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

Abstract

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 ␤ (TGF␤), 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␤, 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.Conclusion. 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␤, and IL-10, whereas the induced tolerance is driven mainly by production of IL-10.

Intrinsic Tolerance in Autologous Collagen-Induced Arthritis Is Generated by CD152-Dependent CD4+ Suppressor Cells

“…T regulatory type 1 cells have been described as being able to suppress diseases such as arthritis and colitis (44,45). These cells were found to mediate their effect by producing large quantities of IL-10, as well as TGF-␤.…”

DNA Fragments of the Human 60-kDa Heat Shock Protein (HSP60) Vaccinate Against Adjuvant Arthritis: Identification of a Regulatory HSP60 Peptide

“…It is conceivable that the HSP60-specific T cells induced after vaccination with pI, pII, or Hu3 supported this cytokine shift by secreting IL-10 and TGF␤1. IL-10 and TGF␤1 are immunomodulatory cytokines capable of inhibiting experimental arthritis (21)(22)(23). Indeed, T cells reactive with self-HSP60 have been previously shown to control AA (24).…”

Alarmins: awaiting a clinical response

“…HSP60 induces a subtype of regulatory T cells that suppress proinflammatory T cells (61)(62)(63)(64). Transfer of these HSP-specific regulatory T cells inhibited inflammation in animal models of arthritis (60,62).…”