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  • Review Article
  • Published:

Evolving knowledge and therapy of inflammatory bowel disease

Nature Reviews Drug Discovery volume 5, pages 197–209 (2006)Cite this article

Key Points

  • The pathophysiology of irritable bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease, reflects the convergence of genetic, environmental and immunological factors initiating an aberrant innate immune response and culminating in a T-cell-driven process.

  • Currently available therapies are inadequate for sizeable groups of patients with UC and Crohn's disease, as many patients are intolerant or unresponsive to existing medications.

  • Biologic therapies, particularly antibodies, have targeted cytokines which are involved in inflammation and T-cell differentiation.

  • Several additional agents directed against tumour-necrosis factor-α (TNFα) are likely to be approved soon for clinical use in Crohn's disease, including adalimumab, a fully human anti-TNFα antibody, and certolizumab (CDP870), a pegylated anti-TNFα fragment.

  • Anti-interleukin-12 (anti-IL-12) antibodies, which bind to a cytokine central to determining a TH1-type response, seem to be effective in Crohn's disease. Fontolizumab, an anti-interferon-γ (IFNγ) antibody, which blocks TH1 polarization, as well as activation of macrophages, monocytes and natural killer cells, is promising for the treatment of active Crohn's disease.

  • A CD3 antibody, visilizumab, appears beneficial in the treatment of UC, though there are concerns about viral activation and infusion reactions.

  • IL-10, though a central immunoregulatory cytokine, was not effective in several studies in Crohn's disease and UC, but continues to be investigated, with strategies which might provide more specific delivery to the gastrointestinal tract, including the use of engineered bacteria.

  • Blockade of selective adhesion molecules is an approach shared by several therapies. Although natalizumab, an α4 integrin antibody, might benefit a subset of patients with Crohn's disease and possibly sustain remission, development has been halted because of several cases of progressive, multifocal leukoencephalopathy (PML). An antibody directed against α4β7 integrin, designated MLN02, is more specific to the intestine, and seems to be promising for active UC.

  • Sargramostim, or recombinant human granulocyte–macrophage colony-stimulating factor (rhuGM-CSF), which may act to stimulate intestinal innate immunity, was effective in active Crohn's disease, and in contrast to most other therapies under investigation which act to suppress the immune response.

  • Modulation of the luminal flora has been investigated using probiotics and prebiotics, though these strategies are still early in development.

Abstract

With recent advances in the understanding of its pathophysiology, inflammatory bowel disease has become a very active area for the development of novel therapeutic agents. New targets for biologics include cytokines involved in T-cell activation, with antibodies directed against IL-12 and interferon-γ. Selective adhesion molecule blockade has produced promising, though mixed, results. Recombinant human granulocyte–macrophage colony-stimulating factor might be effective in active Crohn's disease, presumably through stimulation of intestinal innate immune responses. With increasing evidence for a crucial role for luminal flora in maintaining the health of the bowel, strategies to manipulate intestinal bacteria using probiotics and prebiotics are being actively investigated as well.

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Figure 1: T-cell differentiation and T-cell cytokine profiles.
Figure 2: The intestinal innate immune barrier.
Figure 3: Novel therapeutic targets in inflammatory bowel disease (IBD).
Figure 4: The TNFα pathway: regulation, effects and potential therapeutic targets.

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Authors and Affiliations

  1. Department of Medicine, Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, 02114, Massachusetts, USA

    Joshua R. Korzenik & Daniel K. Podolsky

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  1. Joshua R. Korzenik
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Correspondence to Daniel K. Podolsky.

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Competing interests

J.R.K. has received consulting and lecture fees from Proctor & Gamble, Shire Pharmaceuticals, Isis Pharmaceuticals, Cytokine Pharmasciences, Berlex and Centocor, and research support from Danisco. A US patent entitled 'Stimulating neutrophil function to treat inflammatory bowel disease' (6,500,418) was issued 31 December 2002, on which J.R.K. is an inventor. The patent is owned by Washington University and licensed by Berlex Laboratories. D.K.P. has equity in and serves as a consultant to The GI Company.

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DATABASES

OMIM

CD

IBD

UC

FURTHER INFORMATION

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Glossary

Ulcerative colitis

One of the two main forms of IBD with unknown aetiology, which causes an inflammatory response restricted to the colon, beginning at the rectum and spreading proximally to differing extents.

Crohn's disease

One of the two main forms of IBD with unknown aetiology, characterized by inflammation that can occur anywhere in the gastrointestinal tract, affecting the terminal ileum in more than 70% of individuals.

Probiotic

The use of live bacteria as a therapeutic agent to induce a benefit by altering the microbial balance.

Innate immune response

The innate immune system comprises elements of the immune system that generate a nonspecific reaction to a potential pathogen (for example, superoxide burst for bactericidal function), which contrasts with an adaptive response (for example, an antibody produced by a B cell against a particular antigen).

CARD15

The first gene identified as a susceptibility factor for the development of CD. How the defective gene leads to intestinal inflammation and CD remains an area of controversy.

Toll-like receptors

(TLRs). A group of transmembrane receptors featuring specific pattern-recognition receptors (PRRs) that bind to pathogen-associated molecular patterns (PAMPs) to direct an appropriate immune response.

Type 1 helper T-cells (TH1)

A subclass of CD4+ cells that produce a characteristic immune response with a cytokine profile which includes IL-2, IFNγ and IL-12.

Type 2 helper T-cells (TH2)

A subclass of CD4+ cells that produce a characteristic immune response with a cytokine profile which includes IL-4, IL-5 and IL-13.

Crohn's Disease Activity Index (CDAI)

A composite score determined from various symptoms, clinical complications, the physician's exam, haematocrit and weight, which forms the standard scoring of disease severity used in trials of therapeutic agents for CD. A score below 150 is considered remission and above 220 is considered moderately active disease. A decrease in 70–100 points is considered the minimum reduction for a 'therapeutic' response.

Tregs

A subpopulation of T cells which function to suppress differentiation and activation of other T-cell subsets.

Anti-idiotype antibodies

Antibodies generated against another antibody.

Pouchitis

Patients with UC can undergo an operation in which the colon is removed and a new rectum 'pouch' is fashioned from the terminal ileum. As many as 50% of people will have one episode of inflammation in the pouch, termed pouchitis.

Proctocolectomy

A surgical procedure in which the entire colon and rectum are resected.

Prebiotic

A non-digested product, usually a complex carbohydrate, which enhances the proliferation of certain bacteria to change the microbial composition and induce a therapeutic effect.

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Korzenik, J., Podolsky, D. Evolving knowledge and therapy of inflammatory bowel disease. Nat Rev Drug Discov 5, 197–209 (2006). https://doi.org/10.1038/nrd1986

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