Q000276:immunology*; D013729:Terpenes
D001426:Bacterial Proteins; D018834:Chaperonin 60; D016207:Cytokines; D000939:Epitopes; D007166:Immunosuppressive Agents; D015848:Interleukin-5; D013729:Terpenes; C074119:heat-shock protein 65, Mycobacterium; D016753:Interleukin-10; D015847:Interleukin-4; C009042:pristane; D007371:Interferon-gamma; D018833:Chaperonins