title: Peptide-induced suppression of collagen-induced arthritis in HLA-DR1 transgenic mice.
abstract: OBJECTIVE
  To identify peptides capable of altering the immune response to type II collagen (CII) in the context of HLA-DR.
  
  
  METHODS
  Immunizing mice transgenic for the human HLA-DRB1*0101 immune response gene with CII elicits an arthritis (collagen-induced arthritis [CIA]) that resembles rheumatoid arthritis. We have previously identified an immunodominant determinant of CII, CII (263-270), recognized by T cells in the context of DR1. To produce synthetic peptides with the potential of disrupting the DR1-restricted immune response, synthetic analog peptides were developed that contain site-directed substitutions in critical positions. These peptides were used to treat CIA in DR1 transgenic mice.
  
  
  RESULTS
  An analog peptide, CII (256-276, N(263), D(266)), that inhibited T cell responses in vitro, was identified. When DR1 mice were coimmunized with CII and CII (256-276, N(263), D(266)), the incidence and severity of arthritis were greatly reduced, as was the antibody response to CII. Moreover, CII (256-276, N(263), D(266)) was effective in down-regulating the immune responses to CII and arthritis, even when administered 2 weeks following immunization with CII. Spleen and lymph node cells from CII-immunized mice cultured with CII (256-276, N(263), D(266)) in vitro produced increased amounts of interleukin-4 (IL-4) compared with cells cultured with the wild-type peptide, CII (256-276). Furthermore, CII (256-276, N(263), D(266)) was incapable of preventing arthritis in DR1 IL-4(-/-) mice (genetically deficient in IL-4).
  
  
  CONCLUSIONS
  These data establish that CII (256-276, N(263), D(266)) is a potent suppressor of the DR-mediated immune response to CII. Its effect is mediated, at least in part, by IL-4. These experiments represent the first description of an analog peptide of CII recognized by T cells in the context of a human major histocompatibility complex molecule that can suppress autoimmune arthritis.
authors.affiliation: University of Tennessee, Memphis, USA.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Myers
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Sakurai
authors.forename: B
authors.initials: B
authors.lastname: Tang
authors.forename: Xiaowen
authors.initials: X
authors.lastname: He
authors.forename: Edward F
authors.initials: EF
authors.lastname: Rosloniec
authors.forename: John M
authors.initials: JM
authors.lastname: Stuart
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Kang
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced* / Q000517:prevention & control*; D015551:Autoimmunity / Q000502:physiology; D003094:Collagen; D024043:Collagen Type II / Q000276:immunology / Q000494:pharmacology*; D015798:HLA-DR1 Antigen / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007114:Immunization; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D008822:Mice, Transgenic / Q000235:genetics; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology*; D018417:Th1 Cells / Q000502:physiology
chemical_list: D024043:Collagen Type II; D015798:HLA-DR1 Antigen; D010446:Peptide Fragments; C470085:collagen type II (256-276), Asn(263), Asp(266)-; D015847:Interleukin-4; D003094:Collagen