title: The pathophysiologic rationale for biological therapies in inflammatory bowel disease.
abstract: OBJECTIVE
  Inflammatory bowel disease is driven by an excessive immune response in the gut wall. This review summarises important new developments in understanding this immune response and the downstream mechanisms of intestinal injury, alongside their potential role in opening up new avenues of treatment.
  
  
  RESULTS
  The evidence continues to accumulate that Crohn's disease is primarily due to a T helper cell-type 1 immune response in the gut wall. IL-12 and IL-18 appear to be the cytokines primarily responsible for Th1 polarisation, but IL-21 may also be important. The p40 chain of IL-12 also associates with a novel p19 chain to form IL-23 which is also a potent Th1-inducing cytokine but the expression of IL-23 in Crohn's disease has not been reported. Progress in understanding the immunology of ulcerative colitis remains slow, but IL-13 produced by natural killer T cells may be involved. T-cell resistance to apoptosis occurs in Crohn's disease, and human and mouse studies indicate that the signalling molecule STAT3, which transduces signals from IL-6 and IL-10, is involved in mucosal T cell homeostasis. Fibroblasts and metalloproteinases continue be implicated in ulceration, fibrosis, and fistula formation.
  
  
  CONCLUSIONS
  Understanding the immunology of inflammatory bowel disease continues to underpin the vast majority of new therapies and identifies new targets. Novel approaches, such as exploiting the antiinflammatory role of cannabinoid receptors, may also prove productive in the future.
authors.affiliation: Division of Infection, Inflammation and Repair, University of Southampton School of Medicine, Southampton General Hospital, Southampton, UK.
authors.forename: John N
authors.initials: JN
authors.lastname: Gordon
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Sabatino
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Macdonald
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology*; D007167:Immunotherapy / Q000379:methods*; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000628:therapy; D007413:Intestinal Mucosa / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines