Blocking lymphocyte localization to the gastrointestinal mucosa as a therapeutic strategy for inflammatory bowel diseases

Abstract

Lymphocyte migration (homing) to specific tissues has an important role during protective and pathological immune responses, including inflammatory bowel diseases. Lymphocytes use integrin α4β7 and the chemokine receptor CCR9 to localize to the gastrointestinal mucosa; their respective ligands, mucosal addressin cell adhesion molecule-1 and CCL25, are displayed on endothelial cells in intestinal postcapillary venules. Although gastrointestinal-homing receptors are required for lymphocyte migration to the intestine in the noninflamed steady state, their role during inflammation is a matter of debate. Reagents designed to block interactions between these receptors and their ligands have had variable degrees of success in animal models of inflammatory bowel diseases and patients. We discuss the mechanisms involved in lymphocyte localization to the intestinal mucosa and how they can be applied to therapy for inflammatory bowel diseases.

Figure 1. Different Lymphocyte Subsets Use Distinct Homing Receptors and Ligands to Localize to Specific Regions of the Intestine

A) Effector CD8+ T cells use CCR9 and α4β7, and possibly CXCR4 and/or CXCR3, to localize to the GI mucosa. Th17 cells might also use CCR6 to localize to small bowel and IgA-secreting cells use CCR10 to localize to GI and other mucosal tissue compartments. B) Expression of addressins varies throughout the intestine, even in the steady state. MAdCAM-1 is expressed along the whole intestine (small and large bowel) and it is upregulated during inflammation. CCL25, a ligand for CCR9, is expressed in a proximal-to-distal gradient in the small bowel but absent from the colon. CCL28, a ligand for CCR10, is expressed mostly in colon and other mucosal sites; it regulates localization of IgA-secreting cells, but not T cells. CCL20, a ligand for CCR6, is most highly expressed in Peyer's patches and the small bowel, but also it is upregulated in inflamed colon.

Figure 2. Interfering with Homing Receptors as Therapy for IBD

Natalizumab is a monoclonal antibody (mAb) that blocks the integrins α4β7 and α4β1, preventing their binding to MAdCAM-1 and VCAM-1, respectively. Similarly, AJM300 is an orally bioavailable antagonist of the integrin α4 subunit. The mAbs Velodizumab and Pf-00547,659 bind specifically to α4β7 and MAdCAM-1, respectively, blocking their interaction. Traficet-EN (CCX282-B) is an orally bioavailable selective antagonist of CCR9 that blocks its functional interaction with CCL25. Alicaforsen (ISIS 2302) is an antisense oligodeoxynocleotide that binds to the 3′ UTR portion of the ICAM1 mRNA and prevents its translation.