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

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.

Innate Lymphoid Cells as Regulators of Epithelial Integrity: Therapeutic Implications for Inflammatory Bowel Diseases

“…This ILC3 decrease further correlated with severe disease cases (34), highly suggesting a regulatory or protective function of ILC3s in intestinal inflammation. Contrary to NKp44 + ILC3s, the percentage of ILC1s, ILC2s, and NKp44 − ILC3 was found to be increased in IBD patients (34,(44)(45)(46). Especially in CD patients an enhanced percentage of intestinal ILC1s has been described in multiple studies (17,34,44) and was obviously associated with an advanced disease severity (34).…”

“…Contrary to NKp44 + ILC3s, the percentage of ILC1s, ILC2s, and NKp44 − ILC3 was found to be increased in IBD patients (34,(44)(45)(46). Especially in CD patients an enhanced percentage of intestinal ILC1s has been described in multiple studies (17,34,44) and was obviously associated with an advanced disease severity (34). Regarding the underlying mechanism for the accumulation of ILC1s in the inflamed intestine of CD patients, transdifferentiation of other ILC subtypes into ILC1s was suggested to take place in the IL-12-enriched microenvironment of the inflamed gut of CD patients (25).…”

“…And indeed, an increased local secretion of IL-12 was reported in CD patients ( 51 , 52 ). Moreover, the biological relevance of this in vitro induced ILC3-to-ILC1 transition could be reinforced by an inverse link of ILC3 and ILC1 frequencies in the inflamed mucosa of CD patients ( 17 , 34 , 44 ) and the presence of an ILC subgroup harboring both ILC3 and ILC1 characteristics in human ileal LPMCs ( 53 ). Similarly, IL-13 + IFN-γ + ex-ILC2s were detected in the intestine of CD patients ( 48 ), hinting at ILC2-to-ILC1 transitions in vivo .…”

“…Together with the release of lymphotoxin, ILC3-derived IL-22 was ascribed a predominantly protective effect on enterocytes, goblet cells and even crypt stem and progenitor cells ( 57 – 60 , 87 , 91 , 92 ). Therefore, the observed decrease of intestinal ILC3s ( 17 , 34 , 44 ) in the inflamed mucosa of IBD patients might contribute to local inflammatory responses in IBD. However, the effect of ILC3-derived IL-22 on IECs appeared to highly depend on the surrounding micromilieu ( 67 ) and thus has to be treated with care.…”

“…Significant alterations in local ILC pools were observed in inflamed areas in IBD patients compared to unaffected control tissue ( Figure 1 ), indicating a functional role of ILCs in chronic inflammation of the gut. While NKp44 + ILC3s constitute the dominant helper ILC population in the lower gastrointestinal tract in homeostasis ( 33 , 34 ), their frequency was markedly reduced at sites of active inflammation in patients suffering from IBD, including both UC and CD ( 17 , 34 , 44 ). This ILC3 decrease further correlated with severe disease cases ( 34 ), highly suggesting a regulatory or protective function of ILC3s in intestinal inflammation.…”