title: Immune tolerance induction with multiepitope peptide derived from citrullinated autoantigens attenuates arthritis manifestations in adjuvant arthritis rats.
abstract: Citrullinated peptides are major targets of disease-specific autoantibodies in rheumatoid arthritis. Currently, citrullinated peptides are used as biomarkers for diagnosing rheumatoid arthritis by measuring anti-citrullinated protein Ab (ACPA) titers in patients' sera. The accumulation of citrullinated proteins at synovial inflammation sites suggests that they are possible targets for tolerance induction. The objective of the present study was to determine whether citrullinated peptides could induce tolerance in an experimental arthritis model in rats. In view of the multiplicity of target citrullinated autoantigens described for ACPA, we generated a multiepitope citrullinated peptide (Cit-ME), derived from major prevalent citrullinated autoantigens (citrullinated filaggrin, fibrinogen, vimentin, and collagen type II), and studied its effects on arthritic rats. Adjuvant-induced arthritis was induced in Lewis rats. Beginning at day 7 after disease induction, the rats received eight s.c. injections of Cit-ME on alternate days. Differences in clinical status and modulation of T cell populations were analyzed. In adjuvant-induced arthritis rats treated with Cit-ME, disease severity was significantly reduced compared with that of untreated rats. Moreover, amelioration of disease manifestations was related to an increased regulatory T cell subset and an elevated apoptosis rate of T cells associated with reduced Th17 cells. Thus, the use of citrullinated peptides-based immunotherapy may be a promising approach for tolerance induction in experimental arthritis and perhaps even in susceptible individuals that are ACPA-seropositive in human arthritis.
authors.affiliation: Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 52621, Israel;
authors.forename: Smadar
authors.initials: S
authors.lastname: Gertel
authors.affiliation: Unité Mixte de Recherche 5165, Centre National de la Recherche Scientifique, 1056 INSERM, Université de Toulouse III, 31062 Toulouse, France; and.
authors.forename: Guy
authors.initials: G
authors.lastname: Serre
authors.affiliation: Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 52621, Israel;
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Shoenfeld
authors.affiliation: Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 52621, Israel; Department of Medicine "B," Sheba Medical Center, Tel Hashomer 52621, Israel howard.amital@sheba.health.gov.il.
authors.forename: Howard
authors.initials: H
authors.lastname: Amital
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D002956:Citrulline / Q000378:metabolism; D004195:Disease Models, Animal; D000939:Epitopes / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D005260:Female; D000091344:Filaggrin Proteins; D007108:Immune Tolerance; D016130:Immunophenotyping; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D010455:Peptides; D002956:Citrulline