Blockade of lymphocyte trafficking in inflammatory bowel diseases therapy: importance of specificity of endothelial target

Abstract

Inflammatory bowel diseases (IBD) are chronic, relapsing to continuously active inflammatory disorders of the gastrointestinal tract, of potentially destructive nature. So far, the excessive and/or unbalanced immune response has been the target of the majority of the IBD treatments. Despite the increasing use of immunosuppressants and anti-TNF-α inhibitors, about 30% of patients with Crohn’s disease and about one-tenth of patients with ulcerative colitis still require major abdominal surgery at 5–10 years. As a result, new therapeutic approaches are urgently needed. The endothelium has a key role in the development of the inflammation, as it selectively governs the leukocyte trafficking and the influx of leukocytes into the intestinal mucosa. Drugs blocking such crossing, specifically at intestinal level, are going to be a new therapeutic option in IBD.

Keywords::

• biological therapy
• CAM
• Crohn’s disease
• inflammatory bowel disease
• integrins
• monoclonal antibody
• pathogenesis
• ulcerative colitis

Financial & competing interests disclosure

S Danese has received consulting fees from Schering-Plough, Astra Zeneca, Abbott Laboratories, Novo Nordisk, Takeda Millennium, Danone, Salix Pharmaceuticals and Pfizer and has received lecture fees, including fees for service on speakers’ bureaus, from UCB Pharma, Ferring, Vifor and Merck Sharp & Dohme and AbbVie. G Fiorino has received consulting fees from MSD, AbbVie, Takeda and Janssen. S Vermeire has received grants/research support from UCB; consultancy for AstraZeneca, Ferring and Pfizer; speakers’ bureau for Schering-Plough, Abbott, Ferring and UCB; and advisory committee for Shire and Ferring. W Reinisch has served as a consultant for Centocor Research & Development, a division of Johnson & Johnson Pharmaceutical Research & Development, LLC and Schering-Plough, a subsidiary of Merck & Co, Inc. F Cataldi is senior director of gastroenterology, Pfizer Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Up to one-third of patients with Crohn’s disease still require major abdominal surgery at 5 years, and about one-tenth of patients with ulcerative colitis require colectomy at 5 years.

• The endothelium selectively governs the leukocyte trafficking and the influx of leukocytes into the intestinal mucosa.

• This process is mediated by the expression of adhesion molecules, which are then attractive targets for therapeutic intervention in inflammatory bowel diseases.

• Natalizumab was the first drug that was effective in Crohn’s disease. But its use is hampered by the risk to reactivate the JC virus and to develop progressive multifocal leukoencephalopathy.

• Vedolizumab is a monoclonal antibody against α4β7 integrin that interferes only with the α4β7/mucosal addressin cell adhesion molecule 1 pathway in the gut, without any detected risk to develop progressive multifocal leukoencephalopathy.

• Vedolizumab may represent a promising new alternative treatment for moderate-to-severe cases of inflammatory bowel diseases, also as first-line therapy.

• PF-547656 is a monoclonal antibody directed against mucosal addressin cell adhesion molecule 1, with a very organ-specific target, which may result in a promising safety and efficacy profile.

Notes