Introduction and overview: recent advances in the immunotherapy of inflammatory bowel disease

Abstract

Ulcerative colitis (UC) and Crohn's disease (CD) comprise a series of inflammatory bowel disease (IBD) resulting from chronic upregulation of the mucosal immune system. Although the pathogenesis of IBD remains elusive, it appears that there is chronic activation of the immune and inflammatory cascade in genetically susceptible individuals. Current disease management guidelines have therefore focused on the use of antiinflammatory agents, aminosalicylates and corticosteroids. However, some patients are still refractory to these therapies. Recent advances in the understanding of the pathophysiological conditions of IBD have provided new immune system modulators as therapeutic tools. Cytapheresis has demonstrated effectiveness against UC and has practical use in Japan. Immunosuppressive agents including cyclosporin A and tacrolimus (FK506) have expanded the choice of medical therapies available for certain subgroups of patients. Furthermore, biological therapies have begun to assume a prominent role. Studies with chimeric monoclonal anti-TNF-alpha antibody treatment of CD have been reported with dramatic success. Another antiinflammatory cytokine therapy includes anti-IL-6 receptor, anti-IL-12, or toxin-conjugated anti-IL-7 receptor. Given the diversity of proinflammatory products under its control, NF-kappa B may be viewed as a master switch in lymphocytes and macrophages, regulating inflammation and immunity. In the murine 2,4,6-trinitrobenzen sulfonic acid (TNBS) colitis model, an antisense oligonucleotide to NF-kappa B p65 ameliorated inflammation even after induction of colitis. Recently, a clinical pilot trial of this agent demonstrated promising results. Accumulating evidence suggests that luminal bacterial flora is a requisite and central factor in the development of IBD. Probiotic therapies such as a nonpathogenic Escherichia coli strain have been well tolerated, but larger clinical trials are needed. In addition, novel therapeutic strategies targeting adhesion molecules and costimulatory molecules, or enhancing tissue repair, are under investigation. Although some still need more confirmatory studies, these immune therapies will provide new insights into cell-based and gene-based treatment against IBD in the near future.