Biological Therapy in Inflammatory Bowel Disease Patients Partly Restores Intestinal Innate Lymphoid Cell Subtype Equilibrium.

Brecht Creyns,Séverine Vermeire,Vera Ballet,Bram Verstockt,Inge Jacobs,Marc Ferrante,Christine Breynaert,Jonathan Cremer,Tim Vanuytsel,Jan L Ceuppens,Roselien Vandecasteele,Gert Van Assche

doi:10.3389/fimmu.2020.01847

Brecht Creyns, Séverine Vermeire + Show 10 more

Open Access

https://doi.org/10.3389/fimmu.2020.01847

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Journal: Frontiers in immunology	Publication Date: Aug 27, 2020
Citations: 25	License type: CC BY 4.0

Affiliation: KU Leuven

Abstract

Patients with Crohn disease (CD) and ulcerative colitis (UC) suffer from chronic relapsing intestinal inflammation. While many studies focused on adaptive immunity, less is known about the role of innate immune cells in these diseases. Innate lymphoid cells (ILCs) are recently identified cells with a high cytokine-producing capacity at mucosal barriers. The aim was to study the impact of biological treatment on ILC in CD and UC. Patients initiating anti–tumor necrosis factor (TNF), ustekinumab, or vedolizumab treatment were prospectively followed up and peripheral and intestinal ILCs were determined. In the inflamed gut tissue of patients with inflammatory bowel disease, we found an increase of ILC1 and in immature NKp44− ILC3, whereas there was a decrease of mature NKp44+ ILC3 when compared to healthy controls (HCs). Similar but less pronounced changes in ILC1 were observed in blood, whereas circulating NKp44− ILC3 were decreased. Fifteen percent of CD patients had NKp44+ ILC3 in blood and these cells were not detected in blood of HCs or UC patients. Therapy with three different biologicals (ustekinumab targeting the IL-12/23 cytokines, anti-TNF and vedolizumab) partly restored intestinal ILC subset equilibrium with a decrease of ILC1 (except for ustekinumab) and an increase of NKp44+ ILC3. Anti-TNF also mobilized more NKp44+ ILC3 in circulation. As ILC1 are proinflammatory cells and as NKp44+ ILC3 contribute to homeostasis of intestinal mucosa, the observed effects of biologicals on ILCs might contribute to their clinical efficacy.

Highlights

Patients with inflammatory bowel diseases (IBDs), ulcerative colitis (UC) and Crohn disease (CD), suffer from an uncontrolled intestinal inflammation caused by interactions between genetic factors, the gut microbiome, environmental factors and the immune system [1, 2]
We studied whether changes in Innate lymphoid cells (ILCs) subsets in the circulation may reflect intestinal inflammation and whether differences could be observed between UC and CD patients
We analyzed the distribution of ILC subsets in intestinal tissues and blood of IBD patients and compared this to the distribution in healthy controls

Summary

Introduction

Patients with inflammatory bowel diseases (IBDs), ulcerative colitis (UC) and Crohn disease (CD), suffer from an uncontrolled intestinal inflammation caused by interactions between genetic factors, the gut microbiome, environmental factors and the immune system [1, 2]. ILC1 share a typical transcription factor (T-bet) with TH1 cells and can produce interferon γ (IFN-γ); ILC2, similar to TH2 cells, are dependent on GATA-binding protein 3 (GATA-3) and produce type 2 cytokines interleukin (IL-4), IL-5, IL-9 and IL-13, whereas ILC3 are RAR-related orphan receptor γ-positive and produce IL-17 and IL-22 upon stimulation [9,10,11] These ILC3 can further be subdivided into natural cytotoxic receptor (NCR or NKp44)–negative and NCR-positive (NCR+) ILC3, which are enriched at the intestinal lining and produce IL-22 which are highly important in mucosal homeostasis [12]. NCR− ILC3 have been identified as precursor ILCs with the capacity to differentiate into ILC1, ILC2 and NCR+ ILC3, depending on the stimulation conditions [15, 16]

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