Inflammopharmacology

, Volume 20, Issue 1, pp 1–18 | Cite as

Targeting leukocyte migration and adhesion in Crohn’s disease and ulcerative colitis

Review

Abstract

Crohn’s disease and ulcerative colitis are two chronic inflammatory bowel diseases. Current biologic therapies are limited to blocking tumor necrosis factor alpha. However, some patients are primary non-responders, experience a loss of response, intolerance or side effects defining the urgent unmet need for novel treatments. The rapid recruitment and inappropriate retention of leukocytes is a hallmark of chronic inflammation and a potentially promising therapeutic target. We discuss the immunological mechanisms of leukocyte homing and adhesion in the gut mucosa. The interaction of lymphocytes (CD4+ T-cells, CD8+ T-cells, TREG, TH1, TH17, B-cells), monocytes, macrophages, dendritic cells and granulocytes with endothelial and epithelial cells through integrins [α4β7 (LPAM-1), αEβ7 (HML1 Human Mucosal Lymphocyte Antigen 1), α4β1 (VLA-4), αLβ7, (LFA-1)] and their ligands immunoglobulin superfamily cellular adhesion molecules (CAM) (MAdCAM-1 Mucosal Addressin Cellular Adhesion Molecule 1, ICAM-1 Intercellular Cell Adhesion Molecule, VCAM-1 Vascular Cell Adhesion Molecule), fibronectin as well as chemokine receptors (CCR2, CCR4, CCR5, CCR7, CCR9, CCR10, CXCR3, CX3CR1) and chemokines [CCL5, CCL25 (TECK Thymus Expressed Chemokine), CCL28, CX3CL1, CXCL10, CXCL12] in the process of gut homing is critically reviewed and summarized in scientific cartoons. Moreover, we discuss the clinical trial results of approved and investigational antibodies and small molecules including natalizumab (anti-α4, Tysabri®, Antegren®), AJM300 (anti-α4), etrolizumab (anti-β7, rhuMAb-Beta7), vedolizumab (anti-α4β7, LDP-02, MLN-02, MLN0002), PF-00547659 (anti-MAdCAM), Alicaforsen (anti-ICAM-1), and CCX282-B (anti-CCR9, GSK-1605786, Traficet-EN™) and their risks such as PML reported for natalizumab. Hopefully, the newer gut specific drug designs discussed in this article will have an impact on both efficacy and safety.

Keywords

Crohn’s disease Ulcerative colitis Inflammatory bowel disease IBD Immunoglobulin superfamily cellular adhesion molecules Integrins Chemokines Adhesion Migration Recruitment Leukocytes T-cells Dendritic cells 

Abbreviations

ECM

Extracellular matrix

IBD

Inflammatory bowel disease

UC

Ulcerative colitis

CD

Crohn’s disease

DC

Dendritic cell(s)

T-cell(s)

T-lymphocytes

CNS

Central nervous system

IEL(s)

Intraepithelial lymphocytes

LP

Lamina propria

HEV

High endothelial venule

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© Springer Basel AG 2011

Authors and Affiliations

  1. 1.Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical Center, Virchow HospitalMedical School of the Humboldt University of BerlinBerlinGermany

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