MIP-3alpha 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)-3alpha, a CD4 T cell-directed chemokine, is elevated in inflammatory bowel disease. However, the functional relevance of MIP-3alpha production during intestinal inflammation is poorly understood. The aim of this study was to determine whether MIP-3alpha production is increased during murine 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis and to examine the effect of anti-MIP-3alpha neutralizing monoclonal antibody administration in this model. We found that the administration of TNBS significantly increased colonic MIP-3alpha 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-3alpha 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-3alpha neutralizing monoclonal antibody treatment. Taken together, our findings indicate that blockade of MIP-3alpha bioactivity can significantly reduce TNBS-mediated colonic injury and T cell recruitment, suggesting a role for this chemokine in the pathophysiology of intestinal inflammation.
Katchar
Kianoosh
K
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston University School of Medicine, Boston, MA 02215, USA.
Kelly
Ciarán P
CP
Keates
Sarah
S
O'brien
Michael J
MJ
Keates
Andrew C
AC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D016827:CD8 Antigens / Q000032:analysis; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000276:immunology*; D003092:Colitis / Q000276:immunology / Q000517:prevention & control*; D003108:Colonic Diseases / Q000139:chemically induced / Q000517:prevention & control*; D007413:Intestinal Mucosa / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D014302:Trinitrobenzenesulfonic Acid; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; C493447:CCL20 protein, mouse; D016827:CD8 Antigens; D054418:Chemokine CCL20; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D014302:Trinitrobenzenesulfonic Acid