Inhibition of adjuvant-induced arthritis by interleukin-10-driven regulatory cells induced via nasal administration of a peptide analog of an arthritis-related heat-shock protein 60 T cell epitope.
OBJECTIVE
To prevent and treat experimental arthritis via nasal administration of an altered peptide ligand (APL) from the major arthritogenic epitope in adjuvant-induced arthritis (AIA) and to explore the mechanisms involved.


METHODS
Peptides were administered nasally before and after induction of arthritis. Splenocytes and lymph node cells draining both the site of inflammation and the site of tolerance induction were used for cell transfer and were studied for antigen-specific T cell characteristics. In addition, attempts were made to stop T cell tolerance in vitro, using anticytokine antibodies.


RESULTS
Nasal administration of a modulatory APL of the heat-shock protein 60 (Hsp60) 180-188 T cell epitope, alanine 183, had a suppressive effect in AIA that far exceeded that of the wild-type epitope. In addition to its effectiveness in preventing AIA, alanine 183 may be effective in the treatment of ongoing AIA. The protective effect of alanine 183 can be passively transferred using activated splenocytes. Nasal administration of alanine 183 did not lead to detectable T cell proliferation or interleukin-2 (IL-2) production in mandibular lymph node cells, while transforming growth factor beta (TGF beta), IL-10, and IL-4 were readily produced. Likewise, after nasally induced tolerance, followed by induction of arthritis, inguinal lymph node cells produced IL-4, TGF beta, and IL-10. After neutralizing in vitro the individual cytokines with anticytokine antibodies, only blocking of IL-10 production led to reversal of tolerance, at the site of tolerance induction and the site of inflammation.


CONCLUSIONS
Nasal administration of an APL of Hsp60 180-188 induces highly effective protection against AIA through generation of regulatory cells that produce IL-4, TGF beta, and IL-10, whereas the induced tolerance is driven mainly by production of IL-10.
University of California San Diego, La Jolla, California, USA.
Berent J
BJ
Prakken
Sarah
S
Roord
Peter J S
PJ
van Kooten
Josée P A
JP
Wagenaar
Willem
W
van Eden
Salvatore
S
Albani
Marca H M
MH
Wauben
D000281:Administration, Intranasal; D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy; D018834:Chaperonin 60 / Q000276:immunology*; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D010455:Peptides / Q000008:administration & dosage* / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D018834:Chaperonin 60; D018984:Epitopes, T-Lymphocyte; D007376:Interleukin-2; D008024:Ligands; D010455:Peptides; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4