Immunology of Inflammatory Bowel Disease and Molecular Targets for Biologics

Maneesh Dave, MBBS, MPH, Konstantinos A. Papadakis, MD, PhD and William A. Faubion, Jr., MD∗faubion.william@mayo.edu,     Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA

∗Corresponding author.

Inflammatory bowel disease (IBD) is an immune-mediated disease and involves a complex interplay of host genetics and environmental influences. Recent advances in the field, including data from genome-wide association studies and microbiome analysis, have started to unravel the complex interaction between host genetics and environmental influences in the pathogenesis of IBD. A drawback of current clinical trials is inadequate or lack of immune phenotyping of patients. However, recent advances in high-throughput technologies provide an opportunity to monitor the dynamic and complex immune system, which may to lead to a more personalized treatment approach in IBD.

Keywords

Immunology

IBD

Biologics

Innate immunity

Adaptive immunity

Key points

• Most of the recent advances in inflammatory bowel disease (IBD) have resulted from studies of mucosal immunity in the normal and inflamed intestine.

• Both murine models of IBD and human studies have shown dysfunction of the epithelial barrier, innate immune cells, and adaptive T cells in the pathogenesis of IBD.

• The insight gained from the study of the aberrant immune system in IBD has led to the identification of molecular targets in the immune system for the design of drugs, some of which are already being used in clinical practice with many others in various phases of development.

• Despite the increased knowledge gained from animal and human studies, many aspects of mucosal immunity remain unclear in patients with IBD.

• Recently, significant progress has been made in high-throughput technologies like genomic sequencing and mass cytometry that provide multiparametric data which can be used to not just define the various immune cells states but also assess how these interact with each other in a variety of conditions.

Introduction

Inflammatory bowel disease (IBD), specifically Crohn disease (CD) and ulcerative colitis (UC), are autoimmune diseases whose incidence and prevalence are increasing worldwide.1 Over the last few decades, substantial progress has been made in understanding the pathophysiology of IBD, which has been translated into newer, more effective therapies (biologics) that have reduced flares, brought more patients into remission, and improved the quality of life of patients with IBD.2–4 IBD is considered to be an immune-mediated disease that involves a complex pattern/interplay of host genetics and environmental influences.5 Our knowledge of the immune system and its homeostatic imbalance is derived from mouse models of colitis and human studies involving clinical and laboratory experiments.

The immune system evolved in multicellular organisms/metazoans as a defense mechanism against pathogens like bacteria, protozoa, parasites, and fungi.6 The human immune system can be broadly categorized into innate and adaptive based on the differences in timing of the response and specificity. The immune system comes in contact with a foreign challenge, which could be food, commensal flora, microbial pathogens, and xenobiotics at different sites like the skin, mucous membrane of lungs, gastrointestinal tract, and so forth. The human gastrointestinal tract, with a total surface area roughly equal to that of a tennis court (400 m2), serves as the largest area of interface with the external environment. The gut mucosal immune system, which interacts with this large antigenic load, thus, has the most varied immune cells in the body. In a disease-free host, there is a fine balance between a protective and deleterious response of the immune system, which becomes perturbed in patients with IBD. To understand these perturbations in IBD that produce a disease state, it is necessary to first understand how the intestinal immune system works. In this review, the authors divide their article into subsections of innate and adaptive immunity and link it with the currently identified abnormalities in these pathways in IBD. In addition, the authors have summarized in Table 1 the current and emerging therapies for IBD that target specific molecules in the immune system.

Table 1

Some of the key biologic molecules in active use or under study for treatment of IBD

CCR9 CCX282-B Inhibition of CCR9 CD CCX 025 Inhibition of CCR9 CD IL-21 PF 05230900 IL-21 receptor antagonist CD IL-13 QAX576 IL-13 antagonist CD Anrukinzumab IL-13 antagonist UC Tralokinumab IL-13 antagonist UC IL-17 Vidofludimus Inhibitor of IL-17 A and IL-17F Both IL-12/23 Ustekinumab Blockade of IL-12/23 CD IL-18 GSK1070806 Blockade of soluble IL-18 CD IL-6 and IL-6R Tocilizumab Inhibitor of IL -6 CD PF04236921 Inhibitor of IL -6 CD IP-10 MDX 1100 Blockade of interferon-γ inducible protein (IP-10 or CXCL10) UC IRAK4/TRAF6/MyD88 RDP58 Disrupts IRAK4/TRAF6/MyD88 signaling and reduces production of proinflammatory cytokines Both JAK3 Tofacitinib Inhibition of JAK3 Both MAdCAM-1 PF-547659 Blocks MAdCAM-1 Both NF-κB HE3286 Synthetic steroid that modulates NF-κB activity UC NKG2D NN8555 Anti-NKG2D receptor monoclonal antibody CD PKC AEB071/Sotrastaurin PKC inhibitor UC T Cell Laquinimod Reduces IL-17 level and interferes with migration of T cells CD TLR DIMS0150 Blockade of Toll-like receptor UC BL-7040 Blockade of Toll-like receptor UC TNF-α Infliximab Neutralization of TNF-α Both Adalimumab Neutralization of TNF-α Both Certolizumab pegol Neutralization of TNF-α CD Golimumab Neutralization of TNF-α UC Debiaerse Vaccine against TNF-α consisting of a TNF-α derivative TNF-α kinoid CD Effector T cells, B cells Antigen specific Type 1 regulatory cells (OvaSave) Autologous ova expanded regulatory T cells injected CD α4 integrin AJM-300 Blockade of α4 integrin CD α4 integrin Natalizumab Blockade of α4 integrin Both α4β7 integrin Vedolizumab Blockade of α4β7 integrin Both β7 integrin Etrolizumab (aka rHuMab β7) Anti-β7 integrin UC

Abbreviations: aka, also known as; CCR9, chemokine receptor 9; IL, interleukin; IP, inducible protein; IRAK-4, interleukin-1 receptor-associated kinase 4; JAK3, Janus kinase 3; MAdCAM-1, human mucosal addressin cell adhesion molecule-1; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor-κB; PKC, protein kinase C; TLR, Toll-like receptor; TNF-α, tumor necrosis factor-α; TRAF6, TNF receptor-associated factor 6, E3 ubiquitin protein ligase.

Innate intestinal immunity

Epithelial Barrier

The gastrointestinal tract has a continuous layer of single epithelial cells that are derived from a common progenitor LGR5+ intestinal stem cell.7 The epithelial cells comprise enterocytes (intestinal absorptive cells), goblet cells, neuroendocrine cells, Paneth cells, and microfold (M) cells.7 The epithelial cells are...