title: Suppression of T cell responses by chondromodulin I, a cartilage-derived angiogenesis inhibitory factor: therapeutic potential in rheumatoid arthritis.
abstract: OBJECTIVE
  Chondromodulin I (ChM-I), a cartilage matrix protein, promotes the growth and proteoglycan synthesis of chondrocytes. However, it also inhibits angiogenesis. Since ChM-I is expressed not only in cartilage, but also in the thymus, we investigated the modulation of T cell function by ChM-I to assess its therapeutic potential in rheumatoid arthritis (RA).
  
  
  METHODS
  The localization of ChM-I expression in mouse thymus tissue was examined by in situ hybridization. The proliferative response of peripheral blood T cells and synovial cells obtained from patients with RA was evaluated by (3)H-thymidine incorporation assay. The effects of ChM-I were examined using recombinant human ChM-I (rHuChM-I). Modulation of the antigen-specific immune response was evaluated by the recall response of splenic T cells and the delayed-type hypersensitivity response induced in the ear of mice primed with ovalbumin (OVA). Antigen-induced arthritis (AIA) was induced in mice by injecting methylated bovine serum albumin into the ankle joints 2 weeks after the priming.
  
  
  RESULTS
  ChM-I was expressed in the cortex of the thymus. Recombinant human ChM-I suppressed the proliferative response of mouse splenic T cells and human peripheral blood T cells stimulated with anti-CD3/CD28 antibodies, in a dose-dependent manner. Production of interleukin-2 was decreased in rHuChM-I-treated mouse CD4 T cells. Ten micrograms of rHuChM-I injected intraperitoneally into OVA-primed mice suppressed the induction of the antigen-specific immune response. Finally, rHuChM-I suppressed the development of AIA, and also suppressed the proliferation of synovial cells prepared from the joints of patients with RA.
  
  
  CONCLUSIONS
  These results suggest that ChM-I suppresses T cell responses and synovial cell proliferation, implying that this cartilage matrix protein has a therapeutic potential in RA.
authors.affiliation: University of Tokyo Graduate School of Medicine, Tokyo, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Setoguchi
authors.forename: Yoshikata
authors.initials: Y
authors.lastname: Misaki
authors.forename: Kimito
authors.initials: K
authors.lastname: Kawahata
authors.forename: Kota
authors.initials: K
authors.lastname: Shimada
authors.forename: Takuo
authors.initials: T
authors.lastname: Juji
authors.forename: Sakae
authors.initials: S
authors.lastname: Tanaka
authors.forename: Hiromi
authors.initials: H
authors.lastname: Oda
authors.forename: Chisa
authors.initials: C
authors.lastname: Shukunami
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Nishizaki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hiraki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000276:Adjuvants, Immunologic; D020533:Angiogenesis Inhibitors / Q000302:isolation & purification* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000917:Antibody Formation; D000941:Antigens / Q000276:immunology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D002356:Cartilage / Q000737:chemistry*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003094:Collagen; D000939:Epitopes; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000302:isolation & purification* / Q000378:metabolism / Q000494:pharmacology*; D008565:Membrane Proteins / Q000302:isolation & purification* / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011994:Recombinant Proteins / Q000494:pharmacology; D012710:Serum Albumin, Bovine; D013583:Synovial Membrane / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000276:Adjuvants, Immunologic; D020533:Angiogenesis Inhibitors; D000941:Antigens; C489408:Cnmd protein, mouse; D000939:Epitopes; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011994:Recombinant Proteins; C068675:CNMD protein, human; D012710:Serum Albumin, Bovine; D003094:Collagen