Lymphocyte adhesion and activation in inflammatory bowel diseases : studies relating to the effects of blockade of alpha-4 integrins by a monoclonal antibody

Alpha-4 integrins are glycoprotein mediators of activated leucocyte trafficking to the gut, which may be important in inflammatory bowel disease (IBD) pathogenesis. The studies described in this thesis aimed to assess the clinical and immunological effects of natalizumab, a humanised monoclonal antibody to α4 integrin, in patients with active IBD. A randomised double-blind placebocontrolled study of a single 3mg/kg intravenous natalizumab infusion in patients with mild to moderately active Crohn's disease demonstrated that the drug was safe and well-tolerated. Significant reductions in disease activity scores were found post-natalizumab, but not placebo. An open study of the same dose in patients with active ulcerative colitis suggested that natalizumab may also benefit these patients. Natalizumab produced elevated circulating leucocyte counts for at least four weeks post-infusion. T cells expressing activation antigens, B cells, monocytes and eosinophils were particularly elevated, although circulating NK T cells, NK cells and gamma-delta T cells were generally unaffected, suggesting that natalizumab exerts differential effects on leucocyte trafficking in patients with active IBD. Natalizumab also produced reduced levels of the serum soluble form of its endothelial ligand, vascular cellular adhesion molecule-1 (VCAM-1), but was found to have less consistent effects on other serum soluble adhesion molecules. Consistent T cell activation antigen patterns were noted in the initial patients screened for clinical studies of natalizumab and were felt to merit further study. A wide range of lymphocyte activation markers were studied prospectively comparing patterns in newly-diagnosed and chronic IBD patients with patients with other forms of enteric inflammation and healthy volunteers. Consistent expression patterns existed between CD8+ cell activation markers and NK-type T cells in IBD patients, which were found to a lesser extent in disease control patients but not healthy volunteers. Little difference in lymphocyte activation antigen expression was found between newly-diagnosed and chronic IBD patients.