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Targets for the Immune Balance of Biologics in Inflammatory Bowel Disease

  • Xuan Yan1,#,
  • Sizhe Xie1,#,
  • Xiaowei Yan2,#,
  • He Wang2,
  • Yinyin Guo3,
  • Hebin Tan4 and
  • Shixue Dai5,6,* 
 Author information
Nature Cell and Science   2024;2(2):85-94

doi: 10.61474/ncs.2023.00025

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory condition that affects the gastrointestinal and extra-gastrointestinal system and is strongly associated with immunity. IBD is thought to be primarily caused by an imbalance in immunological barriers, typically demonstrated by a disequilibrium of immune cells with either pro-inflammatory or anti-inflammatory receptors. Despite the well-established efficacy of biological agents (BAs) in treating IBD, which underscores their remarkable therapeutic potential and elucidates their anti-inflammatory mechanisms, the immunomodulatory effects of BAs, particularly on immune balance such as T helper 1/T helper 2 and T helper 17/regulatory T equilibrium, remain to be fully elucidated. This review will summarize the immune balance mechanism of BAs in order to deepen the understanding of the immune mechanisms of BAs with important clinical significance in reducing the non-responses to BAs in IBD.

Keywords

Inflammatory bowel disease, Biological agents, Immune balance, T lymphocytes, Regulatory T cells, Interleukin 12, Interleukin 23

Introduction

Crohn’s disease (CD) and ulcerative colitis (UC) are types of inflammatory bowel disease (IBD). While the exact cause of IBD remains uncertain, current scientific evidence suggests that an abnormal immune response to the microbiota in the intestinal tract is a primary contributing factor.1 Regulatory T (Treg) cells and T helper (Th) 17 cells are two T cell sub sets implicated in the pathophysiology of IBD. Th1 cells are essential for removing intracellular pathogens, while Th2 cells mediate allergic reactions and provide protection against parasites. Patients with IBD have more Th17 cells in the lamina propria. Tregs also play a significant role in maintaining intestinal mucosal homeostasis by suppressing aberrant immune responses to dietary antigens or symbiotic flora. Research has indicated that adaptive immunity mostly affects Th1)/Th2 and Th17/Treg ratios.2,3

The effects of biological agents (BAs) on immune balance and their effectiveness in treating IBD are still not fully understood. Emerging inhibitors targeting cytokines, integrins, cytokine signaling pathways, and cell signaling receptors have shown promise as preferred treatment modalities for many IBD patients. While conventional therapies such as 5-aminosalicylic acid, corticosteroids, immunomodulators, and anti-tumor necrosis factor agents continue to be effective, especially in combination with other drugs, the field is evolving towards more targeted and efficient treatment options. This review consolidates findings from chemical, biological, and adjunct therapies to assess current and future IBD treatments, elucidating the mechanisms of action for each therapy and highlighting potential avenues for further development.

Th1/Th2

Levels of IFNc and interleukin (IL) 12 demonstrate an inverse correlation with platelet counts, similar to the Th1/Th2 ratio. The imbalance between Th1/Th2 and Th17/Treg, potentially triggered by the distinction between plasmacytoid dendritic cells/myeloid dendritic cells, and elevated levels of IL6, IL12, and IL23, leads to the differentiation of CD4+ T cells into Th1 and Th17 cells, ultimately resulting in increased Th1 and Th17 production. IL6 plays a crucial role in regulating the equilibrium between Th17 and Treg cells. IL6, together with transforming growth factor β (TGF-β), induces the differentiation of Th17 cells from T cells while inhibiting the differentiation of Treg cells induced by TGF-β. In addition, dendritic cells (DCs) and macrophages mainly express IL6 and IL23, which promote the differentiation of Th0 cells into Th17 cells.4 DC subsets primarily influence the differentiation of Th0, Th1/Th2 cell ratio, and Th17/Treg ratio by cytokine release, quantity variation, subpopulation proportion imbalance, and maturation. Hence, an imbalance in the ratio of DC subsets may be a key mechanism contributing to this imbalance.4 Based on this premise, biologics that alter the Th1/Th2 ratio will be discussed below.

TNF-α antagonists

In individuals with IBD, there is excessive production of TNF-α by lamina propria cells. This pro-inflammatory mediator can promote the adherence of white blood cells to vascular endothelial cells and their recruitment to the affected site, potentially influenced by abnormal interactions between the host and intestinal flora.5 The mechanism by which anti-TNF-α drugs induce the production of autoantibodies is the subject of numerous theories. These include: (1) the inflammatory cells may undergo apoptosis due to an imbalance between TNF-α and interferon-α; (2) the production of DNA and other nuclear targets is facilitated by the agglomeration of macrophages and the nucleosomes of arrested cells; and (3) the activation of lymphocytes leads to the production of polyclonal B lymphocytes. Anti-TNF-α antibodies can block the binding of soluble TNF-α to the surface of activated T lymphocytes, thereby altering the Th1/Th2 ratio.

Currently, three anti-TNF-α antibodies are used in the treatment of UC patients: infliximab (IFX) and adalimumab (ADL), which primarily exert anti-inflammatory effects by targeting and inhibiting TNF-α.6 IFX is an anti-TNF-α chimeric monoclonal IgG1 antibody composed of a human constant region and a mouse variable region. Apart from its ability to neutralize TNF-α, IFX can also cause T cells and monocytes to undergo apoptosis and inhibit leukocyte migration.7 ADL is a transgenic anti-TNF antibody that is manufactured from animals and specifically binds to TNF-α. It controls the inflammatory response by associating with the TNF cell receptor on the cell membrane to block the signal transduction mechanism that activates inflammation.7

Anti-IL12 and anti-IL23 agents

Antigen-presenting cells secrete cytokines IL12 and IL23 upon innate signals. The binding of these cytokines to their receptors triggers TYK2 and JAK2 activation within immune cells, initiating JAK/STAT signaling. TYK2 mediates downstream signaling of IL12, IL23, and type I interferon receptors on immune cells, promoting STAT phosphorylation. JAK2 is associated with hematopoietic stem cells and progenitors, and JAK2 mutations occur in myeloid cells derived from CD34+ cells. Generation and activation of TYK2 and JAK2 are influenced by cytokines and cell types, potentially playing roles in various cells under physiological or pathological conditions.

The JAK/STAT signaling pathway involves phosphorylation of STAT4 in response to IL12 and IL23. Phosphorylated STAT4 dimers regulate inflammatory and immune genes in the nucleus.8,9 Monoclonal antibodies targeting the shared p40 subunit of IL12 and IL23, including ustekinumab and briakinumab,10 are developed to treat immune-mediated diseases. These antibodies modulate the JAK/STAT pathway by blocking cytokine-receptor interactions, reducing inflammation. Their effectiveness lies in regulating immune cell activation and proliferation through the JAK/STAT pathway.

Anti-integrin antibodies

Integrins are cell surface glycoprotein receptors capable of bidirectional signal transduction and can interact with adhesion molecules to facilitate the migration of white blood cells into surrounding tissues.11 Among them, α4β7 integrins are exclusively expressed on the surface of intestine-specific lymphocytes and play a crucial role in mediating the migration of inflammatory cells to the intestinal mucosa through binding with MAdCAM1, thereby contributing to the initiation of inflammatory reactions.12 Anti-integrin antibodies, a type of biologics, selectively inhibit the binding of integrins to ligands on the surface of intestinal immune cells and endothelial cell adhesion molecules.13 This inhibition effectively hinders the migration of inflammatory cells to intestinal vessels. Furthermore, anti-integrin antibodies not only attenuate the intestinal inflammatory response but also do not compromise the overall immune function of the body, resulting in fewer adverse reactions and a stable therapeutic effect.14,15

Vedolizumab (VDZ), a representative anti-integrin antibody, has been approved by the U.S. Food and Drug Administration for the treatment of IBD.14 It selectively inhibits the migration of Th17 cells expressing IL17 to the lesions of ascending colonic ulcers in Crohn’s disease by specifically antagonizing α4β7 integrin, while exhibiting no affinity for α4β1 integrin. This action effectively blocks the binding of activated α4β7 integrin to its ligand MAdCAM1.16 VDZ also prevents T lymphocytes from migrating to the inflamed regions within the intestines and exerts selective suppression of gut inflammation.15,16

Furthermore, novel anti-integrin antibody drugs are in intensive development. Natalizumab)effectively targets α4β1 and α4β7 and selectively blocks inflammatory cell migration by inhibiting integrin α4 signaling. Etrolizumab specifically targets the β7 subunits of α4β7 and αEβ7 integrins, thereby preventing their involvement in the development of ulcerative colitis.17 The efficacy of induction maintenance therapy remains uncertain. Ontamalimab exerts its action by specifically binding to and inhibiting the activity of MAdCAM1, a crucial molecule involved in endothelial adhesion and lymphocyte migration to the site of inflammation in IBD.18

The therapeutic effect of anti-integrin antibodies plays a significant role in clinical remission rates, reflectivity, and mucosal healing rate, which has a stronger safety margin and deserves an in-depth analysis and study.

JAK inhibitor

sJAK inhibitors, including TYK2, JAK1, JAK2, and JAK3, are intracellular non-receptor tyrosine kinases.19 Upon cytokine receptor-ligand binding, these paired JAK proteins undergo activation and form STAT dimers. Phosphorylated STAT dimers then translocate to the nucleus where they modulate the transcription of target genes.20 This signaling pathway plays a pivotal role in mediating the inflammatory response in IBD, contributing to both physiological and pathological processes.21,22 JAK1 is a pivotal therapeutic target for IBD due to its involvement in the signaling of various cytokines, including IL6, interferons, IL2, IL15, and the gamma chain of cytokine signaling.23 Inhibition of JAK1 effectively abrogates the initiation of inflammatory cascades.24 The proinflammatory cytokine GM-CSF utilizes the JAK2 signaling pathway, thus inhibition of both JAK1 and JAK2 results in a heightened anti-inflammatory response.

Tofacitinib, the pioneering oral small-molecule kinase inhibitor to undergo clinical trials, demonstrates high selectivity for human protein kinases and is categorized as a first-generation non-specific JAK inhibitor. Preclinical studies have validated its potent inhibition of JAK1/JAK3, which holds promise in treating IBD by obstructing cytokine signal transduction activities linked to lymphocyte activation, proliferation, and function, thereby impeding both adaptive and innate immune responses.25 Filgotinib represents the second generation of JAK inhibitors with specific targeting of JAK1.26,27 Filgotinib is a second-generation of JAK inhibitor that can selectively inhibit JAK1.28 Despite its limited inhibitory effect on cytokine receptors as a selective JAK inhibitor, it can exert various anti-inflammatory effects by suppressing IL2, IL6, interferon-γ, and other signaling pathways.21

Currently, the use of selective JAK inhibitors is emerging as a new research trend; however, there is a lack of direct comparative data from clinical trials, and further exploration is needed to determine whether their application results in improved efficacy and safety.

Others

The participation of sphingosine-1-phosphate receptors (S1PRs) in cell migration, proliferation, and differentiation is orchestrated by its diverse receptor subtypes, each accountable for discrete functions.29 The S1PR1 is extensively expressed on immune cells and exerts significant control over the movement of lymphocytes.30 Its agonist activity effectively hinders lymphocyte egress from lymph nodes, thereby impeding their migration to inflammatory sites.31

By binding to S1PRs, Gilenya facilitates the migration of lymphocytes back to lymphoid tissues and diminishes lymphocyte infiltration in the central nervous system.32,33 Ozanimod is a potent selective modulator of sphingosine-1-phosphate (S1P) receptors, exhibiting high affinity for S1P receptor subtypes 1 and 5. This interaction results in the internalization of lymphocyte S1P type 1 receptors, thereby impeding the mobilization of lymphocytes to sites of inflammation.34 Etrasimod (APD334), an orally administered medication, specifically targets the S1P1, S1P4, and S1P5 signaling pathways as a modulator of S1P receptors.35 Fingolimod, Amiselimod, and Laquinimod are S1P receptor modulators, among which Laquinimod has been found to be effective and well tolerated in the treatment of CD.36 However, the exploration of new treatment directions is still insufficient, and more research is needed for drugs treating CD and UC.

The above mentioned biologic agents and their immune responses have been summarized in Table 1 and Figure 1.16,25,34,37–46

Table 1

Mechanisms of biologics targeting IBD

Types of biological agentsName of biological agentsPharmacological targetsEffects associated with immune balance in IBD
Anti-TNF-α preparationsInfliximab (IFX)Targeted inhibition of TNF-α to play an anti-inflammatory role37Specifically binding to TNF-α→neutralizing inflammatory cells or inducing apoptosis→forming regulatory macrophages and other mechanisms→inhibiting the induced immune response→inducing and maintaining disease remission
Adalimumab (ADL)It binds specifically to TNF-α with high affinity and regulates the inflammatory response by blocking the signal transduction process that causes the inflammatory response38
Anti-IL12/IL23 complexUstekinumabInhibition of the p40 subunit common to both IL23 and IL12 acts39IL12 and IL23 bind to receptors→induce naive CD4+T cells to differentiate into Th1 and Th17 cells→produce interferon-γ, IL17 and tumor necrosis factor and other inflammatory factors→Biological agents target the P40 subunit of IL12 and IL23→The above mechanisms are inhibited and promote the relief of inflammation
Anti-integrinVedolizumabBlocking the binding of activated α4β7 integrin to its ligand MAdCAM1 prevents T lymphocytes from migrating to the inflammatory area of the intestinal tract and selectively inhibits the intestinal inflammatory response16,40Specifically blocking α4β7 integrin binding to the gastrointestinal vascular cell adhesion molecule MAdCAM1, or targeting inflammatory factors→inhibiting the aggregation of inflammatory cells to the intestine→reducing the intestinal inflammatory response, has intestinal selectivity
Natalizumab (NTZ)Blocking integrin α4 signaling to selectively block inflammatory cell migration41
EtrolizumabSelectively targets the β7 subunit of α4β7 and αEβ7 integrins to prevent their involvement in the pathogenesis of ulcerative colitis42
OntamalimabBinds MAdCAM1 and prevents adhesion to integrins on lymphocytes, thereby reducing the migration of lymphocytes to the gut43
JAK InhibitorsTofacitinibBlocking the signaling activities of cytokines related to lymphocyte activation, proliferation, and function have potential inhibitory effects on adaptive and innate immunity25Inhibitor activation changes the activity of immune cells and reduces the immune response→blocks the signal transduction of a variety of cytokines related to inflammatory activation→reduces the inflammatory response
FigotinibIt can selectively inhibit JAK1 and inhibit IL2, IL6, interferon-γ, and other signaling pathways to play a variety of anti-inflammatory effects44
UpadacitinibIt selectively inhibits JAK145
S1P receptor modulatorsOzanimodIt has a high binding affinity to S1P receptor subtypes 1 and 5, which allows lymphocyte S1P type 1 receptor internalization and prevents lymphocyte mobilization to inflammatory sites34Targeting S1P1-S1P5 receptors→affecting extracellular activation and participating in a large number of physiological and pathophysiological processes→inhibiting the discharge of lymphocytes from lymph nodes to prevent the movement of lymphocytes to inflammatory sites
Etrasimod (APD334)Selective targeting of S1P1, S1P4, and S1P5 signaling pathways46
Mechanisms of BAs impacting immunologic balance in IBD.
Fig. 1  Mechanisms of BAs impacting immunologic balance in IBD.

IFX, infliximab; ADL, adalimumab; UST, ustekinumab; VDZ, vedolizumab; S1PR, sphingosine-1-phosphate receptor; TNF-R, tumor necrosis factor receptor; NTZ, natalizumab; TGF-β, transforming growth factor bata; TNF-α, tumor necrosis factor alpha; VCAM-1, vascular cell adhesion molecule-1; MAdCAM-1, mucosal vascular addressin cell adhesion molecule 1; JAK, janus kinase; TYK, tyrosine kinase; NF-κB, nuclear factor κB; STAT, signal transducers and activators of transcription; IL, interleukin; TRADD, tumor necrosis factor receptor-associated death domain protein; RIPK1, receptor-interacting serine/threonine-protein kinase 1; TAK1, transforming growth factor-β-activated kinase 1; TAB, TAK1-binding protein; NEMO, NF-κB essential modulator; IKK, inhibitor of NF-κB kinase.

IFX neutralizes TNF-α to limit T cell expansion, inhibit leukocyte migration, and induceapoptosis in monocytes and T lymphocytes via complement activation, antibody-dependent cell-mediated cytotoxicity, and caspase signaling pathways. ADL specifically binds to soluble human TNF-α, blocking its interaction with TNF receptors and effectively suppressing the inflammatory effects of TNF-α. Ustekinumab inhibits the common subunit p40 of IL23 and IL12, thereby interfering with Th1/Th17 differentiation and the release of inflammatory factors. Anti-integrin antibodies prevent the binding between activated integrins and adhesion molecules, preventing T lymphocytes from migrating to the regions affected by enteritis. JAK inhibitors reduce the synthesis of inflammatory cytokines downstream by blocking the JAK-STAT pathways. Ozanimod binds to S1P receptors type 1 and type 5, while Etrasimod (APD334) selectively targets S1P1, S1P4, and S1P5 signaling pathways to prevent lymphocytes from migrating to sites of inflammation.

Th17/Treg

A subpopulation of CD4+ effector T lymphocytes known as Th17 cells can exacerbate the intestinal inflammatory response while protecting the intestinal mucosa by preserving the equilibrium of the immune milieu and releasing proinflammatory cytokines like IL17, IL23, and IL21. Forkhead box P3-expressing Treg cells are essential for regulating the immune response and preserving immunological homeostasis. Treg cells that specifically express Forkhead box P3 play a crucial role in suppressing the immune response and maintaining immune homeostasis. It is important to note that Tregs are not a homogeneous population and can be further classified based on their origin and function. Nevertheless, inducible Treg cells are Tregs created in vitro from naive T lymphocytes in the presence of IL2 and transforming TGF-β. In the presence of IL6, IL23, and TGF-β, CD4+ naive T lymphocytes differentiate into Th17 cells, which are activated by phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and release a large number of proinflammatory cytokines. CD4+ naive T lymphocytes differentiate into Th17 cells in the presence of IL6, IL23, and TGF-β. Increasing evidence shows that inhibition of p-STAT3 hasananti-inflammatory effect and can reduce the proliferation of Th17 cells. Moreover,p-STAT3 inhibitors promote Treg cell proliferation to improve experimental autoimmune diseases.47

Many studies have found that the dynamic balance of Th17 and Treg cells is a key factor in many inflammatory or autoimmune diseases. The imbalance of Th17and Treg cells promotes the occurrence and development of IBD, andrestoring theTh17/Treg balance usually contributes to the treatment of IBD.48,49 Some studies have found that this imbalance may be one of the mechanisms of IBD. Other research has shown that thatrestoringthe balance of Th17/Treg through drug treatment can reduce IBD inflammation levels, providing new avenues for drug therapy in IBD.47,49,50,51–56

TNF-α antagonists

The body’s normal level of TNF-α plays a crucial role in resisting bacterial, viral, and parasitic infections, promoting tissue repair, inducing tumor cell apoptosis, and performing other vital functions. However, excessive production and release of TNF-αcan disrupt the body’s immune balance, leading to various diseases including IBD under the influence of other inflammatory factors. Anti-TNF therapy has been a crucial factor in the treatment of IBD. Previous studies have found that TL1A and its functional receptor DR3 are members of the TNF/TNFR protein superfamily. The interaction between TL1A and DR3 can impact the differentiation of Th17 cells, promote Treg cell proliferation, or inhibit their function. This, in turn, regulates the balance between Th17 and Treg cells, ultimately affecting the local immune response.57 At present, the effect of anti-TNF-α agents on Th17/Treg balance is rarely mentioned in research and efficacy evaluation, and whether it can effectively impact this balance remains to be studied.

Anti-IL12 and anti-IL23 agents

IL12 and IL23, which share a common p40 subunit, are abundantly produced in IBD and play important roles in promoting and/or maintaining proinflammatory cytokine responses in these diseases. IL12 mainly targets T cells and innate lymphoid cells, promoting Th1 cell polarization and the production of interferon-X03b3 and IL21 by activating Stat4. IL23 activates Stat3 to promote the proliferation of Th17 cells. Among the anti-IL12/23 antibodies currently used for the treatment of IBD, ustekinumab blocks the downstream Th17 effector pathway by binding to the common subunit p40 of IL12/23, thereby inhibiting Th17differentiationandthe inflammatory response, demonstrating good therapeutic effects.58–60

Anti-integrin antibodies

Integrin α4/β7 on circulating lymphocytes is thetarget of the humanized antibody vedolizumab for the treatment of IBD.Lymphocytes expressingα4/β7respond strongly to cytokines IL6, IL7, and IL21, which exert typical pro-inflammatory effects. Conversely, these lymphocytes showa weaker response toIL2, which supports Treg lymphocytes. Despite the observation that integrin α4/β7+ CD4+ T lymphocytes were rare among cells expressing the Th2 marker CRTh2, their numbers increased among cells carrying the circulating T follicular helper cell marker CXCR5.Consequently, this anti-integrin treatment may impact the mucosal immune system more qualitatively and optionally substitutes pro-inflammatory effector cells to promote mucosal immune tolerance without depleting lymphocytes in the intestinal mucosa.61

Vedolizumab completely blocks effector T lymphocyte trafficking while allowing residual homing of potent Treg lymphocytes during the optimal “therapeutic window” based on the level of exposure to the target.62 In another study, colon Th17 lymphocytes from vedolizumab non-responders interacted more with classical monocytes compared to responders, while colon Th17 lymphocytes from responders interacted more strongly with myeloid dendritic cells. The proportion of Th17 cells decreased in UC patients who responded to vedolizumab.63 These findings reflect how anti-integrin antibodies influence the regulation of both the number and proportion of Th17 and Treg cells.

JAK inhibitors

JAK inhibitors, a class of BAs currently being researched and applied for the treatment of IBD, target the JAK (Janus kinase) signaling pathway for immune-related disorders. These inhibitors provide more precise targeting and a better balance of the immune response compared to traditional immunosuppressive agents.50 By inhibiting JAK activity, JAK inhibitors block cytokine signaling, reducing inflammatory responses and immune-mediated tissue damage.49 Studies have demonstrated their effectiveness in controlling symptoms and improving patients’ quality of life when used as an immunomodulator in combination with conventional treatments (e.g., 5-aminosalicylic acid, glucocorticoids, etc.) to achieve enhanced therapeutic outcomes. However, JAK inhibitors need to be used and monitored rationally in clinical applications due to potential adverse reactions and safety concerns.51

The mechanisms of immune homeostasis of JAK inhibitors in IBD treatment are not completely understood. Some studies have shown that JAK inhibitors can inhibit T lymphocyte activity, reduce the level of inflammatory factors, and reduce the infiltration of inflammatory cells.52 In addition, JAK inhibitors can affect the functions and differentiation of immune cells to regulate the balance of immune responses.

Others

Severalother BAs are available for IBD treatment, aiming to restore immune homeostasis by modulating the immune response.64

TGF-β1 is an archetypal cytokine with anti-inflammatory effects in diverse inflammatory diseases. Abnormal regulation of TGF-β1 is considered a critical link to the pathophysiology of IBD. Upon binding to its receptor, TGF-βRI is phosphorylated and activated, contributing to the phosphorylation of downstream signaling molecules SMAD2 and SMAD3, which exertanti-inflammatory effects. However, SMAD7, a counter-regulatory member of the SMAD4 family, attenuates TGF-β1 signaling by binding to TGF-β1RI, imply ingreceptor degradation, and subsequently tackling the effects of SMAD2 and SMAD3. Consequently, the anti-inflammatory function of TGF-β1 is restrained.65

Other types of immune responses

Mucosal immune response

Defects in the integrity of the intestinal epithelial barrier are frequently observed in IBD.66 The intestinal epithelium plays an essential role in maintaining guthomeostasis, serving as a barrier between gut microorganisms and the host immune system. It is the first “gateway” to the body’s exposure to various environmental factors that can trigger disease activity.67

In intestinal epithelial cells, the TNF-α-TNFR2 signaling pathway increases the expression of myosin light chain kinase, which disrupts the assembly of tight junctions.68 Pro-inflammatory cytokines may further enhance epithelial leakage. Additionally, inflammation induces the so-called “cupping cell exhaustion”, which results in the inability to secrete normal mucins,69 and the dysregulation of IL7 cytokine secretion,whichprovokeschronic inflammation.70 Candidate risk sites for IBD, particularly the CARD15 mutation site encoding the bacterial sensing protein NOD2, have been associated with reduced alpha-defensin production (i.e., DEFA5 and DEFA6) in adult and pediatric patients with ileal CD.71,72 Therefore, defects in epithelial cell barrier function result inchronic exposure to bacterial molecules, causing the destructive intestinal inflammation characteristic of IBD.73

Humoral immunity

B-lymphocyte-mediated immune response

Humoral immunity is an asset in the development and progression of IBD. Under pathological conditions, abnormal functions of B lymphocytes may lead to changes in plasma cell numbers and activity, triggering autoimmune diseases that attack the body’s own tissues and produce an inflammatory response. Complex interaction sex is tbetween antibody formation and inflammatory mediators.74 BAs improve the condition of IBD patients by modulating the interaction between antibodies and inflammatory mediators. Antibody agents against TNF-αand IL12/23 have been developed for IBD treatment,75 but further research is needed to investigate the role of multiple immune responses.

Immune response of the complement system

The complement system consists of proteins that play a vital part in immune responses.76,77 The activated complement system participates in immune responses by directly killing microorganisms, facilitating phagocytic clearance, and eliciting an inflammatory response. When tissues are physically damaged, chemically stimulated, or infected, the body undergoes an inflammatory response, which is the body’s non-specific defense response to injurious stimuli,78 to remove the cause of the inflammation and restore the function of the damaged tissue.79

The intricate interplay between different immune response types and inflammatory mediators can be therapeutic for IBD. BAs are innovative in modulating these immune response types. By targeting specific subpopulations of immune cells, more precise regulation of immune homeostasis can be achieved.

Other immune reactions introduction

Cellular immunity

In IBD, increasing the number and/or function of Tregs can control inflammation and improve symptoms. Some therapies, such as anti-IL2 antibodies and anti-CTLA4 antibodies, have been proven to increase the number and function of Tregs, resulting in therapeutic effects on IBD.80 Other studies have explored increasing the number and function of Tregs through genetic engineering and cell therapy. For instance, one study used genetic engineering technology to introduce the IL10 gene into Tregs,81 increasing their number and function and successfully treating experimental colitis models. Additionally, another study cultured and expanded patients’ Tregs in vitro and then transfused them into the patient’s body to control inflammation and improve IBD symptoms.82

Cytokine-mediated immunity

Cytokines are proteins secreted by immune cells that play an essential regulatory role in immune responses.83 Cytokines can regulate the strength and type of immune response by acting on immune cells or other target cells, participating in the regulation of immune reactions and inflammatory processes. In IBD, the production and regulation of cytokines may be abnormal, leading to persistent and aggravated inflammation. Therefore, regulating cytokine production and activity can control inflammation and immune-mediated tissue damage, restoring immune balance.

Transforming TGF-β can inhibit the activation of immune cells and promote tissue repair. In IBD, the expression level of TGF-β may decrease, leading to persistent and aggravated inflammation. Increasing TGF-β expression or its biological activity can control inflammation and improve IBD symptoms.84 Similarly, IL10 can inhibit the activation of immune cells and the production of inflammatory mediators. In IBD, the expression level of IL10 may decrease, leading to exacerbated inflammation. Therefore, increasing IL10 expression or its biological activity can control inflammation and improve IBD symptoms.85

The immune responses mentioned in point 4 have been summarized in Table 2.86–90

Table 2

Other types of immune responses involved in IBD

Type of immune responsesMain mechanisms
Mucosal immune responseTNF-α-TNFR2→myosin light-chain kinase(MLCK)↑→disrupting tight junctions; Pro-inflammatory cytokines→Enhancement of Epithelial Barrier Disruption; Inflammation→goblet cells↓→the inability to secrete normal mucus; Dysregulation of IL7 cytokine secretion→chronic inflammation86
Humoral immune responseMain components: B cells and antibodies; B cells→antigen receptor→Identify pathogen→Differentiation into plasma cells→Producing a large amount of antibodies87
Acquired immune responseStrong expression of pro-inflammatory cytokines→Performance: CD (Th1), UC (Th2)→Th17 cells change their activity88
Other types of immune responseCellular immune responseCell-mediated immunity→Direct interaction→An immune response against pathogens88
Cytokines mediate immune responseCytokines→Immune cells/other target cell→Regulating the intensity and type of immune response→Regulating immune responses and inflammatory processes89
Immune response of complement systemActivated complement system→Directly kills microorganisms, promoting phagocyte clearance, and causing inflammatory reactions→Participating in immune response90

Conclusions and perspective

Maintaining the balance of Th1/Th2 and Th17/Treg cells are vital immunological targets for BAs in IBD. The regulation mechanisms of these targets provide important strategies for reducing the non-response rates and the risk to patients from biological agents. In addition to the studied Th1/Th2andTh17/Treg balances, we could also focus on other balance, such as macrophages/natural killer (NK) cells, partly for that BAs can adjust the balance between macrophages and NK cells. Besides, BAs such as IFX can inhibit the TNF-α receptor on the macrophage surface, and ADL can inhibit TNF-α, thereby hindering macrophage activation and proliferation. Moreover, VDZ can inhibit CD4+ and CD8+ T cells as well as NK cells, while ustekinumab can stimulate the activation and proliferation of NK cells and promote the release of IFNγ, playing an anti-inflammatory and anti-tumor role.

Collectively, we hypothesize that future research directions of BAs in IBD could include explorations of the mechanisms and regulation methods of macrophage and NK cell balance. Itis possible that gene editing technology could be applied to adjust the balance of macrophages and NK cells to better control inflammation for IBD.

Declarations

Acknowledgement

None.

Funding

This article is funded by the High-Level Personnel Program of Guangdong Provincial People’s Hospital (2021DFJH0008/KY012021458),theStarting Program fortheNational Natural Science Foundation of China at Guangdong Provincial People’s Hospital (8207034250),theNational Natural Science Foundation of China (NSFC, No. 81300370),theNatural Science Foundation of Guangdong (NSFG, No. 2018A030313161), and by a General Program (No. 2017M622650) and a Special Support Program (No. 2018T110855) from the China Postdoctoral Science Foundation (CPSF).

Conflict of interest

Dr. Shixue Dai has been an Early Career Editor of Nature Cell and Science since June 2023. The authors have no other conflicts of interest related to this publication.

Authors’ contributions

Contributed to study concept and design (XY (Xuanyan), XY (Xiaowei Yan), SX, HW and SD), acquisition of the data (XY (Xuanyan), XY (Xiaowei Yan), SX and HW), assay performance and data analysis (XY (Xuanyan), XY (Xiaowei Yan), SX and HW), drafting of the manuscript (XY (Xuanyan), XY (Xiaowei Yan), SX, HW, YG and HT), critical revision of the manuscript (XY (Xuanyan), XY (Xiaowei Yan), SX, HW, YG and HT), supervision (SD).

References

  1. Lee SH, Kwon JE, Cho ML. Immunological pathogenesis of inflammatory bowel disease. Intest Res 2018;16(1):26-42 View Article PubMed/NCBI
  2. Geremia A, Biancheri P, Allan P, Corazza GR, Di Sabatino A. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev 2014;13(1):3-10 View Article PubMed/NCBI
  3. Matia-Garcia I, Vadillo E, Pelayo R, Muñoz-Valle JF, García-Chagollán M, Loaeza-Loaeza J, et al. Th1/Th2 Balance in Young Subjects: Relationship with Cytokine Levels and Metabolic Profile. J Inflamm Res 2021;14:6587-6600 View Article PubMed/NCBI
  4. Li Q, Liu Y, Wang X, Sun M, Wang L, Wang X, et al. Regulation of Th1/Th2 and Th17/Treg by pDC/mDC imbalance in primary immune thrombocytopenia. Exp Biol Med (Maywood) 2021;246(15):1688-1697 View Article PubMed/NCBI
  5. Papadakis KA, Targan SR. Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med 2000;51:289-298 View Article
  6. Pithadia AB, Jain S. Treatment of inflammatory bowel disease (IBD). Pharmacol Rep 2011;63(3):629-642 View Article PubMed/NCBI
  7. Choi SY, Kang B. Adalimumab in Pediatric Inflammatory Bowel Disease. Front Pediatr 2022;10:852580 View Article PubMed/NCBI
  8. Verstockt B, Salas A, Sands BE, Abraham C, Leibovitzh H, Neurath MF, et al. IL-12 and IL-23 pathway inhibition in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2023;20(7):433-446 View Article PubMed/NCBI
  9. Chang JT. Pathophysiology of Inflammatory Bowel Diseases. N Engl J Med 2020;383(27):2652-2664 View Article PubMed/NCBI
  10. Verstockt B, Ferrante M, Vermeire S, Van Assche G. New treatment options for inflammatory bowel diseases. J Gastroenterol 2018;53(5):585-590 View Article PubMed/NCBI
  11. Chang JT. Pathophysiology of Inflammatory Bowel Diseases. N Engl J Med 2020;383(27):2652-2664 View Article PubMed/NCBI
  12. Zundler S, Becker E, Schulze LL, Neurath MF. Immune cell trafficking and retention in inflammatory bowel disease: mechanistic insights and therapeutic advances. Gut 2019;68(9):1688-1700 View Article PubMed/NCBI
  13. Kuwada T, Shiokawa M, Kodama Y, Ota S, Kakiuchi N, Nannya Y, et al. Identification of an Anti-Integrin αvβ6 Autoantibody in Patients With Ulcerative Colitis. Gastroenterology 2021;160(7):2383-2394.e21 View Article PubMed/NCBI
  14. Zundler S, Neurath MF. Novel Insights into the Mechanisms of Gut Homing and Antiadhesion Therapies in Inflammatory Bowel Diseases. Inflamm Bowel Dis 2017;23(4):617-627 View Article PubMed/NCBI
  15. Cai Z, Wang S, Li J. Treatment of Inflammatory Bowel Disease: A Comprehensive Review. Front Med (Lausanne) 2021;8:765474 View Article PubMed/NCBI
  16. Sandborn WJ, Baert F, Danese S, Krznarić Ž, Kobayashi T, Yao X, et al. Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of Patients With Ulcerative Colitis. Gastroenterology 2020;158(3):562-572.e12 View Article PubMed/NCBI
  17. Rosenfeld G, Parker CE, MacDonald JK, Bressler B. Etrolizumab for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2015;2015(12):CD011661 View Article PubMed/NCBI
  18. Picardo S, Panaccione R. Anti-MADCAM therapy for ulcerative colitis. Expert Opin Biol Ther 2020;20(4):437-442 View Article PubMed/NCBI
  19. Chovatiya R, Paller AS. JAK inhibitors in the treatment of atopic dermatitis. J Allergy Clin Immunol 2021;148(4):927-940 View Article PubMed/NCBI
  20. Xue C, Yao Q, Gu X, Shi Q, Yuan X, Chu Q, et al. Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer. Signal Transduct Target Ther 2023;8(1):204 View Article PubMed/NCBI
  21. Roskoski R. Janus kinase (JAK) inhibitors in the treatment of neoplastic and inflammatory disorders. Pharmacol Res 2022;183:106362 View Article PubMed/NCBI
  22. Villarino AV, Kanno Y, O’Shea JJ. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol 2017;18(4):374-384 View Article PubMed/NCBI
  23. Nielsen OH, Boye TL, Gubatan J, Chakravarti D, Jaquith JB, LaCasse EC. Selective JAK1 inhibitors for the treatment of inflammatory bowel disease. Pharmacol Ther 2023;245:108402 View Article PubMed/NCBI
  24. Hodge JA, Kawabata TT, Krishnaswami S, Clark JD, Telliez JB, Dowty ME, et al. The mechanism of action of tofacitinib - an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clin Exp Rheumatol 2016;34(2):318-328 PubMed/NCBI
  25. Harris C, Cummings JRF. JAK1 inhibition and inflammatory bowel disease. Rheumatology (Oxford) 2021;60(Supple 2):ii45-ii51 View Article PubMed/NCBI
  26. Clark JD, Flanagan ME, Telliez JB. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem 2014;57(12):5023-5038 View Article PubMed/NCBI
  27. Boland BS, Sandborn WJ, Chang JT. Update on Janus kinase antagonists in inflammatory bowel disease. Gastroenterol Clin North Am 2014;43(3):603-617 View Article PubMed/NCBI
  28. Rogler G. Efficacy of JAK inhibitors in Crohn’s Disease. J Crohns Colitis 2020;14(Supplement_2):S746-S754 View Article PubMed/NCBI
  29. Verstockt B, Vetrano S, Salas A, Nayeri S, Duijvestein M, Vande Casteele N, et al. Sphingosine 1-phosphate modulation and immune cell trafficking in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2022;19(6):351-366 View Article PubMed/NCBI
  30. Tian L, Wu Y, Choi HJ, Sui X, Li X, Sofi MH, et al. S1P/S1PR1 signaling differentially regulates the allogeneic response of CD4 and CD8 T cells by modulating mitochondrial fission. Cell Mol Immunol 2022;19(11):1235-1250 View Article PubMed/NCBI
  31. Pérez-Jeldres T, Tyler CJ, Boyer JD, Karuppuchamy T, Yarur A, Giles DA, et al. Targeting Cytokine Signaling and Lymphocyte Traffic via Small Molecules in Inflammatory Bowel Disease: JAK Inhibitors and S1PR Agonists. Front Pharmacol 2019;10:212 View Article PubMed/NCBI
  32. Roy R, Alotaibi AA, Freedman MS. Sphingosine 1-Phosphate Receptor Modulators for Multiple Sclerosis. CNS Drugs 2021;35(4):385-402 View Article PubMed/NCBI
  33. McGinley MP, Cohen JA. Sphingosine 1-phosphate receptor modulators in multiple sclerosis and other conditions. Lancet 2021;398(10306):1184-1194 View Article PubMed/NCBI
  34. Pérez-Jeldres T, Alvarez-Lobos M, Rivera-Nieves J. Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis. Drugs 2021;81(9):985-1002 View Article PubMed/NCBI
  35. Liu MZ, Liu ZH, Long XQ, Xu XP, Wu MH. New Advances in Immunotherapy for Inflammatory Bowel Disease. Modern Digest Intervention 2023;28:121-127 View Article
  36. D’Haens G, Sandborn WJ, Colombel JF, Rutgeerts P, Brown K, Barkay H, et al. A phase II study of laquinimod in Crohn’s disease. Gut 2015;64(8):1227-35 View Article PubMed/NCBI
  37. Lichtenstein L, Ron Y, Kivity S, Ben-Horin S, Israeli E, Fraser GM, et al. Infliximab-Related Infusion Reactions: Systematic Review. J Crohns Colitis 2015;9(9):806-815 View Article PubMed/NCBI
  38. Sands BE, Irving PM, Hoops T, Izanec JL, Gao LL, Gasink C, et al. Ustekinumab versus adalimumab for induction and maintenance therapy in biologic-naive patients with moderately to severely active Crohn’s disease: a multicentre, randomised, double-blind, parallel-group, phase 3b trial. Lancet 2022;399(10342):2200-2211 View Article PubMed/NCBI
  39. Sands BE, Sandborn WJ, Panaccione R, O’Brien CD, Zhang H, Johanns J, et al. Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med 2019;381(13):1201-1214 View Article PubMed/NCBI
  40. Lamb CA, O’Byrne S, Keir ME, Butcher EC. Gut-Selective Integrin-Targeted Therapies for Inflammatory Bowel Disease. J Crohns Colitis 2018;12(suppl_2):S653-S668 View Article PubMed/NCBI
  41. Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 2005;353:1912-1925 View Article PubMed/NCBI
  42. Tang MT, Keir ME, Erickson R, Stefanich EG, Fuh FK, Ramirez-Montagut T, et al. Review article: nonclinical and clinical pharmacology, pharmacokinetics and pharmacodynamics of etrolizumab, an anti-β7 integrin therapy for inflammatory bowel disease. Aliment Pharmacol Ther 2018;47(11):1440-1452 View Article PubMed/NCBI
  43. Solitano V, Parigi TL, Ragaini E, Danese S. Anti-integrin drugs in clinical trials for inflammatory bowel disease (IBD): insights into promising agents. Expert Opin Investig Drugs 2021;30:1037-1046 View Article
  44. Feagan BG, Danese S, Loftus EV, Vermeire S, Schreiber S, Ritter T, et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet 2021;397:2372-2384 View Article PubMed/NCBI
  45. Sandborn WJ, Feagan BG, Loftus EV, Peyrin-Biroulet L, Van Assche G, D'Haens G, Schreiber S, et al. Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's Disease. Gastroenterology 2020;158(8):2123-2138.e2128 View Article PubMed/NCBI
  46. Sandborn WJ, Vermeire S, Peyrin-Biroulet L, Dubinsky MC, Panes J, Yarur A, Ritter T, et al. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies. Lancet 2023;401(10383):1159-1171 View Article PubMed/NCBI
  47. Lee SY, Lee SH, Yang EJ, Kim EK, Kim JK, Shin DY, 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(9):e0135858 View Article PubMed/NCBI
  48. Yang W, Zhou G, Yu T, Chen L, Yu L, Guo Y, et al. Critical role of ROCK2 activity in facilitating mucosal CD4+ T cell activation in inflammatory bowel disease. J Autoimmun 2018;89:125-138 View Article PubMed/NCBI
  49. Yao J, Gao R, Luo M, Li D, Guo L, Yu Z, et al. Close homolog of L1-deficient ameliorates inflammatory bowel disease by regulating the balance of Th17/Treg. Gene 2020;757:144931 View Article PubMed/NCBI
  50. Geng X, Xue J. Expression of Treg/Th17 cells as well as related cytokines in patients with inflammatory bowel disease. Pak J Med Sci 2016;32(5):1164-1168 View Article PubMed/NCBI
  51. Yan JB, Luo MM, Chen ZY, He BH. The Function and Role of the Th17/Treg Cell Balance in Inflammatory Bowel Disease. J Immunol Res 2020;2020:8813558 View Article PubMed/NCBI
  52. Li Q, Shan Q, Sang X, Zhu R, Chen X, Cao G. Total Glycosides of Peony Protects Against Inflammatory Bowel Disease by Regulating IL-23/IL-17 Axis and Th17/Treg Balance. Am J Chin Med 2019;47(1):177-201 View Article PubMed/NCBI
  53. Xie F, Xiong Q, Li Y, Yao C, Wu R, Wang Q, et al. Traditional Chinese Medicine Regulates Th17/Treg Balance in Treating Inflammatory Bowel Disease. Evid Based Complement Alternat Med 2022;2022:6275136 View Article PubMed/NCBI
  54. Liu YJ, Tang B, Wang FC, Tang L, Lei YY, Luo Y, et al. Parthenolide ameliorates colon inflammation through regulating Treg/Th17 balance in a gut microbiota-dependent manner. Theranostics 2020;10(12):5225-5241 View Article PubMed/NCBI
  55. Fan Y, Fan Y, Liu K, Lonan P, Liao F, Huo Y, et al. Edible Bird’s Nest Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in C57BL/6J Mice by Restoring the Th17/Treg Cell Balance. Front Pharmacol 2021;12:632602 View Article PubMed/NCBI
  56. Szandruk-Bender M, Wiatrak B, Dzimira S, Merwid-Ląd A, Szczukowski Ł, Świątek P, et al. Targeting Lineage-Specific Transcription Factors and Cytokines of the Th17/Treg Axis by Novel 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone Attenuates TNBS-Induced Experimental Colitis. Int J Mol Sci 2022;23(17):9897 View Article PubMed/NCBI
  57. Valatas V, Kolios G, Bamias G. TL1A (TNFSF15) and DR3 (TNFRSF25): A Co-stimulatory System of Cytokines With Diverse Functions in Gut Mucosal Immunity. Front Immunol 2019;10:583 View Article PubMed/NCBI
  58. Tillack C, Ehmann LM, Friedrich M, Laubender RP, Papay P, Vogelsang H, et al. Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-γ-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment. Gut 2014;63(4):567-577 View Article PubMed/NCBI
  59. Imamura E, Taguchi K, Sasaki-Iwaoka H, Kubo S, Furukawa S, Morokata T. Anti-IL-23 receptor monoclonal antibody prevents CD4+ T cell-mediated colitis in association with decreased systemic Th1 and Th17 responses. Eur J Pharmacol 2018;824:163-169 View Article PubMed/NCBI
  60. Abraham C, Dulai PS, Vermeire S, Sandborn WJ. Lessons Learned From Trials Targeting Cytokine Pathways inPatients With Inflammatory Bowel Diseases. Gastroenterology 2017;152(2):374-388.e4 View Article PubMed/NCBI
  61. Lord JD, Long SA, Shows DM, Thorpe J, Schwedhelm K, Chen J, et al. Circulating integrin alpha4/beta7+ lymphocytes targeted by vedolizumab have a pro-inflammatory phenotype. Clin Immunol 2018;193:24-32 View Article PubMed/NCBI
  62. Becker E, Dedden M, Gall C, Wiendl M, Ekici AB, Schulz-Kuhnt A, et al. Residual homing of α4β7-expressing β1+PI16+ regulatory T cells with potent suppressive activity correlates with exposure-efficacy of vedolizumab. Gut 2022;71(8):1551-1566 View Article PubMed/NCBI
  63. Hsu P, Choi EJ, Patel SA, Wong WH, Olvera JG, Yao P, et al. Responsiveness to Vedolizumab Therapy in Ulcerative Colitis is Associated With Alterations in Immune Cell-Cell Communications. Inflamm Bowel Dis 2023;29(10):1602-1612 View Article PubMed/NCBI
  64. Kwon Y, Kim YZ, Choe YH, Kim MJ. Increased monocyte abundance as a marker for relapse after discontinuation of biologics in inflammatory bowel disease with deep remission. Front Immunol 2022;13:996875 View Article PubMed/NCBI
  65. Laudisi F, Dinallo V, Di Fusco D, Monteleone G. Smad7 and its Potential as Therapeutic Target in Inflammatory Bowel Diseases. Curr Drug Metab 2016;17(3):303-306 View Article PubMed/NCBI
  66. Hou Q, Huang J, Ayansola H, Masatoshi H, Zhang B. Intestinal Stem Cells and Immune Cell Relationships: Potential Therapeutic Targets for Inflammatory Bowel Diseases. Front Immunol 2020;11:623691 View Article PubMed/NCBI
  67. McCole DF. IBD candidate genes and intestinal barrier regulation. Inflamm Bowel Dis 2014;20(10):1829-1849 View Article PubMed/NCBI
  68. Suzuki M, Nagaishi T, Yamazaki M, Onizawa M, Watabe T, Sakamaki Y, et al. Myosin light chain kinase expression induced via tumor necrosis factor receptor 2 signaling in the epithelial cells regulates the development of colitis-associated carcinogenesis. PLoS One 2014;9(2):e88369 View Article PubMed/NCBI
  69. Surawicz CM, Haggitt RC, Husseman M, McFarland LV. Mucosal biopsy diagnosis of colitis: acute self-limited colitis and idiopathic inflammatory bowel disease. Gastroenterology 1994;107(3):755-763 View Article PubMed/NCBI
  70. Oshima S, Nakamura T, Namiki S, Okada E, Tsuchiya K, Okamoto R, et al. Interferon regulatory factor 1 (IRF-1) and IRF-2 distinctively up-regulate gene expression and production of interleukin-7 in human intestinal epithelial cells. Mol Cell Biol 2004;24(14):6298-6310 View Article PubMed/NCBI
  71. Jäger S, Stange EF, Wehkamp J. Inflammatory bowel disease: an impaired barrier disease. Langenbecks Arch Surg 2013;398(1):1-12 View Article PubMed/NCBI
  72. Wehkamp J, Harder J, Weichenthal M, Schwab M, Schäffeler E, Schlee M, et al. NOD2 (CARD15) mutations in Crohn’s disease are associated with diminished mucosal alpha-defensin expression. Gut 2004;53(11):1658-1664 View Article PubMed/NCBI
  73. Elson CO, Cong Y. Host-microbiota interactions in inflammatory bowel disease. Gut Microbes 2012;3(4):332-344 View Article PubMed/NCBI
  74. Li S, Young KH, Medeiros LJ. Diffuse large B-cell lymphoma. Pathology 2018;50(1):74-87 View Article PubMed/NCBI
  75. Doherty J, Morain NO, Stack R, Girod P, Tosetto M, Inzitiari R, et al. Reduced Serological Response to COVID-19 Vaccines in Patients with IBD is Further Diminished by TNF Inhibitor Therapy; Early Results of the VARIATION study [VAriability in Response in IBD Against SARS-COV-2 ImmunisatiON]. J Crohns Colitis 2022;16(9):1354-1362 View Article PubMed/NCBI
  76. Li Y, Maimaiti M, Yang B, Lu Z, Zheng Q, Lin Y, et al. Comprehensive analysis of subtypes and risk model based on complement system associated genes in ccRCC. Cell Signal 2023;111:110888 View Article PubMed/NCBI
  77. Bourgonje AR, Vogl T, Segal E, Weersma RK. Antibody signatures in inflammatory bowel disease: current developments and future applications. Trends Mol Med 2022;28(8):693-705 View Article PubMed/NCBI
  78. di Flora DC, Dionizio A, Pereira HABS, Garbieri TF, Grizzo LT, Dionisio TJ, et al. Analysis of Plasma Proteins Involved in Inflammation, Immune Response/Complement System, and Blood Coagulation upon Admission of COVID-19 Patients to Hospital May Help to Predict the Prognosis of the Disease. Cells 2023;12(12):1601 View Article PubMed/NCBI
  79. Defendenti C, Atzeni F, Malandrin S, Ardizzone S, Almasio PL, Saibeni S, et al. Anti-tumour necrosis factor-α antibodies and B cell homeostasis in human inflammatory bowel diseases. Int Immunopharmacol 2018;54:329-335 View Article PubMed/NCBI
  80. Lee JY, Lee E, Hong SW, Kim D, Eunju O, Sprent J, et al. TCB2, a new anti-human interleukin-2 antibody, facilitates heterodimeric IL-2 receptor signaling and improves anti-tumor immunity. Oncoimmunology 2019;9(1):1681869 View Article PubMed/NCBI
  81. Shiri AM, Zhang T, Bedke T, Zazara DE, Zhao L, Lücke J, et al. IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction. J Hepatol 2024;80(4):634-644 View Article PubMed/NCBI
  82. Cook L, Reid KT, Häkkinen E, de Bie B, Tanaka S, Smyth DJ, et al. Induction of stable human FOXP3+ Tregs by a parasite-derived TGF-β mimic. Immunol Cell Biol 2021;99(8):833-847 View Article PubMed/NCBI
  83. Friedrich M, Pohin M, Powrie F. Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. Immunity 2019;50(4):992-1006 View Article PubMed/NCBI
  84. Ihara S, Hirata Y, Koike K. TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota. J Gastroenterol 2017;52(7):777-787 View Article PubMed/NCBI
  85. Neumann C, Scheffold A, Rutz S. Functions and regulation of T cell-derived interleukin-10. Semin Immunol 2019;44:101344 View Article PubMed/NCBI
  86. Wang H, Dong J, Shi P, Liu J, Zuo L, Li Y, et al. Anti-mouse CD52 monoclonal antibody ameliorates intestinal epithelial barrier function in interleukin-10 knockout mice with spontaneous chronic colitis. Immunology 2015;144(2):254-262 View Article PubMed/NCBI
  87. Inoue T, Kurosaki T. Memory B cells. Nat Rev Immunol 2024;24(1):5-17 View Article PubMed/NCBI
  88. Tatiya-Aphiradee N, Chatuphonprasert W, Jarukamjorn K. Immune response and inflammatory pathway of ulcerative colitis. J Basic Clin Physiol Pharmacol 2018;30(1):1-10 View Article PubMed/NCBI
  89. Saraiva M, Vieira P, O’Garra A. Biology and therapeutic potential of interleukin-10. J Exp Med 2020;217(1):e20190418 View Article PubMed/NCBI
  90. Pouw RB, Ricklin D. Tipping the balance: intricate roles of the complement system in disease and therapy. Semin Immunopathol 2021;43(6):757-771 View Article PubMed/NCBI
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Targets for the Immune Balance of Biologics in Inflammatory Bowel Disease

Xuan Yan, Sizhe Xie, Xiaowei Yan, He Wang, Yinyin Guo, Hebin Tan, Shixue Dai
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