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Blockade of Chemokine Receptor CXCR3 Inhibits T Cell Recruitment to Inflamed Joints and Decreases the Severity of Adjuvant Arthritis¹

Karkada Mohan^* and Thomas B. Issekutz^2,*,

^* Department of Pediatrics and Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada

T lymphocytes expressing the chemokine receptors, CCR2, CCR5, CXCR3, and CXCR6 are increased in inflamed tissues in rheumatoid arthritis. The role of CXCR3 in autoimmune arthritis induced in Lewis rats was investigated. CXCR3⁺ T cells migrated 2- to 3-fold more than CXCR3^– T cells to inflamed joints in arthritic animals. CXCR3-expressing in vivo Ag-activated T lymphoblasts and in vitro-activated lymph node cells from arthritic animals were strongly recruited to the arthritic joints, and treatment with anti-CXCR3 mAb significantly inhibited this T cell recruitment by 40–60%. Immune T cells from the spleen and lymph nodes of actively immunized arthritic donors adoptively transferred arthritis to naive rats. Treatment with anti-CXCR3 mAb delayed the onset of arthritis and significantly reduced the severity of joint inflammation with a >50% decrease in the clinical arthritis score. Blockade of CXCR3 also significantly reduced the weight loss in the arthritic animals and inhibited neutrophil accumulation in the joints by 50–60%. There was a marked reduction in the leukocyte infiltration of the synovium in the presence of CXCR3 blockade and a decrease in the loss of articular cartilage of the joints. In conclusion, CXCR3 on T cells has an essential role in T cell recruitment to inflamed joints and the development of joint inflammation in adjuvant arthritis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant MOP-42379 from the Canadian Institutes of Health Research.

² Address correspondence and reprint requests to Dr. Thomas B. Issekutz, Department of Pediatrics, Dalhousie University, IWK Health Centre, 5850 University Avenue, Halifax, Nova Scotia B3K 6R8, Canada. E-mail address: thomas.issekutz{at}dal.ca

³ Abbreviations used in this paper: RA, rheumatoid arthritis; AA, adjuvant arthritis; CIA, collagen-induced arthritis; LN, lymph node.