MIP-3α neutralizing monoclonal antibody protects against TNBS-induced colonic injury and inflammation in mice

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)-3 alpha, a CD4 T cell- directed chemokine, is elevated in inflammatory bowel disease. However, the functional relevance of MIP-3 alpha production during intestinal inflammation is poorly understood. The aim of this study was to determine whether MIP-3 alpha production is increased during murine 2,4,6- trinitrobenzene sulfonic acid ( TNBS)- induced colitis and to examine the effect of anti-MIP-3 alpha neutralizing monoclonal antibody administration in this model. We found that the administration of TNBS significantly increased colonic MIP-3 alpha 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-3 alpha 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-3 alpha neutralizing monoclonal antibody treatment. Taken together, our findings indicate that blockade of MIP-3 alpha bioactivity can significantly reduce TNBS- mediated colonic injury and T cell recruitment, suggesting a role for this chemokine in the pathophysiology of intestinal inflammation.