Blockade of chemokine receptor CXCR3 inhibits T cell recruitment to inflamed joints and decreases the severity of adjuvant arthritis.
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.
Mohan
Karkada
K
Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
Issekutz
Thomas B
TB
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002465:Cell Movement; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D009161:Mycobacterium; D009504:Neutrophils / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D054367:Receptors, CXCR3 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015431:Weight Loss
D000911:Antibodies, Monoclonal; D054367:Receptors, CXCR3