ATTENUATION OF COLITIS IN THE COTTON-TOP TAMARIN BY ANTI-ALPHA-4 INTEGRIN MONOCLONAL-ANTIBODY

Recent studies have demonstrated the induced expression of endothelial adhesion molecules including E-selectin (also called endothelial leuk ocyte adhesion molecule-1), vascular cell adhesion molecule and interc ellular adhesion molecule in actively involved mucosa of patients with ulcerative colitis and Crohn's disease. Similar induction has been de monstrated in the colon of the Cotton-top tamarin (CTT), a New World p rimate that experiences a spontaneous acute and chronic colitis resemb ling ulcerative colitis. To assess the potential importance of leukocy te adhesion as a necessary step in acute colitis, the effect of parent eral mAb directed against adhesion molecules on CTT colitis was evalua ted in placebo-controlled blinded trials. Serial administration of eit her of two anti-E-selectin mAb designated BB11 and EH8 effectively coa ted endothelial surfaces expressing this vascular adhesion molecule. A lthough colitis activity was slightly diminished after the 10-d treatm ent period in CTT receiving either BB1 1 or EH8, this reduction was no t significantly different than that seen in animals given a placebo co ntrol when assessed by a previously validated standardized scale of in flammatory activity: mean histologic activity grade 2.2+/-0.2 pretreat ment vs 1.5+/-0.5 posttreatment in group receiving mAb and 2.1+/-0.1 p retreatment vs 1.3+/-0.5 posttreatment in the placebo group (P > 0.2). In contrast, administration of an anti-alpha4 integrin mAb designated HP1/2 that binds VLA4 (alpha4beta1) and presumably alpha4beta7 integr ins resulted in significant attenuation of acute colitis when compared to both pretreatment activity index (P = 0.005) and the placebo contr ol group (P < 0.01):mean histologic activity grade 1.6+/-0.3 pretreatm ent vs 0.2+/-0.1 posttreatment in the group receiving HP1/2 and 1.8+/- 0.5 pretreatment and 1.2+/-0.2 posttreatment in the placebo control gr oup. These studies using a model of spontaneous colitis in the CTT dem onstrate the feasibility of modulation of leukocyte-vascular adhesion and/or other integrin-mediated events possibly including T cell aggreg ation and T cell-stromal interactions, as well as lymphocyte homing. T hese results suggest both that these processes are important and possi bly essential elements in sustaining acute colitis and that their disr uption may result in therapeutic benefit.