Therapeutic effect of an altered peptide ligand derived from heat-shock protein 60 by suppressing of inflammatory cytokines secretion in two animal models of rheumatoid arthritis.

Abstract

Rheumatoid arthritis is a systemic autoimmune disease mediated by T cells. Productive engagement of T cell receptors by major histocompatibility complex-peptide leads to proliferation, differentiation and the definition of effector functions. Altered peptide ligands (APL) generated by amino acid substitutions in the antigenic peptide have diverse effects on T cell response. We predicted a novel T cell epitope from human heat-shock protein 60, an autoantigen involved in the pathogenesis of rheumatoid arthritis. Three APLs were designed from this epitope and it was demonstrated that these peptides induce the activation of T cells through their ability to modify cell cycle phase's distribution of CD4+T cells from RA patients. Also, IL-17, TNF-α and IL-10 levels were determined in PBMC from these patients. Unlike the wild-type peptide and the other two APLs, APL2 increased the IL-10 level and suppressed IL-17 secretion in these assays. Therapeutic effect of this APL in adjuvant arthritis (AA) and collagen-induced arthritis (CIA) models was also evaluated. Clinical score, histopathology, inflammatory and regulatory cytokine concentration were monitored in the animals. APL2 efficiently inhibited the progression of AA and CIA with a significant reduction of the clinical and histopathologic score. Therapeutic effect of APL2 on CIA was similar to that obtained with MTX; the standard treatment for RA. This effect was associated with a decrease of TNF-α and IL-17 levels. These results suggest that the therapeutic effect of APL2 is mediated in part by down-regulation of inflammatory cytokines and support the potential use of APL2 as a therapeutic drug in RA patients.

• Authors: N Lorenzo, A Barberá, M C Domínguez, A M Torres, M V Hernandez, I Hernandez, R Gil, J Ancizar, H Garay, O Reyes, F Altruda, L Silengo, G Padrón
• Journal: Autoimmunity (Autoimmunity) Vol. 45 Issue 6 Pg. 449-59 (Sep 2012) ISSN: 1607-842X [Electronic] England
• PMID: 22686732 (Publication Type: Journal Article)

Chemical References

• Chaperonin 60
• Cytokines
• Epitopes, T-Lymphocyte
• Interleukin-17
• Ligands
• Peptides

Topics

• Amino Acid Sequence
• Amino Acid Substitution
• Animals
• Arthritis, Rheumatoid (drug therapy, immunology, pathology)
• Chaperonin 60 (chemistry)
• Cytokines (drug effects, immunology, metabolism)
• Disease Models, Animal
• Epitopes, T-Lymphocyte (chemistry, immunology)
• Female
• Humans
• Inflammation
• Interleukin-17 (immunology, metabolism)
• Ligands
• Lymphocyte Activation (drug effects)
• Mice
• Mice, Inbred DBA
• Molecular Sequence Data
• Peptides (chemistry, immunology, metabolism, therapeutic use)
• Rats
• Rats, Inbred Lew
• T-Lymphocytes (immunology)
• Treatment Outcome