A characteristic feature of human inflammatory bowel disease, particularly Crohn's disease, is the presence of activated CD4+T cells. Recently, we have shown that colonic epithelial cell production of macrophage inflammatory protein (MIP)-3α, a CD4 T cell-directed chemokine, is elevated in inflammatory bowel disease. However, the functional relevance of MIP-3α production during intestinal inflammation is poorly understood. The aim of this study was to determine whether MIP-3α production is increased during murine 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis and to examine the effect of anti-MIP-3α neutralizing monoclonal antibody administration in this model. We found that the administration of TNBS significantly increased colonic MIP-3α protein levels in Balb/c mice. Consistent with this, a marked increase in the number of CCR6-bearing lamina propria CD4+and CD8+T cells was also observed in TNBS-treated animals. Treatment of mice with an anti-MIP-3α neutralizing monoclonal antibody significantly reduced TNBS-mediated increases in colonic weight-to-length ratio, mucosal ulceration, histological damage, and myeloperoxidase activity. TNBS-mediated increases in the number of CCR6-bearing lamina propria T cells were also substantially reduced by anti-MIP-3α neutralizing monoclonal antibody treatment. Taken together, our findings indicate that blockade of MIP-3α bioactivity can significantly reduce TNBS-mediated colonic injury and T cell recruitment, suggesting a role for this chemokine in the pathophysiology of intestinal inflammation.
A minimal physiologically based pharmacokinetic model to characterize colon TNF suppression and treatment effects of an anti-TNF monoclonal antibody in a mouse inflammatory bowel disease model
