Immunological pathogenesis of inflammatory bowel disease

Seung Hoon Lee; Jeong eun Kwon; Mi-La Cho

doi:10.5217/ir.2018.16.1.26

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Lee, Kwon, and Cho: Immunological pathogenesis of inflammatory bowel disease

Review

Intestinal Research 2018; 16(1): 26-42.

Published online: 18 January 2018

DOI: https://doi.org/10.5217/ir.2018.16.1.26

Immunological pathogenesis of inflammatory bowel disease

Seung Hoon Lee, Jeong eun Kwon, Mi-La Cho

The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea.

Correspondence to Mi-La Cho, The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea. Tel: +82-2-2258-7467, Fax: +82-2-599-4287, iammila@catholic.ac.kr

Received 15 March 2017 Revised 18 April 2017 Accepted 19 April 2017

Korean Association for the Study of Intestinal Diseases

(open-access, http://creativecommons.org/licenses/by-nc/4.0):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory state of the gastrointestinal tract and can be classified into 2 main clinical phenomena: Crohn's disease (CD) and ulcerative colitis (UC). The pathogenesis of IBD, including CD and UC, involves the presence of pathogenic factors such as abnormal gut microbiota, immune response dysregulation, environmental changes, and gene variants. Although many investigations have tried to identify novel pathogenic factors associated with IBD that are related to environmental, genetic, microbial, and immune response factors, a full understanding of IBD pathogenesis is unclear. Thus, IBD treatment is far from optimal, and patient outcomes can be unsatisfactory. As result of massive studying on IBD, T helper 17 (Th17) cells and innate lymphoid cells (ILCs) are investigated on their effects on IBD. A recent study of the plasticity of Th17 cells focused primarily on colitis. ILCs also emerging as novel cell family, which play a role in the pathogenesis of IBD. IBD immunopathogenesis is key to understanding the causes of IBD and can lead to the development of IBD therapies. The aim of this review is to explain the pathogenesis of IBD, with a focus on immunological factors and therapies.

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Keywords: Inflammatory bowel disease, Th17 cells, Innate lymphoid cells

INTRODUCTION

The gastrointestinal tract is chronically exposed to various antigens found in bacteria and food. In the normal state in the absence of intestinal inflammation, gut homeostasis is maintained by suppressing excessive immune responses to foreign antigens. IBD is an idiopathic disorder caused by chronic and excessive inflammation of the gastrointestinal tract, leading to rectal bleeding and weight loss.1 2 IBD, a dysregulated immune inflammatory state of the gastrointestinal tract, is classified into 2 archetypal phenotypes, UC and CD. These 2 subtypes of IBD are characterized by chronic inflammation in the gastrointestinal tract and repeated cycles of relapse and remission. Although UC and CD show differences in their clinical presentation, the same risk factors are implicated in the pathogenesis of both subtypes. Phenotypes common to both subtypes include chronic inflammation and a dysregulated immune inflammatory response; therefore, much of the research on IBD pathogenesis has focused on the immune system. The pathogenesis of both UC and CD involve genetic factors, changes in the gut microbiome, and immune response cells including cytokines and immune cells.

Even though the pathogenesis of IBD is complicated, several studies have demonstrated that excessive interleukin (IL)-17 production is involved in the progression of IBD.3 Recently, research on IBD pathogenesis has focused on T helper (Th)17 cells, which secrete IL-17. It is well documented that Th17 inhibition can decrease the development of acute colitis by reducing inflammation.4 Additionally, innate lymphoid cells (ILCs) were recently discovered to be novel pathogenic effector lymphocytes in IBD. In this review, this topic will be discussed primarily in the context of human IBD and experimental IBD animal models. Additionally, current therapeutics targeting Th17 and ILCs will be discussed.

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IBD-RELATED CYTOKINES AND CHEMOKINES

Immune cells secrete products that are actively involved in the initiation and preservation of inflammation, leading to gut tissue damage. In IBD patients, colonic lesions show excessive immune cell infiltration and tissue devastation (Fig. 1A). The expression of STAT3 and IL-17 are also increased in inflamed colon tissue (Fig. 1B and C). Many cytokines and chemokines are associated with IBD development.

Fig. 1

Histology of colon tissue from IBD patients. (A) H&E of colon tissue from UC and CD patients (H&E, ×40). (B, C) Signal transducer and activator of transcription 3 (STAT3) and interleukin 17 (IL-17) expression in colon tissue from UC and CD patients (immunohistochemistry, ×200).

1. Cytokines

Several pro-inflammatory cytokines are involved in the progression of IBD. For example, the IL-1 family of cytokines has a key role in IBD pathogenesis.5 In UC, IL-1β promotes inflammation because IL-1 originates from monocytes and macrophages, and active IL-1β is expressed in the colonic mucosa.6 IL-18 is also an IL-1 family member and is increased in the mucosa of CD patients.7 It has been suggested that IL-18 increases the Th1 response.8 9 However, in CD patients with active disease, IL-10 released from mucosal T cells was decreased by IL-18.10 IL-33, another member of the IL-1 family, stimulates mucus secretion to protect the epithelium and upregulates the expression of IL-5 and IL-13 as part of the Th2 response.11 There is evidence that the expression of IL-33 and its receptor ST2 are increased in UC patients.12 13

IL-6 activates signal transducer and activator of transcription 3 (STAT3) and has an important function in the inflammatory response. IL-6 and its soluble IL-6 receptor were increased in UC and CD patients.14 15 IL-6 also has a key role in the pathogenesis of UC and the carcinogenesis of colorectal cancers related to UC.16

Tumor necrosis factor α (TNF-α) has a significant function in IBD pathogenesis because IL-1β, IL-6, and IL-33 expression can all be increased by TNF-α.17 18 The clinical severity of UC and CD were correlated with TNF-α levels in the serum of IBD patients.

IL-10 is a typical immunosuppressive cytokine that may have therapeutic value for treating chronic IBD.19 Although IL-10 is an anti-inflammatory cytokines, there are inconsistencies of IL-10 concentrations in IBD. A study showed that gut IL-10 expression levels were either the same or higher in IBD patients than in normal controls.20 It is well documented that IL-10 gene expression is higher in the mucosal T cells of UC patients than normal controls.21 Furthermore, IL-10 production is enhanced in the serum of CD patients.22 On the other hand, other investigation demonstrated that IL-10 levels in serum of patients with UC and CD are similar to healthy subjects.23 It is also well documented that downregu-lation of IL-10 promotes disease progression in patients with CD.24 25

Transforming growth factor β (TGF-β) has dual activities in the pathogenesis of IBD. It stimulates epithelial compensation and fibrosis and induces tolerance and homeostasis through an impressive immunoregulatory function.26 In the lamina propria, TGF-β1 levels in mononuclear cells were enhanced in UC patients but decreased in CD patients.27 TGF-β improved intestinal inflammation by reducing the expression of IL-33.28

IL-17 is a pro-inflammatory cytokine that activates STAT3, which stimulates a strong chronic immune inflammatory response.29 30 Thus, IL-17 is critical in the pathogenesis of IBD. Indeed, IL-17 mRNA levels were enhanced in the inflamed mucosa of patients with IBD, both UC and CD.31 IL-17 has many isoforms, including IL-17A (also known as IL-17), IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25), and IL-17F.32 Although IL-17A inhibition can attenuate the inflammatory response, whether IL-17A has a pathogenic role in IBD is controversial. It has been suggested that IL-17A inhibition mediated by phosphorylated STAT3 suppression decreases inflammation and the progression of acute colitis,4 whereas IL-17A can improve experimental colitis.33 Additionally, by reinforcing tight junction formation, IL-17 can also protect human intestinal epithelial cells.34 However, IL-17 is recognized as a significant inflammatory factor in CD pathogenesis. Previous studies found higher levels of IL-17 and CD161⁺ memory cells expressing IL-17 and interferon γ (IFN-γ) in CD patients.35 36 It has been reported that IL-17 can increase the recruitment of T cells into the lamina propria during the inflammatory response.37

2. Chemokines

IL-8 is mainly a neutrophil chemoattractant that induces the migration of neutrophils from peripheral blood into inflamed tissue. It is well known that IL-8 production is increased in the tissue of UC patients compared with that of normal controls.38 Moreover, other chemokines are elevated in the mucosa of IBD patients. Various reports have shown that the expression of chemokine (C-C motif) ligand (CCL) 2 (also known as monocyte chemoattractant protein [MCP]-1), CCL3 (also known as macrophage inflammatory proteins [MIP]-1α), CCL4 (also known as MIP-1β), CCL7 (also known as MCP-3), CCL20 (also known as MIP-3α), CX-C motif chemokine (CXCL) 5, CXCL8, CXCL10 and regulated on activation, normal T cell expressed and secreted (RANTES) are upregulated in tissues from IBD patients.39 40 41 42

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Th17 CELLS ARE KEY FACTORS IN THE PATHOGENESIS OF IBD

Presently, Th17 cells are considered a main pathogenic factor in IBD. A study found a massive infiltration of Th17 cells in the inflamed intestinal mucosa of IBD patients.43 Cells that release IL-17 and Th17-related cytokines were also increased in inflamed tissue from IBD patients compared with normal tissue.31 43

1. Th17 Cell Differentiation in the Intestine

T cells can be differentiated into Th17 cells when they interact with various inflammatory mediators in the intestine. Naive T cells can be differentiated into Th1, Th2, Th17, and regulatory T (Treg) cells through a process controlled by effector cytokines produced by antigen-presenting cells. During Th17 polarization, many cytokine receptors (IL-1R, IL-6R, IL-21R, IL-23R, and TGF-βR) of naive T cells have important roles. Many reports have shown that specific cytokines such as IL-1β, IL-6, IL-21, IL-23, and TGF-β induce Th17 polarization.44 45 46 STAT3 was first identified as a Th17 cell specific transcription factor It has been suggested that STAT3 overexpression can promote Th17 differentiation and proliferation. Consistent with this, loss of STAT3 can suppress the differentiation of naive T cells into Th17 cells.47

2. Th17 Cells and the Microbiota

The gastrointestinal tract contains a large microbial community. Thus, gut microbial settlement in the gastrointestinal tract is crucial to the formation of the immune system.48 The microbiota also plays a key role in the pathogenesis of IBD. Indeed, metagenomics research has revealed that various intestinal microbiota genes are involved in host mRNA expression.49 Destruction of the intestinal mucosal barrier is caused by genetic susceptibility in IBD patients.50 Analyses of biopsy samples from UC and CD patients have shown that changes in the composition of the microbiota may be associated with IBD pathogenesis.51 52 53

Communication of T cells with microbes in the gastrointestinal tract is very important for maintaining intestinal immunity. The process of Th17 cell differentiation is determined by factors such as the composition of the endogenous microbiota in the intestine.54 55 Correspondingly, Th17 cell differentiation in the intestine is remarkably decreased in a germ-free system and in the presence of antibiotics.56 57 Additionally, many studies have shown that specific gut microbiota drive Th17 cell differentiation.56 58

3. Th17 Cells Function in Intestinal Inflammation

Th cells are relevant to the pathogenesis of IBD because they are fundamentally plastic to provocation from the surrounding state.59 Th17 cells releasing IL-17 are a strong pro-inflammatory factor in IBD. In a study on IBD patients, IL-17 expression and IL-17A and IL-17F mRNA levels were higher in the mucosa and serum of IBD patients than healthy controls. 31 60 In a subtype of IBD, IL-17 was more abundant in CD patients than UC patients.31 Recently, various cytokines related to Th17 were found to be upregulated in both UC and CD patients compared with normal subjects, but they were higher in the UC patients.61 It has also been documented that UC severity is correlated with IL-17 expression in peripheral blood mononuclear cells.62 Genome-wide association scans showed that various UC and CD susceptibility genes, such as STAT3, were related to Th17 genes; therefore, the Th17 signaling pathway may be involved in the pathogenesis of IBD.63 64

Although it is known that Th17 cells play a role in the pathogenesis of IBD, a dextran sulfate sodium (DSS)-induced colitis model showed that IL-17A and IL-17F have contrasting roles. Studies using this model found that antibody-mediated IL-17A protein suppression and gene knockout caused excessive inflammation and damage to the intestinal epithelium.65 66 On the other hand, in mice with DSS-induced colitis, it was shown that IL-17F could also have a protective role.67 It has also been reported that loss of IL-17F can improve the intestinal inflammatory response.67 Thus, the focus of current IBD therapies is on blocking IL-17A and IL-17F.68

4. Maintenance of Intestinal Th17 and Treg Cell Proliferation

Generally, Th17 and Treg cells modulate the proliferation of each other to maintain balance. It has been reported that the developmental pathways of Th17 and Tregs are related with their differentiation and Th17/Treg balance is important to maintain immune response in intestine.69 This influences the outcome of immune responses in the context of inflammatory conditions.

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PROTECTIVE FUNCTION OF Treg CELLS IN IBD

Treg cells are associated with the pathogenesis of IBD because the intestinal inflammatory response in IBD is mediated mainly by the T-cell response.70 Treg cells perform a critical role in preserving immune homeostasis and establishing inflammation in response to foreign or non-pathogenic antigens such as commensal bacteria, and failure of Treg cell function can lead to an inflammatory disorder. Indeed, mutations in CD25 and IL-10, which are involved in Treg cell differentiation, lead to aberrant Treg cell function and increased susceptibility to IBD.71 Moreover, loss of IL-10 results in intestinal inflammation, and Treg cells lacking the IL-10 receptor are more susceptible to colitis.72 73

As research using IBD mouse models has shown that Treg cells could suppress intestinal inflammation,74 it is said that Treg cells have an anti-colitis effect. Indeed, ablation of Treg cells or impairment of TGF-β1 signaling in Treg cells increased colitis progression.75 76 Additionally, there is evidence that IL-10 released from Treg cells can decrease colitis progression.77 78 79 In a mouse model, an increase in Treg cell differentiation downregulated the development of experimental ileitis, and co-transfer of conventional T cells and Treg cells decreased intestinal inflammation in a RAG1 knock-out mouse model.80

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RECIPROCAL BALANCE BETWEEN Th17 AND Treg CELLS IN IBD

As the concentration of T cell differentiation and balance has moved from the Th1/Th2 to that of Th17/Treg, this paradigm has indeed been shown to affect in IBD. Th17 and Treg cells exist primarily in the intestinal mucosa, where they have a significant role in T-cell-mediated immune responses.81 82 It is well known that IL-17-releasing Th17 cells are entirely dependent on STAT3 and are primarily pro-inflammatory.83 On the other hand, Foxp3-expressing Treg cells show anti-inflammatory activity that is mediated through the suppression of the Th17 response. In an experimental colitis model, Treg cells prevented intestinal inflammation and reduced the expression of Th17-related cytokines.84

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IBD THERAPIES THAT TARGET Th17

As Th17 cells play a key function in intestinal inflammation, it has been proposed that they may be therapeutic targets to regulate the intestinal inflammatory response.

1. Th17 Cell Blockade

Theoretically, pro-inflammatory cytokines, including IL-6, can increase Th17 cell differentiation and proliferation. Therefore, it has been suggested that new IBD therapies may involve neutralizing monoclonal antibodies that target these cytokines or their receptors. It is well documented that monoclonal antibodies against IL-12/23 p40 can improve colitis severity in murine models.85 86 Consistent with this, neutralizing IL-21 antibody treatment downregulated the infiltration of colonic T cells and the expression of pro-inflammatory cytokines such as IL-6 and IL-17A in inflamed intestinal tissue from mice with DSS-induced colitis.87

Potential strategies for IBD treatment include a blockade of pro-inflammatory cytokines related to Th17 cells. Suppression of IL-17 expression using the oral immunosuppressive drug vidofludimus reduced the proliferation of lymphocytes in vitro. Furthermore, the safety and therapeutic efficacy of vidofludimus was demonstrated in a clinical trial involving IBD patients.88 89 However, IL-17 inhibition is controversial in IBD therapy. Although genetic deletion of the IL-17 receptor improved intestinal inflammation in mice with trinitrobenzenesulfonic acid (TNBS)-induced colitis,90 IL-17A deficiency exacerbated the intestinal inflammatory response in mice with DSS-induced colitis.67 In a clinical trial involving CD patients, secukinumab, a monoclonal antibody that neutralizes IL-17A, showed no therapeutic effect.91 A blockade of both IL-17A and IL-17F led to reduced colonic inflammation in experimental colitis; therefore, this may be a potential strategy for IBD therapy.68 92

2. Inhibition of Specific Transcription Factors Associated with Th17 Cells

Other potential IBD therapies involve blocking the transcription factors associated with Th17 cells. Therefore, these transcription factors have been intensely studied. Transcription factors that are potential pharmacological targets include RAR-related orphan receptor (ROR)γt and STAT3. These transcription factors are essential for the regulation of Th17 proliferation and function. Indeed, one study found that dual inhibition of nuclear factor (NF)-κB and STAT3 attenuated intestinal inflammation.93 Consistent with this, vidofludimus, which can improve experimental colitis by decreasing IL-17A and IL-17F levels via inhibition of NF-κB and STAT3 activation, had a therapeutic effect in IBD clinical trials.88 89 Moreover, pioglitazone, a nuclear receptor peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, decreased Th17 cell differentiation through RORγt and improved DSS-induced colitis.94 95 Recently, inhibition of STAT3 activation also had a positive therapeutic effect. In an experimental DSS-induced colitis mouse model, overexpression of the STAT3 inhibitors metformin and gene-associated retinoid-interferon-induced mortality (GRIM)-19 ameliorated intestinal inflammation and Th17 cell differentiation.4 96

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ILCs IN IBD

1. Innate Lymphoid Cells

ILCs provide host protective immunity in the mucosal tissues. ILCs are a novel family of effector lymphocytes in IBD that produce IBD-relevant cytokines. ILCs are unique in that they lack antigen-specific receptors and phenotypic markers associated with immune cells but do have a lymphoid morphology.97 The ILC family can be subdivided into 3 subsets based on the types of transcription factors they express for lineage differentiation: ILC1, ILC2, and ILC3. The lineage-specific transcription factors expressed in ILC1, ILC2, and ILC3 are T-bet, GATA-3, and RORγt, respectively.98 99 100 Cytokines secreted by ILCs are the same as those of T effector cells (Fig. 2).

Fig. 2

Pathogenic innate lymphoid cells (ILCs) and T cells in mucosal cells from IBD patients. ILCs have common properties with T effector cells. Lineage-specific transcription factors expressing ILCs or a subset of T cells produce the same cytokine. Natural cytotoxicity receptor (NCR)-expressing ILCs are classified differently from T cells. T-bet, T-box expressed in T cells; IFN, interferon; TNF, tumor necrosis factor; IL, interleukin; RORγt, retinoic acid receptor-related orphan receptor γt.

2. ILCs in Intestinal Innate Immunity

ILC3s, in particular, are involved in host defense to extracellular bacteria and fungi.101 102 103 ILC3s can be further subdivided based on whether they express the natural cytotoxicity receptor (NCR). NCR⁺ILC3 produces IL-22; however, NCR-ILC3, similar to Th17 cells, produces both IL-22 and IL-17.104 On the other hand, RORγt-dependent NCR⁺ILC3 downregulated RORγt expression and subsequently differentiated into T-bet-dependent IFN-γ-producing cells under IL-12 effects.98 101 105 ILCs that produce IL-17 and IFN-γ are implicated in the pathogenesis of IBD. The pathogenicity of ILC3 was shown in a Helicobacter hepaticus IBD model and a Tbx21^−/− Rag2^−/− UC model.106 107 108 109 Moreover, innate immune cells isolated from IBD patients expressed ILC3 genes (IL17A , IL22, RORC, and IL23R ).110

The levels of T-bet responsive and IFN-γ-producing ILC1 are also higher in CD patients.111 112 IL-12- and IL-15-responsive intraepithelial CD103⁺NKp46⁺ILC1 and lamina propria NKp46⁺ ILC1 were increased in CD patients, and it was suggested that they may have a pathogenic role in the ileum.111 112 113 Meanwhile, ILC2s may contribute to intestinal fibrosis via IL-13 production in the gut. IL-13 producing CD3-KIR⁺ cells are more abundant in fibrotic areas of the intestine in CD patients.114 Fibrotic lesions have higher levels of IL-13, IL-13Rα2 and collagen expression than non-fibrotic lesions, which is evidence that ILC2s can also aggravate IBD.114

3. Cytokines

Similar to Th17 cells, pathogenic ILC3s are also responsible for IL-23 production, which induces the secretion of IL-17 and IL-22 by ILC3. TNF-α, a key cytokine in IBD pathogenesis, also increased IL-17 production in ILC3s in a mouse model of colitis.107 115 IL-12 stimulates the production of ILC1-specific cytokines in synergy with IL-15 and IL-18.111 112 IL-12 and IL-23 can also contribute to differentiation to either ILC1 or ILC3. It seems that ILC differentiation and contribution to IBD pathogenesis is orchestrated by a combination of these cytokines.111

4. Interaction of ILCs with Mucosal Cells

Interactions between ILCs and immune and non-immune cells determine how ILCs respond to the environment (Fig. 3). Crosstalk between ILCs and mucosal, epithelial, and dendritic cells contributes to the host immune response via ILCs. Mononuclear phagocytes have an important role in the activation of ILCs in the intestine. CD14+CX3CR1+ mononuclear phagocytes produce IL-23, IL-1β, IL-6, TNF-α, and TL1A, which promote the activation of ILCs.116 117 118 CX3CR1⁺ or CD14⁺ mononuclear phagocytes mediate ILC3 activation, and this contact is important for ILC3 responsiveness to the gut environment.116 119

Fig. 3

Present IBD therapeutic strategies that involve prevention of T cell and innate lymphoid cells (ILC) production or their inhibition. T cells and ILCs have a common therapeutic target. Compared with classical IBD therapeutic agents, new therapeutic strategies may involve T cells; ILCs such as interleukin (IL)-23 and IL-12-, tumor necrosis factor (TNF)-, and integrin-targeting agents; and signal transducer and activator of transcription (STAT) inhibitors. NF, nuclear factor; AP-1, activator protein 1; cAMP, cyclic adenosine 3′:5′-monophosphate.

ILCs also interact with Treg cells, which are important for intestinal immune control. Commensal bacteria-responsive, IL-1β-producing mononuclear phagocytes induce GM-CSG secretion by ILC3s, and these ILC3s produce retinoic acid and TGF-β for Treg cell differentiation.120

With the exception of ILC1, ILC2 and ILC3 express major histocompatibility complex (MHC) class II and can influence CD4⁺T cells. ILC2 activates Th2 cell differentiation through MHC class II, CD80 and CD86.121 ILC3 that is lacking CD80, CD86, and CD40 cause dysregulated T-cell regulation and increased IL-17 secretion, illustrating the immunoregulatory role of ILC3 in gut T cells.122 123 124 Interactions between ILCs and B cells promote Ig production T-cells-independently. Thus, B-cell activating factor (BAFF), CD40L and Notch ligand delta-like 1 (DLL1) are increased by ILCs interaction in splenic marginal zone and augments antibody secretion by B1 cells.125 ILC3s also produce IL-10 and express the CCL60 receptor, CCR6, for trafficking to Peyer's patches and the intestinal epithelium. These properties of ILC3 are dependent on IL-22 signaling, because a lack of IL-22 causes a loss in tolerance to commensal bacteria and unchecked growth of pathogenic bacteria, which, together, increase the probability of developing colitis.126 127 128

Although cytokines secreted by ILCs are very similar to T cells, this new population of cytokines has unique property that expresses both receptors for T cells and NK cells. In IBD patients, ILCs are abundant in inflamed lesions of the intestine; therefore, ILCs have a pathological role and should be considered targets in the development of future IBD therapies. Moreover, ILCs mediate environmental signals for T and B cell development. Therefore, ILCs should be validated in IBD patients and may be key targets to treat IBD.

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IBD THERAPEUTICS

1. Classical Drugs for IBD Treatment

There are 2 main categories of therapeutics for treating IBD: (1) anti-inflammatories or immunosuppressive agents, and (2) biological agents. Classically, anti-inflammatory drugs, such as 5-aminosalicylates (5-ASAs), are used to treat UC. 5-ASAs are effective for maintenance of remission in UC and also reduce tumor development by inhibiting PG synthesis, reducing pro-inflammatory cytokine levels, blocking neutrophil attraction and activating mast cells by inhibiting NF-κB in immune cells, and promoting PPAR-γ expression and nuclear translocation.129 130 131 132 Unfortunately, 5-ASAs have little efficacy in CD patients.133 Corticosteroids are also used for induction of remission in UC patients. Glucocorticoids inactivate NF-κB, activator protein 1 and prevent the production of inflammatory cytokines such as IL-1 and IL-6.134 135 136

Azathioprine, methotrexate, and cyclosporine-A are classical immunosuppressive drugs used in IBD therapy. Methotrexate is used for maintenance of remission in CD and cyclosporine-A is used to induce remission state of UC, while azathioprine has efficacy in both CD and UC.137 138 139 140 141 Cyclosporine-A and methotrexate suppress the secretion of pro-inflammatory cytokines and induce apoptosis.142 143 144 145 Cyclosporine-A suppresses the production of IL-22 and TNF-α by NCR⁺ILC3.146

TNF-α is the main pathogenic factor that is produced by immune and non-immune cells in the gut of IBD patients. Anti-TNF agents, including infliximab, adalimumab, and golimumab, are classic IBD therapies. Combination therapy with infliximab and azathioprine is very effective for maintenance of remission in both CD and UC.139 147 148 However, IBD treatments that involve simply blocking or neutralizing the TNF receptor using incomplete antibodies, such as etanercept, are not effective because such antibodies have a short half-life and low efficacy, consistent with the in vivo results of anti-TNF therapy.149 150

2. Inhibition of Lymphoid Cell Homing

In the last decade, clinical trials have shown that 30% to 50% of IBD patients do not respond to anti-TNF therapy. Therefore, various strategies are attempted to target IBD mechanism. Natalizumab, an antibody targeting α4 integrin, is a promising new target for CD therapy and works by blocking T-cell recruitment into lesions via α4β7 integrins, 151 152 153 154 however, risk of progressive multifocal leukoencephalopathy in the use of natalizumab was reported.155 156 Some ILC subsets also express α4β7 integrins for homing to the gut.98 157 Thus, the more specific α4β7 integrin blocker, vedolizumab, was developed and showed good efficacy in both CD and UC.158 159 160 161 162 Vedolizumab also can be used in patients who do not respond to anti-TNF agents.163 Starting with anti-α4β7 therapy, subsequent trials involved the inhibition of T-cell homing using antibodies against MAdCM1 and β7 integrin.164 165 166

3. Inhibition of IBD-Related Lymphoid Cell Survival

Some IBD therapies target signaling pathways specific to lymphoid cell survival. Sphinogosine-1-phosphate (S1P) and G protein-coupled receptor (S1PR) signaling pathways both activate NF-κB and STAT3, resulting in T-cell proliferation and angiogenesis.167 In clinical trials, ozanimod, a S1PR agonist, induced lymphopenia, suppressed experimental colitis, and induced remission of UC.168 169 170 Preclinical challenges for pathogenic ILCs have been developed too. In a mouse colitis model, the ILC-specific cytokine, IL-7, controlled ILC3 survival and ILC3-specific cytokine production. Additionally, blockade of IL-7R effectively reduced intestinal ILCs.107 146 In other studies, CD90 inhibition depleted ILCs and ameliorated IBD in a mouse model.106 158

4. Targeting Epithelial Cells

Intestinal epithelial cells can also be targeted to treat IBD. MMP9 (GS-5746) is an enzyme that induces proteolysis, stimulates the infiltration of immune cells into inflamed gut tissue, and increases TNF-α levels. In a clinical trial, however, targeting MMP9 failed to reduce inflammation in UC patients.171 Repeated cycles of inflammation and healing also induce the formation of tissue fibrosis. Small-interfering RNAs mediated silencing of CHST15, a chondroitin synthetic enzyme, resulted in reduced α-SMA levels in fibroblasts and reduced collagen deposition in animal models of colitis. CHST15-specific small-interfering RNA (STNM01) reduced inflammation and fibrosis in CD clinical trials.172

5. Targeting Cytokines in IBD Therapy

Main cytokines related with IBD were classical targets for IBD treatment. Surprisingly, studies showed that anti-IFN-γ and anti-IL-17A antibody therapies aggravated CD, possibly due to unexpected effects or their protective roles in gut epithelial cells.91 173 174 IL-6 is one of the main pro-inflammatory cytokines that activates immune cells. The IL-6-targeting antibody tocilizumab (previously known as MRA) showed high efficacy in a colitis model and induced remission in CD patients.175 176 Considering the role played by IL-6 signaling in the proliferation of gut epithelial cells, the therapeutic value of anti-IL-6 or anti-gp130 (IL-6R) antibodies should be investigated. The pro-inflammatory cytokines IL-23 (heterodimer of p19 and p40) and IL-12 (heterodimer of p19 and p40) cause inflammation by induction of Th17, Th1 or ILCs development in the gut mucosa of CD patients.177 178 Therefore, anti-p40 and p19 antibodies targeting IL-23 and IL-12 have been developed. In clinical trials involving p40 blockers, such as ABT-874 and ustekinumab, a high response was induced in CD patients, even among patients who had anti-TNF therapy.179 180 Neutralization of IL-23 (p19) also blocked the stimulation of pathogenic ILC3s and the production of IL-17A- and IL-22-producing cells.106 107 Clinical trials are currently investigating the efficacy of p19-targeting drugs (BI655066 and AMG139) in CD patients.181 Other targets in IBD therapy include cytokine-related signaling proteins, including Janus kinases (JAK1-3 and TYK2), which can suppress the secretion of cytokines into the mucosa. In another study, the JAK inhibitor tofacitinib was promising in UC but not CD patients.182 183 In contrast, the JAK1-specific inhibitor filgotinib stabilized the remission state in CD patients. Phos phodiesterase-4 inhibition by apremilast negatively regulated cyclic adenosine 3′5′-monophosphate (cAMP), a key mediator of inflammation, by suppressing the pro-inflammatory cytokines IFN-γ, TNF-α, IL-12, IL-17, and IL-23.184

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CONCLUSIONS

Although the pathogenesis of IBD is complicated and involves many pro-inflammatory mediators, it is clear that Th17 cells play a central role in the induction and maintenance of chronic intestinal inflammation in IBD patients. With regard to reducing intestinal inflammation, research has shown that Th17 cells should be the primary targets for IBD therapy. Many studies have shown that Th17 cells have a pathogenic roles in intestinal inflammation; however, there is still much to be investigated. Therefore, a better understanding of Th17 cells and their targeting could lead to the development of an effective IBD therapy. ILCs should be considered for IBD therapy. ILCs have common therapeutic targets with Th17 cells and are abundant in the gut of IBD patients. Further studies on the role of ILCs in gut immunity would lead to the development of better IBD therapies (Fig. 4).

Fig. 4

Reciprocal balance for intestinal immune homeostasis and inflammation. The normal state is mediated by a reciprocal balance between immune cells (Treg and Breg vs. Th17 and ILC1) and cytokines that are secreted to maintain the conditions in the intestine. However, an imbalance in immune cells leads to the destruction of intestinal epithelial cells and the invasion of commensal microbiota. This situation leads to the uncontrolled release of cytokines, which is a key event in the pathogenesis of IBD. Treg, regulatory T; Breg, regulatory B; ILC, innate lymphoid cells; DC, dendritic cell; IL, interleukin; NKT, natural killer T; Th17, T helper 17.

Beyond innate immunity, adaptive immunity also has a direct role in the pathogenesis of IBD. An overwhelming number of effector cells, such as Th17 cells and ILCs, induce self-destructive immunity; therefore, a cure for IBD would involve understanding how immunological balance is controlled.

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Notes

FINANCIAL SUPPORT: This study was supported by a grant of the Korean Health Technology R&D Project, Ministry for Health & Welfare, Republic of Korea (HI14C3417).

CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.

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References

1. Bernstein CN, Fried M, Krabshuis JH, et al. Inflammatory bowel disease: a global perspective. Global guidelines. Milwaukee: World Gatroenterology Organization;2009.

2. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007; 369:1641–1657. PMID: 17499606.

3. Leppkes M, Becker C, Ivanov II, et al. RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology. 2009; 136:257–267. PMID: 18992745.

4. Lee SY, Lee SH, Yang EJ, et al. Metformin ameliorates inflammatory bowel disease by suppression of the STAT3 signaling pathway and regulation of the between Th17/Treg balance. PLoS One. 2015; 10:e0135858. DOI: 10.1371/journal.pone.0135858. PMID: 26360050.

5. Dinarello CA. Interleukin-1beta and the autoinflammatory diseases. N Engl J Med. 2009; 360:2467–2470. PMID: 19494224.

6. McAlindon ME, Hawkey CJ, Mahida YR. Expression of interleukin 1 beta and interleukin 1 beta converting enzyme by intestinal macrophages in health and inflammatory bowel disease. Gut. 1998; 42:214–219. PMID: 9536946.

7. Pizarro TT, Michie MH, Bentz M, et al. IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn's disease: expression and localization in intestinal mucosal cells. J Immunol. 1999; 162:6829–6835. PMID: 10352304.

8. Dinarello CA. IL-18: a TH1-inducing, proinflammatory cytokine and new member of the IL-1 family. J Allergy Clin Immunol. 1999; 103:11–24. PMID: 9893178.

9. Kanai T, Watanabe M, Okazawa A, et al. Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease. Gastroenterology. 2001; 121:875–888. PMID: 11606501.

10. Maerten P, Shen C, Colpaert S, et al. Involvement of interleukin 18 in Crohn's disease: evidence from in vitro analysis of human gut inflammatory cells and from experimental colitis models. Clin Exp Immunol. 2004; 135:310–317. PMID: 14738461.

11. Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005; 23:479–490. PMID: 16286016.

12. Beltran CJ, Nunez LE, Diaz-Jimenez D, et al. Characterization of the novel ST2/IL-33 system in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2010; 16:1097–1107. PMID: 20014018.

13. Kobori A, Yagi Y, Imaeda H, et al. Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis. J Gastroenterol. 2010; 45:999–1007. PMID: 20405148.

14. Mitsuyama K, Toyonaga A, Sasaki E, et al. Soluble interleukin-6 receptors in inflammatory bowel disease: relation to circulating interleukin-6. Gut. 1995; 36:45–49. PMID: 7890234.

15. Reinisch W, Gasché C, Tillinger W, et al. Clinical relevance of serum interleukin-6 in Crohn's disease: single point measurements, therapy monitoring, and prediction of clinical relapse. Am J Gastroenterol. 1999; 94:2156–2164. PMID: 10445543.

16. Li Y, de Haar C, Chen M, et al. Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis. Gut. 2010; 59:227–235. PMID: 19926618.

17. Murch SH, Braegger CP, Walker-Smith JA, MacDonald TT. Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease. Gut. 1993; 34:1705–1709. PMID: 8031350.

18. Sanchez-Munoz F, Dominguez-Lopez A, Yamamoto-Furusho JK. Role of cytokines in inflammatory bowel disease. World J Gastroenterol. 2008; 14:4280–4288. PMID: 18666314.

19. Li MC, He SH. IL-10 and its related cytokines for treatment of inflammatory bowel disease. World J Gastroenterol. 2004; 10:620–625. PMID: 14991925.

20. Schreiber S, Heinig T, Thiele HG, Raedler A. Immunoregulatory role of interleukin 10 in patients with inflammatory bowel disease. Gastroenterology. 1995; 108:1434–1444. PMID: 7729636.

21. Melgar S, Yeung MM, Bas A, et al. Over-expression of interleukin 10 in mucosal T cells of patients with active ulcerative colitis. Clin Exp Immunol. 2003; 134:127–137. PMID: 12974765.

22. Wang AH, Lam WJ, Han DY, et al. The effect of IL-10 genetic variation and interleukin 10 serum levels on Crohn's disease susceptibility in a New Zealand population. Hum Immunol. 2011; 72:431–435. PMID: 21354456.

23. Nielsen OH, Køppen T, Rüdiger N, Horn T, Eriksen J, Kirman I. Involvement of interleukin-4 and -10 in inflammatory bowel disease. Dig Dis Sci. 1996; 41:1786–1793. PMID: 8794795.

24. Mitsuyama K, Tomiyasu N, Takaki K, et al. Interleukin-10 in the pathophysiology of inflammatory bowel disease: increased serum concentrations during the recovery phase. Mediators Inflamm. 2006; 2006:26875. PMID: 17392581.

25. Ljuca F, Gegic A, Salkic NN, Pavlovic-Calic N. Circulating cytokines reflect mucosal inflammatory status in patients with Crohn's disease. Dig Dis Sci. 2010; 55:2316–2326. PMID: 19834804.

26. Li MO, Flavell RA. TGF-beta: a master of all T cell trades. Cell. 2008; 134:392–404. PMID: 18692464.

27. Del Zotto B, Mumolo G, Pronio AM, Montesani C, Tersigni R, Boirivant M. TGF-beta1 production in inflammatory bowel disease: differing production patterns in Crohn's disease and ulcerative colitis. Clin Exp Immunol. 2003; 134:120–126. PMID: 12974764.

28. Rani R, Smulian AG, Greaves DR, Hogan SP, Herbert DR. TGF-beta limits IL-33 production and promotes the resolution of colitis through regulation of macrophage function. Eur J Immunol. 2011; 41:2000–2009. PMID: 21469118.

29. Gu FM, Li QL, Gao Q, et al. IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma. Mol Cancer. 2011; 10:150. PMID: 22171994.

30. Wruck CJ, Fragoulis A, Gurzynski A, et al. Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice. Ann Rheum Dis. 2011; 70:844–850. PMID: 21173018.

31. Fujino S, Andoh A, Bamba S, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003; 52:65–70. PMID: 12477762.

32. Fort MM, Cheung J, Yen D, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity. 2001; 15:985–995. PMID: 11754819.

33. O'Connor W Jr, Kamanaka M, Booth CJ, et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol. 2009; 10:603–609. PMID: 19448631.

34. Kinugasa T, Sakaguchi T, Gu X, Reinecker HC. Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology. 2000; 118:1001–1011. PMID: 10833473.

35. Sakuraba A, Sato T, Kamada N, Kitazume M, Sugita A, Hibi T. Th1/Th17 immune response is induced by mesenteric lymph node dendritic cells in Crohn's disease. Gastroenterology. 2009; 137:1736–1745. PMID: 19632232.

36. Kleinschek MA, Boniface K, Sadekova S, et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J Exp Med. 2009; 206:525–534. PMID: 19273624.

37. Strober W, Zhang F, Kitani A, Fuss I, Fichtner-Feigl S. Proinflammatory cytokines underlying the inflammation of Crohn's disease. Curr Opin Gastroenterol. 2010; 26:310–317. PMID: 20473158.

38. Mahida YR, Ceska M, Effenberger F, Kurlak L, Lindley I, Hawkey CJ. Enhanced synthesis of neutrophil-activating peptide-1/interleukin-8 in active ulcerative colitis. Clin Sci (Lond). 1992; 82:273–275. PMID: 1312411.

39. Grimm MC, Doe WF. Chemokines in inflammatory bowel disease mucosa: expression of RANTES, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and gamma-interferon-inducible protein-10 by macrophages, lymphocytes, endothelial cells, and granulomas. Inflamm Bowel Dis. 1996; 2:88–96. PMID: 23282513.

40. Uguccioni M, Gionchetti P, Robbiani DF, et al. Increased expression of IP-10, IL-8, MCP-1, and MCP-3 in ulcerative colitis. Am J Pathol. 1999; 155:331–336. PMID: 10433925.

41. Kaser A, Ludwiczek O, Holzmann S, et al. Increased expression of CCL20 in human inflammatory bowel disease. J Clin Immunol. 2004; 24:74–85. PMID: 14997037.

42. Mitsuyama K, Toyonaga A, Sasaki E, et al. IL-8 as an important chemoattractant for neutrophils in ulcerative colitis and Crohn's disease. Clin Exp Immunol. 1994; 96:432–436. PMID: 8004812.

43. Zenewicz LA, Antov A, Flavell RA. CD4 T-cell differentiation and inflammatory bowel disease. Trends Mol Med. 2009; 15:199–207. PMID: 19362058.

44. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol. 2007; 8:942–949. PMID: 17676045.

45. Zhou L, Ivanov II, Spolski R, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007; 8:967–974. PMID: 17581537.

46. Gálvez J. Role of Th17 cells in the pathogenesis of human IBD. ISRN Inflamm. 2014; 2014:928461. PMID: 25101191.

47. Yang XO, Panopoulos AD, Nurieva R, et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem. 2007; 282:9358–9363. PMID: 17277312.

48. Lathrop SK, Bloom SM, Rao SM, et al. Peripheral education of the immune system by colonic commensal microbiota. Nature. 2011; 478:250–254. PMID: 21937990.

49. Venema K. Role of gut microbiota in the control of energy and carbohydrate metabolism. Curr Opin Clin Nutr Metab Care. 2010; 13:432–438. PMID: 20531179.

50. Asquith M, Powrie F. An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer. J Exp Med. 2010; 207:1573–1577. PMID: 20679404.

51. Manichanh C, Rigottier-Gois L, Bonnaud E, et al. Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut. 2006; 55:205–211. PMID: 16188921.

52. Lepage P, Häsler R, Spehlmann ME, et al. Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology. 2011; 141:227–236. PMID: 21621540.

53. Guarner F, Bourdet-Sicard R, Brandtzaeg P, et al. Mechanisms of disease: the hygiene hypothesis revisited. Nat Clin Pract Gastroenterol Hepatol. 2006; 3:275–284. PMID: 16673007.

54. Ivanov II, Atarashi K, Manel N, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009; 139:485–498. PMID: 19836068.

55. Wu S, Rhee KJ, Albesiano E, et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med. 2009; 15:1016–1022. PMID: 19701202.

56. Ivanov II, Frutos Rde L, Manel N, et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe. 2008; 4:337–349. PMID: 18854238.

57. Atarashi K, Nishimura J, Shima T, et al. ATP drives lamina propria T(H)17 cell differentiation. Nature. 2008; 455:808–812. PMID: 18716618.

58. Kamada N, Núñez G. Role of the gut microbiota in the development and function of lymphoid cells. J Immunol. 2013; 190:1389–1395. PMID: 23378581.

59. Murphy KM, Stockinger B. Effector T cell plasticity: flexibility in the face of changing circumstances. Nat Immunol. 2010; 11:674–680. PMID: 20644573.

60. Seiderer J, Elben I, Diegelmann J, et al. Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD. Inflamm Bowel Dis. 2008; 14:437–445. PMID: 18088064.

61. Kobayashi T, Okamoto S, Hisamatsu T, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease. Gut. 2008; 57:1682–1689. PMID: 18653729.

62. Raza A, Shata MT. Letter: pathogenicity of Th17 cells may differ in ulcerative colitis compared with Crohn's disease. Aliment Pharmacol Ther. 2012; 36:204. PMID: 22703461.

63. Thompson AI, Lees CW. Genetics of ulcerative colitis. Inflamm Bowel Dis. 2011; 17:831–848. PMID: 21319274.

64. Biancheri P, Powell N, Monteleone G, Lord G, MacDonald TT. The challenges of stratifying patients for trials in inflammatory bowel disease. Trends Immunol. 2013; 34:564–571. PMID: 24035478.

65. Ogawa A, Andoh A, Araki Y, Bamba T, Fujiyama Y. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin Immunol. 2004; 110:55–62. PMID: 14962796.

66. Garrido-Mesa N, Utrilla P, Comalada M, et al. The association of minocycline and the probiotic Escherichia coli Nissle 1917 results in an additive beneficial effect in a DSS model of reactivated colitis in mice. Biochem Pharmacol. 2011; 82:1891–1900. PMID: 21930116.

67. Yang XO, Chang SH, Park H, et al. Regulation of inflammatory responses by IL-17F. J Exp Med. 2008; 205:1063–1075. PMID: 18411338.

68. Wedebye Schmidt EG, Larsen HL, Kristensen NN, et al. TH17 cell induction and effects of IL-17A and IL-17F blockade in experimental colitis. Inflamm Bowel Dis. 2013; 19:1567–1576. PMID: 23689808.

69. Omenetti S, Pizarro TT. The Treg/Th17 axis: a dynamic balance regulated by the gut microbiome. Front Immunol. 2015; 6:639. PMID: 26734006.

70. Brand S. Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease. Gut. 2009; 58:1152–1167. PMID: 19592695.

71. Boden EK, Snapper SB. Regulatory T cells in inflammatory bowel disease. Curr Opin Gastroenterol. 2008; 24:733–741. PMID: 19125486.

72. Wirtz S, Neurath MF. Mouse models of inflammatory bowel disease. Adv Drug Deliv Rev. 2007; 59:1073–1083. PMID: 17825455.

73. Chaudhry A, Samstein RM, Treuting P, et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity. 2011; 34:566–578. PMID: 21511185.

74. Geem D, Harusato A, Flannigan K, Denning TL. Harnessing regulatory T cells for the treatment of inflammatory bowel disease. Inflamm Bowel Dis. 2015; 21:1409–1418. PMID: 25793328.

75. Boehm F, Martin M, Kesselring R, et al. Deletion of Foxp3+ regulatory T cells in genetically targeted mice supports development of intestinal inflammation. BMC Gastroenterol. 2012; 12:97. PMID: 22849659.

76. Huber S, Schramm C, Lehr HA, et al. Cutting edge: TGF-beta signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. J Immunol. 2004; 173:6526–6531. PMID: 15557141.

77. Rubtsov YP, Rasmussen JP, Chi EY, et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity. 2008; 28:546–558. PMID: 18387831.

78. Maloy KJ, Salaun L, Cahill R, Dougan G, Saunders NJ, Powrie F. CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J Exp Med. 2003; 197:111–119. PMID: 12515818.

79. Uhlig HH, Coombes J, Mottet C, et al. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol. 2006; 177:5852–5860. PMID: 17056509.

80. Collins CB, Aherne CM, McNamee EN, et al. Flt3 ligand expands CD103⁺ dendritic cells and FoxP3⁺ T regulatory cells, and attenuates Crohn's-like murine ileitis. Gut. 2012; 61:1154–1162. PMID: 22068168.

81. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441:235–238. PMID: 16648838.

82. Xu L, Kitani A, Fuss I, Strober W. Cutting edge: regulatory T cells induce CD4+CD25−Foxp3−T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J Immunol. 2007; 178:6725–6729. PMID: 17513718.

83. de Beaucoudrey L, Puel A, Filipe-Santos O, et al. Mutations in STAT3 and IL-12RB1 impair the development of human IL-17-producing T cells. J Exp Med. 2008; 205:1543–1550. PMID: 18591412.

84. Ogino H, Nakamura K, Ihara E, Akiho H, Takayanagi R. CD4+CD25+ regulatory T cells suppress Th17-responses in an experimental colitis model. Dig Dis Sci. 2011; 56:376–386. PMID: 20521112.

85. Becker C, Dornhoff H, Neufert C, et al. Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis. J Immunol. 2006; 177:2760–2764. PMID: 16920909.

86. Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006; 116:1310–1316. PMID: 16670770.

87. Stolfi C, Rizzo A, Franzè E, et al. Involvement of interleukin-21 in the regulation of colitis-associated colon cancer. J Exp Med. 2011; 208:2279–2290. PMID: 21987656.

88. Fitzpatrick LR, Small JS, Doblhofer R, Ammendola A. Vidofludimus inhibits colonic interleukin-17 and improves hapten-induced colitis in rats by a unique dual mode of action. J Pharmacol Exp Ther. 2012; 342:850–860. PMID: 22691298.

89. Herrlinger KR, Diculescu M, Fellermann K, et al. Efficacy, safety and tolerability of vidofludimus in patients with inflammatory bowel disease: the ENTRANCE study. J Crohns Colitis. 2013; 7:636–643. PMID: 23078909.

90. Zhang Z, Zheng M, Bindas J, Schwarzenberger P, Kolls JK. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis. 2006; 12:382–388. PMID: 16670527.

91. Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012; 61:1693–1700. PMID: 22595313.

92. McLean LP, Cross RK, Shea-Donohue T. Combined blockade of IL-17A and IL-17F may prevent the development of experimental colitis. Immunotherapy. 2013; 5:923–925. PMID: 23998727.

93. Fitzpatrick LR. Inhibition of IL-17 as a pharmacological approach for IBD. Int Rev Immunol. 2013; 32:544–555. PMID: 23886112.

94. Klotz L, Burgdorf S, Dani I, et al. The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J Exp Med. 2009; 206:2079–2089. PMID: 19737866.

95. Hontecillas R, Horne WT, Climent M, et al. Immunoregulatory mechanisms of macrophage PPAR-gamma in mice with experimental inflammatory bowel disease. Mucosal Immunol. 2011; 4:304–313. PMID: 21068720.

96. Kim JK, Lee SH, Lee SY, et al. Grim19 attenuates DSS induced colitis in an animal model. PLoS One. 2016; 11:e0155853. DOI: 10.1371/journal.pone.0155853. PMID: 27258062.

97. Spits H, Cupedo T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu Rev Immunol. 2012; 30:647–675. PMID: 22224763.

98. Klose CS, Flach M, Möhle L, et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell. 2014; 157:340–356. PMID: 24725403.

99. Fallon PG, Ballantyne SJ, Mangan NE, et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J Exp Med. 2006; 203:1105–1116. PMID: 16606668.

100. Reynders A, Yessaad N, Vu Manh TP, et al. Identity, regulation and in vivo function of gut NKp46+RORgammat+ and NKp46+RORgammat-lymphoid cells. EMBO J. 2011; 30:2934–2947. PMID: 21685873.

101. Satoh-Takayama N, Vosshenrich CA, Lesjean-Pottier S, et al. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity. 2008; 29:958–970. PMID: 19084435.

102. Gladiator A, Wangler N, Trautwein-Weidner K, LeibundGut-Landmann S. Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J Immunol. 2013; 190:521–525. PMID: 23255360.

103. Sonnenberg GF, Monticelli LA, Elloso MM, Fouser LA, Artis D. CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity. 2011; 34:122–134. PMID: 21194981.

104. Takatori H, Kanno Y, Watford WT, et al. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med. 2009; 206:35–41. PMID: 19114665.

105. Sanos SL, Bui VL, Mortha A, et al. RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat Immunol. 2009; 10:83–91. PMID: 19029903.

106. Buonocore S, Ahern PP, Uhlig HH, et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature. 2010; 464:1371–1375. PMID: 20393462.

107. Powell N, Walker AW, Stolarczyk E, et al. The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells. Immunity. 2012; 37:674–684. PMID: 23063332.

108. Garrett WS, Lord GM, Punit S, et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell. 2007; 131:33–45. PMID: 17923086.

109. Garrett WS, Punit S, Gallini CA, et al. Colitis-associated colorectal cancer driven by T-bet deficiency in dendritic cells. Cancer Cell. 2009; 16:208–219. PMID: 19732721.

110. Geremia A, Arancibia-Cárcamo CV, Fleming MP, et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J Exp Med. 2011; 208:1127–1133. PMID: 21576383.

111. Bernink JH, Peters CP, Munneke M, et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat Immunol. 2013; 14:221–229. PMID: 23334791.

112. Fuchs A, Vermi W, Lee JS, et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells. Immunity. 2013; 38:769–781. PMID: 23453631.

113. Vonarbourg C, Mortha A, Bui VL, et al. Regulated expression of nuclear receptor RORgmamat confers distinct functional fates to NK cell receptor-expressing RORgammat(+) innate lymphocytes. Immunity. 2010; 33:736–751. PMID: 21093318.

114. Bailey JR, Bland PW, Tarlton JF, et al. IL-13 promotes collagen accumulation in Crohn's disease fibrosis by down-regulation of fibroblast MMP synthesis: a role for innate lymphoid cells? PLoS One. 2012; 7:e52332. DOI: 10.1371/journal.pone.0052332. PMID: 23300643.

115. Ermann J, Staton T, Glickman JN, de Waal Malefyt R, Glimcher LH, et al. Nod/Ripk2 signaling in dendritic cells activates IL-17A-secreting innate lymphoid cells and drives colitis in T-bet−/−.Rag2−/− (TRUC) mice. Proc Natl Acad Sci U S A. 2014; 111:E2559–E2566. PMID: 24927559.

116. Longman RS, Diehl GE, Victorio DA, et al. CX₃CR1⁺ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J Exp Med. 2014; 211:1571–1583. PMID: 25024136.

117. Kamada N, Hisamatsu T, Okamoto S, et al. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Invest. 2008; 118:2269–2280. PMID: 18497880.

118. Ogino T, Nishimura J, Barman S, et al. Increased Th17-inducing activity of CD14+ CD163 low myeloid cells in intestinal lamina propria of patients with Crohn's disease. Gastroenterology. 2013; 145:1380–1391.e1. PMID: 23993972.

119. Mizuno S, Mikami Y, Kamada N, et al. Cross-talk between RORgammat+ innate lymphoid cells and intestinal macrophages induces mucosal IL-22 production in Crohn's disease. Inflamm Bowel Dis. 2014; 20:1426–1434. PMID: 24991784.

120. Mortha A, Chudnovskiy A, Hashimoto D, et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science. 2014; 343:1249288. PMID: 24625929.

121. Neill DR, Wong SH, Bellosi A, et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature. 2010; 464:1367–1370. PMID: 20200518.

122. Hepworth MR, Monticelli LA, Fung TC, et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature. 2013; 498:113–117. PMID: 23698371.

123. Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol. 2011; 12:383–390. PMID: 21502992.

124. Goto Y, Panea C, Nakato G, et al. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity. 2014; 40:594–607. PMID: 24684957.

125. Magri G, Miyajima M, Bascones S, et al. Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat Immunol. 2014; 15:354–364. PMID: 24562309.

126. Cella M, Fuchs A, Vermi W, et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature. 2009; 457:722–725. PMID: 18978771.

127. Goto Y, Obata T, Kunisawa J, et al. Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science. 2014; 345:1254009. PMID: 25214634.

128. Pham TA, Clare S, Goulding D, et al. Epithelial IL-22RA1-mediated fucosylation promotes intestinal colonization resistance to an opportunistic pathogen. Cell Host Microbe. 2014; 16:504–516. PMID: 25263220.

129. Desreumaux P, Romano O. 5-Aminosalicylates and colorectal cancer: preventive role in chronic inflammatory bowel disease? Gastroenterol Clin Biol. 2004; 28:509. PMID: 15243337.

130. Rousseaux C, Lefebvre B, Dubuquoy L, et al. Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma. J Exp Med. 2005; 201:1205–1215. PMID: 15824083.

131. Allgayer H. Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease. Aliment Pharmacol Ther. 2003; 18(Suppl 2):10–14. PMID: 12950415.

132. Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalysis of observational studies. Am J Gastroenterol. 2005; 100:1345–1353. PMID: 15929768.

133. Lim WC, Wang Y, MacDonald JK, Hanauer S. Aminosalicylates for induction of remission or response in Crohn's disease. Cochrane Database Syst Rev. 2016; 7:CD008870. DOI: 10.1002/14651858.CD008870. PMID: 27372735.

134. Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011; 365:1713–1725. PMID: 22047562.

135. Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol. 2013; 132:1033–1044. PMID: 24084075.

136. Rezaie A, Kuenzig ME, Benchimol EI, et al. Budesonide for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2015; (6):CD000296. DOI: 10.1002/14651858.CD000296.pub4. PMID: 26039678.

137. Tiede I, Fritz G, Strand S, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest. 2003; 111:1133–1145. PMID: 12697733.

138. D'Haens G, Geboes K, Ponette E, Penninckx F, Rutgeerts P. Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn's disease. Gastroenterology. 1997; 112:1475–1481. PMID: 9136824.

139. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010; 362:1383–1395. PMID: 20393175.

140. Feagan BG, Fedorak RN, Irvine EJ, et al. North American Crohn's Study Group Investigators. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. N Engl J Med. 2000; 342:1627–1632. PMID: 10833208.

141. Feuerstein JD, Akbari M, Tapper EB, Cheifetz AS. Systematic review and meta-analysis of third-line salvage therapy with infliximab or cyclosporine in severe ulcerative colitis. Ann Gastroenterol. 2016; 29:341–347. PMID: 27366036.

142. Steiner S, Daniel C, Fischer A, et al. Cyclosporine A regulates pro-inflammatory cytokine production in ulcerative colitis. Arch Immunol Ther Exp (Warsz). 2015; 63:53–63. PMID: 25155925.

143. Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. 2000; 47:119–125. PMID: 10878286.

144. Nielsen CH, Albertsen L, Bendtzen K, Baslund B. Methotrexate induces poly(ADP-ribose) polymerase-dependent, caspase 3-independent apoptosis in subsets of proliferating CD4+ T cells. Clin Exp Immunol. 2007; 148:288–295. PMID: 17286800.

145. Wessels JA, Huizinga TW, Guchelaar HJ. Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology (Oxford). 2008; 47:249–255. PMID: 18045808.

146. Glatzer T, Killig M, Meisig J, et al. RORgammat⁺ innate lymphoid cells acquire a proinflammatory program upon engagement of the activating receptor NKp44. Immunity. 2013; 38:1223–1235. PMID: 23791642.

147. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002; 359:1541–1549. PMID: 12047962.

148. Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014; 146:392–400.e3. PMID: 24512909.

149. Biancheri P, Brezski RJ, Di Sabatino A, et al. Proteolytic cleavage and loss of function of biologic agents that neutralize tumor necrosis factor in the mucosa of patients with inflammatory bowel disease. Gastroenterology. 2015; 149:1564–1574.e3. PMID: 26170138.

150. Van den Brande JM, Koehler TC, Zelinkova Z, et al. Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohn's disease. Gut. 2007; 56:509–517. PMID: 17082252.

151. Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn's disease. N Engl J Med. 2003; 348:24–32. PMID: 12510039.

152. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med. 2005; 353:1912–1925. PMID: 16267322.

153. Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn's disease: results of the ENCORE trial. Gastroenterology. 2007; 132:1672–1683. PMID: 17484865.

154. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med. 2005; 353:362–368. PMID: 15947080.

155. Warnke C, Menge T, Hartung HP, et al. Natalizumab and progressive multifocal leukoencephalopathy: what are the causal factors and can it be avoided? Arch Neurol. 2010; 67:923–930. PMID: 20697042.

156. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012; 366:1870–1880. PMID: 22591293.

157. Munneke JM, Bjorklund AT, Mjosberg JM, et al. Activated innate lymphoid cells are associated with a reduced susceptibility to graft-versus-host disease. Blood. 2014; 124:812–821. PMID: 24855210.

158. Fischer A, Zundler S, Atreya R, et al. Differential effects of alpha4beta7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo. Gut. 2016; 65:1642–1664. PMID: 26209553.

159. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013; 369:699–710. PMID: 23964932.

160. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 2013; 369:711–721. PMID: 23964933.

161. Wyant T, Leach T, Sankoh S, et al. Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results. Gut. 2015; 64:77–83. PMID: 24763133.

162. Lam MC, Bressler B. Vedolizumab for ulcerative colitis and Crohn's disease: results and implications of GEMINI studies. Immunotherapy. 2014; 6:963–971. PMID: 25341118.

163. Stallmach A, Langbein C, Atreya R, et al. Vedolizumab provides clinical benefit over 1 year in patients with active inflammatory bowel disease: a prospective multicenter observational study. Aliment Pharmacol Ther. 2016; 44:1199–1212. PMID: 27714831.

164. Zundler S, Schillinger D, Fischer A, et al. Blockade of alpha-Ebeta7 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo. Gut. 2017; 66:1936–1948. PMID: 27543429.

165. Vermeire S, O'Byrne S, Keir M, et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet. 2014; 384:309–318. PMID: 24814090.

166. Rutgeerts PJ, Fedorak RN, Hommes DW, et al. Randomised phase I study of etrolizumab (rhuMAb beta7) in moderate to severe ulcerative colitis. Gut. 2013; 62:1122–1130. PMID: 22717454.

167. Gonzalez-Cabrera PJ, Brown S, Studer SM, Rosen H. S1P signaling: new therapies and opportunities. F1000Prime Rep. 2014; 6:109. PMID: 25580263.

168. Deguchi Y, Andoh A, Yagi Y, et al. The S1P receptor modulator FTY720 prevents the development of experimental colitis in mice. Oncol Rep. 2006; 16:699–703. PMID: 16969482.

169. Degagné E, Saba JD. S1pping fire: sphingosine-1-phosphate signaling as an emerging target in inflammatory bowel disease and colitis-associated cancer. Clin Exp Gastroenterol. 2014; 7:205–214. PMID: 25061328.

170. Sandborn WJ, Feagan BG, Wolf DC, et al. Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med. 2016; 374:1754–1762. PMID: 27144850.

171. Gilead terminates phase 2/3 study of GS-5745 in patients with ulcerative colitis. Gilead Science, Inc.;Accessed July 12, 2017. http://www.gilead.com/news/press-releases/2016/9/gilead-terminates-phase-23-study-of-gs5745-in-patients-with-ulcerative-colitis .

172. Suzuki K, Yokoyama J, Kawauchi Y, et al. Phase 1 clinical study of siRNA targeting carbohydrate sulphotransferase 15 in Crohn's disease patients with active mucosal lesions. J Crohns Colitis. 2017; 11:221–228. PMID: 27484097.

173. Reinisch W, Hommes DW, Van Assche G, et al. A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn's disease. Gut. 2006; 55:1138–1144. PMID: 16492717.

174. Maxwell JR, Zhang Y, Brown WA, et al. Differential roles for interleukin-23 and interleukin-17 in intestinal immunoregulation. Immunity. 2015; 43:739–750. PMID: 26431947.

175. Atreya R, Mudter J, Finotto S, et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo. Nat Med. 2000; 6:583–588. PMID: 10802717.

176. Ito H, Takazoe M, Fukuda Y, et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology. 2004; 126:989–996. PMID: 15057738.

177. Fuss IJ, Becker C, Yang Z, et al. Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflamm Bowel Dis. 2006; 12:9–15. PMID: 16374252.

178. Monteleone G, Biancone L, Marasco R, et al. Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology. 1997; 112:1169–1178. PMID: 9098000.

179. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology. 2008; 135:1130–1141. PMID: 18706417.

180. Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N Engl J Med. 2012; 367:1519–1528. PMID: 23075178.

181. Kock K, Pan WJ, Gow JM, et al. Preclinical development of AMG 139, a human antibody specifically targeting IL-23. Br J Pharmacol. 2015; 172:159–172. PMID: 25205227.

182. Sandborn WJ, Ghosh S, Panes J, et al. A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn's disease. Clin Gastroenterol Hepatol. 2014; 12:1485–1493.e2. PMID: 24480677.

183. Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012; 367:616–624. PMID: 22894574.

184. Mazur M, Karczewski J, Lodyga M, Żaba R, Adamski Z. Inhibitors of phosphodiesterase 4 (PDE 4): a new therapeutic option in the treatment of psoriasis vulgaris and psoriatic arthritis. J Dermatolog Treat. 2015; 26:326–328. PMID: 25424050.

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