Gastroenterology

Gastroenterology

Volume 122, Issue 6, May 2002, Pages 1592-1608
Gastroenterology

Biologic therapy of inflammatory bowel disease☆,☆☆

https://doi.org/10.1053/gast.2002.33426Get rights and content

Abstract

Advancing knowledge regarding the biology of chronic inflammation has led to the development of specific biologic therapies that mechanistically target individual inflammatory pathways. Many biologic therapies are being evaluated for the treatment of the chronic inflammatory bowel diseases, Crohn's disease and ulcerative colitis. Biologic compounds proven to be effective for Crohn's disease include monoclonal antibodies to tumor necrosis factor (infliximab and CDP571) and to the leukocyte adhesion molecule α4 integrin (natalizumab). Other biologic compounds for which there is insufficient evidence to judge efficacy for inflammatory bowel disease include: p55 tumor necrosis factor binding protein (onercept); interferon α; interferon β-1a; anti-interferon γ antibody; anti-interleukin 12 antibody; p65 anti-sense oligonucleotide (blocks NF-κB); granulocyte colony stimulating factor, and granulocyte macrophage colony stimulating factor; anti-interleukin 2 receptor antibody; epidermal growth factor; keratinocyte growth factor 2 (repifermin); human growth hormone; anti-CD4 antibody; and anti-α4β7 antibody. Biologic therapies that have been proven ineffective for inflammatory bowel disease include: interleukin 10; interleukin 11; anti-sense intercellular adhesion molecule-1; and the tumor necrosis factor receptor fusion protein etanercept. Based on the early successes of infliximab, CDP571 and natalizumab, it seems certain that biologic therapy will play an important role in the future treatment of inflammatory bowel disease.

GASTROENTEROLOGY 2002;122:1592-1608

Section snippets

Definitions of biologic therapy and vehicles of therapy delivery

Biologic therapies include: (1) native biologic preparations and isolates such as blood products and vaccines containing live, attenuated, or killed microorganisms; (2) recombinant peptides or proteins such as growth hormone, erythropoietin, and so on; (3) antibody-based therapies; (4) nucleic acid–based therapies; and (5) cell and gene therapies.13 At the present time, the biotechnology therapies that are being used in clinical practice or investigated for the treatment of IBD are

TNF inhibitors

A variety of therapeutic approaches have been used to inhibit TNF in patients with IBD including the monoclonal antibodies infliximab (formerly called cA2) and CDP571; the p 75 soluble TNF receptor fusion protein etanercept or the p55 soluble TNF receptor onercept; the MAP kinase inhibitor CNI-1493; and thalidomide. The step in the TNF production and secretion pathway that each therapy targets is shown in Figure 3.

Inhibitors of lymphocyte trafficking

A variety of therapeutic approaches have been used to inhibit lymphocyte trafficking in patients with IBD including monoclonal antibodies to α4 integrin (natalizumab) and α4β7 integrin (LDP-02); and antisense to intercellular adhesion molecule-1 (ICAM-1). The targets for these therapies are shown in Table 1. The α4 integrin is expressed at a moderate or high level on almost all lymphocytes.60 α4 Integrin usually exists in combination with either a β1 or β7 subunit and interacts predominantly

Inhibitors of TH1 polarization

The therapeutic approaches that have been or may be used to inhibit TH1 polarization in patients with IBD include monoclonal antibodies to IL-12, interferon (IFN)-γ, IL-18, and IL-2 receptor (daclizumab and basiliximab); and the immunomodulatory recombinant human protein IL-10. The targets for these therapies are showed in Figure 2.

Inhibitors of NF-κB

NF-κB designates a group of transcription factors with important functions in the intestinal immune system including the transcriptional control of various promoters of pro-inflammatory cytokines (including IL-1β, IL-2, IL-12, and TNF-α), cell-surface receptors, transcription factors, and adhesion molecules (including ICAM-1).11 The NF-κB family consists of NF-κB1 (p50; precursor protein: p105), NF-κB2 (p52; precursor protein: p100), p65 (RelA), c-Rel (Rel), and RelB which share the Rel

Inhibitors of T-cell activation

The activation of T cells is a complex process that requires the presentation of an antigen by MHC class II on an antigen-presenting cell to the T-cell receptor on a T cell.101 However, this antigen presentation in isolation leads to anergy (tolerance) or apoptosis and additional signals from costimulatory molecules are required for T-cell activation. Antigen recognition by T cells induces the expression of the costimulatory molecule CD40 ligand (CD40L) on the T-cell surface. CD40L then engages

Anti-CD4 antibodies

T cells with the CD4 marker, T helper cells, play a central role in modulating cellular immunity through the secretion of multiple cytokines, which in turn modulate numerous effector functions including: immunoglobulin secretion, complement activation, neutrophil chemotaxis, and macrophage activation. In patients with IBD, T suppressor (CD8) and T helper (CD4) cells in the intestinal lamina propria and the epithelium are present in the usual proportions108, 109 but they appear to have an

Growth factors

A variety of growth factors may play an important role in IBD including transforming growth factor β (which is secreted by Th3 cells and provides negative feedback on the differentiation of naive T helper cells to Th1 or Th2 subtypes), epidermal growth factor (EGF), and keratinocyte growth factor-1 (KGF-1).119

IFN-α

Interferon α is produced naturally by virally infected cells to induce resistance of the cells to viral infection. Recombinant IFN-α-2a, IFN-α-2b, and IFN-α-n are used clinically to treat HIV-related Kaposi's sarcoma, melanoma, chronic hepatitis B infection, and chronic hepatitis C infection.78 The cellular responses to interferon α appear to be mediated through the JAK-STAT pathway.125 Uncontrolled studies with IFN-α-2a reported response rates of up to 50%126, 127 in patients with CD and up to

Conclusions

Cell-mediated immunity, dependent on T-cell activation and Th1 polarization, or blunted regulatory responses are important in the initiation and perpetuation of inflammation of intestinal inflammation in patients with IBD. Biotechnology agents targeted against TNF, leukocyte adhesion, TH1 polarization, T-cell activation (and T-cell depletion), NF-κB, and other miscellaneous therapies are being evaluated as potential therapies for the treatment of IBD. New targets will be defined by genetic

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    • Cited by (0)

    ☆

    Dr. Sandborn receives grants/research support or has worked as a consultant for Celltech Therapeutics, Ltd., Human Genome Sciences, Inc., Schering-Plough Research Institute, Genetics Institute, Immunex Corp., Serono Inc., Centocor, Genentech, Elan Pharmaceuticals, IDEC Pharmaceuticals Corp., ISIS Pharmaceuticals, Biogen Inc., and Amgen Inc. He is also a shareholder in Millenium Pharmaceuticals.

    ☆☆

    Address requests for reprints to: William J. Sandborn, M. D., Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. e-mail: [email protected]; fax: (507) 266-0335.

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    Copyright © 2002 American Gastroenterological Association. Published by Elsevier Inc. All rights reserved.