Biologic and Novel Therapy of the Inflammatory Bowel Diseases

IBD is now best considered as a group of genetic disorders of immune dysregulation with failure of downregulation of the intestinal mucosa's normal immune response to its intraluminal commensal bacterial milieu combined with inappropriate migration of antigenic material triggered by multiple host (appendectomy, pregnancy, breast feeding, age) and environmental factors (tobacco smoking, birth control pill, NSAIDS). The result is the predominance of an effector or pro-inflammatory cytokine response due to clonal expansion of T1 and T2 helper lymphocytes (Th1 and Th2 response) combined with an inadequate regulatory cytokine response by T3 helper (Th 3) and T1 regulatory (Tr1) lymphocytes. The persistence of this imbalance in the inflammatory response then leads to tissue damage resulting in both local and systemic illness. In human IBD, a distinction can now be drawn between Crohn's disease with its Th1 effector response characterized by high levels of the cytokines interleukin-12 (IL-12), interferon gamma (IFNγ) and tumor necrosis factor (TNF) leading to transmural inflammation with granulomas, and ulcerative colitis with a Th2 effector response, high levels of interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), and interleukin-13 (IL-13) characterized by strictly mucosal inflammation. The difficulty with adherence to current maintenance therapy for the inflammatory bowel diseases as well as the toxicity and relative ineffectiveness of induction therapy has provided the impetus for the development of new biologic and novel therapies which will be reviewed in this article. Biologic therapy has been divided into five areas of study: 1) native biologic preparations and isolates such as vaccines, hormone fragments and blood products, 2) recombinant peptides or proteins, including granulocyte macrophage colony stimulating factor, 3) monoclonal antibody-based therapies, 4) anti-sense nucleotides to nucleic acids, and 5) cell and gene therapies. Since the early 1990's, investigation in all five of these areas has yielded numerous potential agents for use in treating IBD more effectively and safely. While only one, infliximab (Remicade), is FDA-approved, several additional agents should be available for clinical use in the near future with the promise of more to follow. Our discussion of biologic and novel therapies represents a review of the most promising treatments and a status report of on-going clinical trials. Peripheral leukocyte apheresis and stem cell transplants, while suggesting an exciting new pathway for investigation, will not be reviewed. Our discussion is organized by each agent's hypothesized mode of intervention in altering the pathogenesis of IBD.