Prevention and reversal of experimental colitis by a monoclonal antibody which inhibits leukocyte adherence

Abstract

The role of neutrophils in the pathogenesis of acute colitis was investigated using a rabbit model. Colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid in 30% ethanol. Myeloperoxidase activity was measured at various times after induction of colitis as an index of neutrophil infiltration, and this was confirmed by histology. The permeability of the colonic epithelium to [51Cr]EDTA was also measured at various times after induction of colitis. The most marked increase in neutrophil infiltration of the colon occurred during the period 3-6 h after induction of colitis. This was also the period in which the greatest increase in colonic permeability was observed. Pretreatment with a monoclonal antibody (IB-4) directed against the leukocyte adhesion molecule, CD18, markedly suppressed neutrophil infiltration into the colonic tissue after induction of colitis. This pretreatment also significantly reduced the extent of epithelial injury. Administration of IB-4 to rabbits 12 h after induction of colitis resulted in a rapid decline in tissue myeloperoxidase activity. When measured 12 h after IB-4 administration (3 mg/kg), colonic myeloperoxidase activity was reduced by about 80% compared to the control group treated with the vehicle. These results are consistent with the hypothesis that neutrophils contribute significantly to the epithelial dysfunction that characterizes colitis and suggest that antibodies directed against adhesion molecules may represent a novel approach to the treatment of intestinal inflammatory disorders.