Targeting Immune Cell Trafficking – Insights From Research Models and Implications for Future IBD Therapy

Abstract

Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC) are multifactorial diseases with still unknown aetiology and an increasing prevalence and incidence worldwide. Despite plentiful therapeutic options for IBDs, the lack or loss of response in certain patients demands the development of further treatments to tackle this unmet medical need. In recent years, the success of the anti-α4β7 antibody vedolizumab highlighted the potential of targeting the homing of immune cells, which is now an important pillar of IBD therapy. Due to its complexity, leukocyte trafficking and the involved molecules offer a largely untapped resource for a plethora of potential therapeutic interventions. In this review, we aim to summarise current and future directions of specifically interfering with immune cell trafficking. We will comment on concepts of homing, retention and recirculation and particularly focus on the role of tissue-derived chemokines. Moreover, we will give an overview of the mode of action of drugs currently in use or still in the pipeline, highlighting their mechanisms and potential to reduce disease burden.

Tilting the Balance: Therapeutic Prospects of CD83 as a Checkpoint Molecule Controlling Resolution of Inflammation

“…Inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, are severe inflammatory conditions that preferentially affect the distal small intestine or colon, with little signs of spontaneous resolution. Tissue-targeted immune reactions, as observed upon intestinal infection or in IBD, pose a vital threat to the organism and are often a result of disturbed homeostatic immune mechanisms and intestinal dysbiosis [ 86 , 87 ]. Tissue-resident immune cells e.g., intestinal DCs and MΦs and their mutual interactions with intestinal epithelial cells (IECs) of the gut are crucial for the maintenance of intestinal immune homeostasis.…”

Limited dose-dependent effects of vedolizumab on various leukocyte subsets

“…Anti-trafficking agents with the prime example of the anti-α4β7 integrin antibody vedolizumab (VDZ) have emerged as a new pillar for the treatment of the inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis (UC) ( 1 , 2 ). The α4β7 integrin heterodimer is expressed on a plethora of leukocytes and mediates firm adhesion to and subsequent extravasation through the endothelium into the tissue (a process known as homing).…”

Recruitment of α4β7 monocytes and neutrophils to the brain in experimental colitis is associated with elevated cytokines and anxiety-like behavior

“…Inflammatory effector lymphocytes expressing α4β7 are recruited to the bowel in IBD patients, and this observation precipitated the development of α4β7 blockade using vedolizumab as an effective treatment strategy in IBD [ 34 , 35 ]. However, it has become increasingly clear that α4β7 is also expressed on monocytes, in both mice and humans, and regulates the trafficking of both inflammatory and repair monocytes to the bowel [ 36 , 37 ].…”

“…Specifically, the integrin, α4β7 was found to be a key regulator for intestinal homing of lymphocytes through binding to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is upregulated in response to intestinal inflammation [ 32 , 33 ]. This important observation led to the development and clinical use of the α4β7 monoclonal antibody vedolizumab for treating IBD [ 34 , 35 ]. However, it has become clear that α4β7 is expressed not only on gut-homing lymphocytes, but also on monocyte subsets that can regulate intestinal inflammation [ 36 , 37 ].…”