Antagonists of chemokine receptor CCR9 synergize with anti-TNFα immunotherapy to reduce inflammation in the MDR1a−/− mouse model of colitis

Abstract

Abstract The development of anti-TNFα immunotherapies has led to great advances in quality of life for Crohn’s and colitis patients, and has allowed a reduction in steroid use for these diseases. However, a significant proportion of IBD patients is resistant to anti-TNFα agents, or becomes resistant over time. Preclinical research and clinical trials suggest that CCR9 antagonism can effectively reduce colon inflammation. CCR9 is expressed on a subset of T cells dedicated to intestinal trafficking. Antagonism of this receptor inhibits the accumulation of T cells within inflamed intestinal epithelium and lamina propria. Since anti-TNFα and CCR9 antagonists act through entirely different mechanisms, we asked whether these two approaches might synergize and expand the effectiveness and scope of each therapy. We used a piroxicam-accelerated version of the MDR1a−/− spontaneous colitis model in mice. We have found that combined dosing of piroxicam-fed MDR1a−/− mice with a CCR9 antagonist and an anti-TNFα MAb significantly reverses loss of body weight, diarrhea score and colon inflammation. The combined dosing was more effective than anti-TNFα or CCR9 antagonist alone, as measured by colon length/weight ratio, neutrophil accumulation in the colonic epithelium and reversal of the loss in body weight characteristic of this model. These data suggest that combining a CCR9 antagonist with existing anti-TNFα treatment regimens may extend the benefits of anti-TNFα immunotherapy to a larger class of patients suffering from IBD, and may prolong the effectiveness of anti-TNFα immunotherapy for those patients already undergoing such treatments.