Immune cell trafficking and retention in inflammatory bowel disease: mechanistic insights and therapeutic advances

Correspondence to Prof Markus F Neurath, Department of Medicine 1, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Ulmenweg 18, Erlangen 91054, Germany; [email protected]

Introduction

The incidence and prevalence of inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC) is increasing worldwide and a medical cure is still not available.¹ However, pivotal advances in our understanding of IBD pathogenesis in recent years have helped to optimise the medical management of these diseases by facilitating the introduction of new targeted therapeutic agents.² One of these advances was the discovery and translational exploration of specific gut homing and cell trafficking pathways controlling the locomotion of immune cells in the healthy and diseased intestine, which led to the development of specific antibodies interfering with such cell trafficking.

The current concept of IBD pathogenesis assumes that a complex interplay of genetic predisposition and environmental factors leads to translocation of luminal antigens over a weakened epithelial barrier resulting in undercontrolled activation of the intestinal immune system with subsequent structural alterations of the bowel wall.^3–5 Most established therapeutic concepts tackle the disease by impacting on the intestinal immune system, for example, by inducing cell death of immune cells or by blocking proinflammatory signalling pathways.² Since such mechanisms are mostly shared between the immune cells of different organs across the body, this entails the potential of systemic complications such as infections.⁶ Hence, the idea of specifically interfering with aspects of immune cell trafficking to or within the gut is an intriguing concept potentially combining local immunosuppression with minimisation of systemic side effects.

The following review will describe and illustrate the basic principles of intestinal immune cell trafficking in the context of IBD. Moreover, we will detail the translational progress in the field by discussing past, ongoing and future efforts to design therapeutic anti-trafficking agents (ATAs) for the treatment of IBD with strong focus on the basic science evidence supporting these approaches. Finally, we will outline major open questions remaining to be solved.

Immune cell trafficking: physiological and pathological aspects

Trafficking describes all processes controlling the localisation of immune cells. More specifically, in the case of T cells, this implies regulation of homing, recirculation and retention in the various differentiation states.⁷

Adhesion cascade

Adhesion is a central step...