The effects of an ELR+CXC chemokine antagonist in a model of experimental arthritis

Rheumatoid arthritis is an autoimmune disease that can cause chronic inflammation of the joints and other areas of the body. Neutrophils contribute to the pathogenesis of arthritis, and are recruited to the site of inflammation by chemokines. CXCL8/IL-8 is a member of a sub-family of chemokines (ELR+CXC chemokines) that activate and attract neutrophils through the CXCR1 and CXCR2 receptors. Our lab developed a high affinity human CXCR1/CXCR2 antagonist, called human CXCL8(3-72)K11R/G31P (hG31P). This antagonist has been shown to be highly effective in blocking ELR+CXC chemokine-driven neutrophilic inflammation. In this study we looked at the therapeutic effect of blocking ELR+CXC chemokine receptors (CXCR1 and CXCR2) in an experimental model of arthritis. We induced type II collagen (CII)-induced arthritis (CIA) in mice and treated them with hG31P after the onset of disease. The parameters we looked at to assess disease severity were clinical scores (paws were graded on the severity of edema), clinical measurements (measuring inflammation by change in circumference of paw), serum levels of anti-CII antibodies, and inflammatory cytokines mRNA (IL-1β, TNF, KC, and MIP-2) and protein levels (IL-1β, IL-6, KC, and MIP-2) in paw tissue. Initially, when we analyzed all mice together, we were unable to see a change in clinical scores and measurement when CIA mice were treated with hG31P. All CIA mice did not develop arthritis simultaneously, but rather in a serendipitous fashion; therefore we subdivided our mice and analyzed data from mice that developed arthritis early versus those that developed it late. Treatment with hG31P in mice that developed arthritis early (within 5 weeks of initial CII injection) significantly reduced clinical scores (p=0.02) in one, but not both, of our experiments. When CIA mice were treated with hG31P we saw a significant reduction (p