Suppression of T cell responses by chondromodulin I, a cartilage‐derived angiogenesis inhibitory factor: Therapeutic potential in rheumatoid arthritis

• Published in: Arthritis and rheumatism 2004-03, Vol.50 (3), p.828-839
• Main Authors: Setoguchi, Keigo, Misaki, Yoshikata, Kawahata, Kimito, Shimada, Kota, Juji, Takuo, Tanaka, Sakae, Oda, Hiromi, Shukunami, Chisa, Nishizaki, Yuriko, Hiraki, Yuji, Yamamoto, Kazuhiko
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic; Angiogenesis Inhibitors - isolation & purification; Angiogenesis Inhibitors - metabolism; Angiogenesis Inhibitors - pharmacology; Animals; Antibody Formation; Antigens - immunology; Arthritis, Experimental - chemically induced; Arthritis, Experimental - immunology; Arthritis, Experimental - prevention & control; Arthritis, Rheumatoid - drug therapy; Biological and medical sciences; Cartilage - chemistry; Cell Division - drug effects; Cell Line; Collagen; Diseases of the osteoarticular system; Epitopes; Humans; Inflammatory joint diseases; Intercellular Signaling Peptides and Proteins - isolation & purification; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - pharmacology; Medical sciences; Membrane Proteins - isolation & purification; Membrane Proteins - metabolism; Membrane Proteins - pharmacology; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Recombinant Proteins - pharmacology; Serum Albumin, Bovine; Synovial Membrane - pathology; T-Lymphocytes - cytology; Thymus Gland - metabolism; Time Factors; Tissue Distribution
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.20193

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 3H‐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. Conclusion 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.