title: Mucosal administration of an altered CII263-272 peptide inhibits collagen-induced arthritis by suppression of Th1/Th17 cells and expansion of regulatory T cells.
abstract: Rheumatoid arthritis (RA) is a systemic autoimmune disease mediated by T cells. Collagen type II (CII) is one of the autoantigens associated with RA. CII263-272 is a predominant CII antigenic peptide that can induce T-cell activation upon binding to MHC and interaction with the appropriate T-cell receptor (TCR). Altered CII263-272 peptides with substitution of specific amino acids could bind to RA-associated HLA-DR4/1 with no T cell stimulating effects and could inhibit T cell activation in RA. We performed this study to evaluate the effect of mucosal administration and to explore the mechanism of the inhibitory effect of altered CII263-272 peptide (267Q-->A, 270K-->A and 271G-->A) on collagen induced arthritis (CIA). CIA was induced in Lewis rats by immunization with bovine CII. Altered CII263-272 peptide was given intranasally beginning from arthritis onset. Wild CII263-272 peptide or PBS was administered as controls. Therapeutic effects were evaluated by arthritis scores, body weight change, and joint pathologic scores. The anti-CII antibody and its subtypes and the cytokines, IFN-gamma, IL-10, and IL-17 were measured with ELISA. Foxp3+CD4+CD25+ regulatory T cell induction was assessed by FACS analysis. Following treatment with the altered CII263-272 peptide, arthiritis scores were reduced and body weight was increased. The altered CII263-272 peptide could retard the histologic lesion of the joints. The titers of anti-CII antibodies IgG2a in altered CII263-272 peptide treated rats decreased markedly compared to PBS-treated rats. The serum levels of IFN-gamma in rats treated with altered peptide was lower than that of rats treated with wild CII263-272 peptide and PBS. No differences were observed in the levels of serum IL-10 among the three groups. The altered CII263-272 peptide could decrease serum level of IL-17 and increase peripheral Foxp3+CD4+CD25+ T cells at early stage of CIA. Mucosal administration of altered CII263-272 peptide could effectively inhibit the progression of CIA. Altered CII263-272 peptide could suppress Th17 cells and expand regulatory T cells in the early stage of the disease. The IgG2a subtype of anti-CII antibodies and IFN-gamma were reduced and in vivo Th1 responses were inhibited as a result of altered CII peptide treatment. Altered CII peptide is likely therapeutic in RA.
authors.affiliation: Department of Rheumatology and Immunology, People's Hospital, Peking University Medical School, 11 Xizhimen South St., Beijing, 100044, China. zhao-jinxia@163.com
authors.forename: Jinxia
authors.initials: J
authors.lastname: Zhao
authors.forename: Ru
authors.initials: R
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.forename: Jinxia
authors.initials: J
authors.lastname: Shi
authors.forename: Li
authors.initials: L
authors.lastname: Long
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Li
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006614:Hindlimb; D007596:Joints / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D009297:Nasal Mucosa / Q000187:drug effects; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D012720:Severity of Illness Index; D013047:Specific Pathogen-Free Organisms; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology
chemical_list: D016207:Cytokines; D010446:Peptide Fragments