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

Abstract

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.

Towards Small‐Molecule CXCR3 Ligands with Clinical Potential

“…[51,60,[63][64][65] An antibody directed against CXCR3 not only reduced T cell recruitment to inflamed arthritic joints in a rat model of arthritis, but also prevented weight loss by the animals and decreased the severity of arthritis in general. [66] Indeed, the CXCL10 antibody MDX1100 (vide supra) will also be investigated in a Phase II trial for rheumatoid arthritis. [62] Last, a CXCL10 antibody suppressed metastasis of melanoma cells to the lymph nodes in mice.…”

Targeting Cytokines, Chemokines and Adhesion Molecules in Rheumatoid Arthritis

“…Thus, blockade of the CXCR4 receptor for SDF-1/CXCL12 with the synthetic non-peptide antagonist, AMD3100, inhibited murine CIA in IFN-receptordeficient mice in both a prophylactic as well as a therapeutic protocol [139]. Recently, Mohan et al [140] examined the role of CXCR3 in murine adjuvant arthritis (AA) and found that CXCR3 + T-cells migrated 2-to 3-fold faster than CXCR3-T-cells into inflamed joints, suggesting the importance of this chemokine receptor for T-cell recruitment. The blockade of CXCR3 with a monoclonal antibody resulted in inhibition of T-cell recruitment by 40-60%, a delay in the onset of arthritis, and reduced severity of joint inflammation with a > 50% decrease in the clinical arthritis score [140].…”

“…Recently, Mohan et al [140] examined the role of CXCR3 in murine adjuvant arthritis (AA) and found that CXCR3 + T-cells migrated 2-to 3-fold faster than CXCR3-T-cells into inflamed joints, suggesting the importance of this chemokine receptor for T-cell recruitment. The blockade of CXCR3 with a monoclonal antibody resulted in inhibition of T-cell recruitment by 40-60%, a delay in the onset of arthritis, and reduced severity of joint inflammation with a > 50% decrease in the clinical arthritis score [140]. CXCR3 blockade also resulted in a 50-60% decrease in neutrophil accumulation in the synovium as well as reducing weight loss in the arthritic animals.…”

Defining Novel Targets for Intervention in Rheumatoid Arthritis: An Overview

“…Some of the newly developed anti-chemokine [44] and anti-adhesion molecule [45] antibodies have also clearly demonstrated efficacy and disease-modifying activity in animal models of RA. However, an anti-chemokine monoclonal antibody therapy met with less success in a recently completed human RA clinical trial [46].…”