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Special Issue "Dissecting Mechanisms of Action of Biologics in Inflammatory Bowel Diseases"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 July 2017).

Special Issue Editors

Guest Editor
Prof. Dr. Silvio Danese Website E-Mail
Humanitas University, Milan, Italy
Interests: Inflammatory bowel disease; inflammation; gut vascular barrier; immune response; leukocyte trafficking; lipid mediators; colorectal cancer
Guest Editor
Prof. Laurent Peyrin-biroulet E-Mail
Institut National de la Santé et de la Recherche Médicale U954 and Department of Gastroenterology, Nancy University Hospital, Lorraine University, France.
Interests: Crohn’s disease; ulcerative colitis; intestinal fibrosis; mucosal healing; autophagy
Guest Editor
Dr. Clelia Cicerone Website E-Mail
Gastroenterology Unit, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
Interests: inflammatory bowel disease

Special Issue Information

Dear Colleagues,

In the last years, new and different biological agents that target specific immunological pathways have been investigated and approved.

Strategies targeting the recruitment, adhesion and interaction of leukocytes from circulation in the gastrointestinal tract were developed, as the integrin antagonists (vedolizumab, natalizumab, etrolizumab, alicaforsen and abrilumab). Another approach is represented by agents blocking pro-inflammatory cytokines, such as ustekinumab or briakinumab, MAb targeting IL-12/IL-23 or by IL-23 selective inhibitor. Interesting results are coming from the anti-IL6 antibody in subjects with Crohn’s disease, and probably will become an antagonist of gut-specific chemokine and a selective inhibitor of matrix metalloproteinase 9 (GS-5745).

In addition to the biological agents, we observe the development of small molecules, such as mongersen (Smad7 antisense oligonucleotide) or apremilast (phosphodiesterase 4 inhibitor). Other biological targets are the tyrosine kinases inhibitors (tofacitinib or filgotinib) which play a pivotal role in cytokine receptor signaling and the sphingosine-1-phosphate receptors’ agonist (Ozanimod) which controls lymphocyte migration.

The establishment of new goals in the management of IBD and the continuation in the understanding of the pathogenetic mechanisms of IBD have allowed the development of new biological drugs and small molecules. We expect promising results and new scenarios through the study of on-going, and future, trials. Thus, with this Special Issue, we are particularly interested in articles that describe the mechanism and the specific targets of these new biological agents and their clinical applications.

Prof. Silvio Danese
Prof. Laurent Peyrin-Biroulet
Dr. Clelia Cicerone
Guest Editors

Manuscript Submission Information

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Keywords

  • Inflammatory bowel disease
  • Target therapy
  • Biologic agents
  • Small molecules
  • Adhesion antagonists
  • Anti-TNF
  • Inflammatory cytokines
  • Lymphocyte control

Published Papers (8 papers)

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Research

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Open AccessArticle
Systemic Chemokine Levels with “Gut-Specific” Vedolizumab in Patients with Inflammatory Bowel Disease—A Pilot Study
Int. J. Mol. Sci. 2017, 18(8), 1827; https://doi.org/10.3390/ijms18081827 - 22 Aug 2017
Abstract
Vedolizumab, a gut-specific biological treatment for inflammatory bowel disease (IBD), is an antibody that binds to the α4β7 integrin and blocks T-cell migration into intestinal mucosa. We aimed to investigate chemokine levels in serum of IBD-patients treated with vedolizumab. In [...] Read more.
Vedolizumab, a gut-specific biological treatment for inflammatory bowel disease (IBD), is an antibody that binds to the α4β7 integrin and blocks T-cell migration into intestinal mucosa. We aimed to investigate chemokine levels in serum of IBD-patients treated with vedolizumab. In this pilot study, we included 11 IBD patients (8 Crohn’s disease, 3 ulcerative colitis) previously non-respondent to anti-tumor necrosis factor (TNF)-agents. Patients received vedolizumab at week 0, 2 and 6 and were evaluated for clinical efficacy at week 10. Clinical characteristics and routine laboratory parameters were obtained and patients were classified as responders or non-responders. Expression of 21 chemokines in serum was measured using Proximity Extension Assay and related to clinical outcome. At week 10, 6 out of 11 patients had clinically responded. Overall expression of CCL13 increased after treatment. In non-responders, expression of CCL13 and CXCL8 increased after treatment, and CCL20 and CXCL1 expressions were higher compared to responders. In responders, CCL28 decreased after treatment. C-reactive protein (CRP) correlated negatively with 6 chemokines before therapy, but not after therapy. Systemic CCL13 expression increases in IBD-patients after vedolizumab therapy and several chemokine levels differ between responders and non-responders. An increased CCL13-level when starting vedolizumab treatment, might indicate potential prognostic value of measuring chemokine levels when starting therapy with vedolizumab. This study provides new information on modulation of systemic chemokine levels after vedolizumab treatment. Full article
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Open AccessArticle
Stability Profiles and Therapeutic Effect of Cu/Zn Superoxide Dismutase Chemically Coupled to O-Quaternary Chitosan Derivatives against Dextran Sodium Sulfate-Induced Colitis
Int. J. Mol. Sci. 2017, 18(6), 1121; https://doi.org/10.3390/ijms18061121 - 24 May 2017
Cited by 2
Abstract
Superoxide dismutase (SOD) has attracted considerable attention on treatment of reactive oxygen species (ROS)-related disorders. We previously conjugated Cu/Zn SOD to O-quaternary chitosan derivatives (O-HTCC) to yield a polymer–enzyme conjugate O-HTCC-SOD that demonstrated superior therapeutic effect to native SOD. [...] Read more.
Superoxide dismutase (SOD) has attracted considerable attention on treatment of reactive oxygen species (ROS)-related disorders. We previously conjugated Cu/Zn SOD to O-quaternary chitosan derivatives (O-HTCC) to yield a polymer–enzyme conjugate O-HTCC-SOD that demonstrated superior therapeutic effect to native SOD. The present study demonstrated that O-HTCC-SOD had wider pH activity range, better thermal stability, excellent long-term stability for storage, as well as unique reinstatement of activity exposure to proteolytic degradation that was helpful for longer half-life in vivo. O-HTCC-SOD exerted significant anti-inflammatory effects on lipopolysaccharides (LPS)-stimulated mouse peritoneal macrophages by down-regulating production of pro-inflammatory cytokines and intracellular ROS. O-HTCC-SOD significantly attenuated dextran sodium (DSS)-induced colitis in mice as observed by the colitis severity, neutrophil infiltration and histopathological damage, whereas native SOD failed to do so. In conclusion, conjugation of O-HTCC conferred SOD with better stability and enhanced therapeutic potential, offering a promising option in treatment of inflammatory bowel disease. Full article
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Open AccessArticle
Serum-Infliximab Trough Levels in 45 Children with Inflammatory Bowel Disease on  Maintenance Treatment
Int. J. Mol. Sci. 2017, 18(3), 575; https://doi.org/10.3390/ijms18030575 - 07 Mar 2017
Cited by 8
Abstract
The role of trough serum infliximab (s-IFX) and antibodies toward IFX (ATI) during maintenance treatment remains unclear in children. The aim of the present study was to investigate trough s-IFX and ATI to identify any correlation with inflammatory activity and clinical response in [...] Read more.
The role of trough serum infliximab (s-IFX) and antibodies toward IFX (ATI) during maintenance treatment remains unclear in children. The aim of the present study was to investigate trough s-IFX and ATI to identify any correlation with inflammatory activity and clinical response in a pediatric inflammatory bowel disease (IBD) cohort. We investigated the s-IFX trough levels in pediatric IBD patients (n = 45) on maintenance IFX treatment. Ninety-three blood samples were collected and demographics, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and albumin were recorded. The mean s-IFX trough level was 5.2 µg/mL. The mean trough s-IFX level was significantly higher in the samples taken during remission (7.2 µg/mL) compared to active disease (4.5 µg/mL, p < 0.05). The trough s-IFX levels correlated with ESR, CRP, and albumin. S-IFX was undetectable in eight of the patients, all with positive ATI and active disease. Surprisingly, clinical and biochemical remission was observed at only 26 of the 93 visits. The correlation between dose variations and changes in trough s-IFX was not evident. In line with studies in adults, the s-IFX trough levels correlated with response to infliximab. Full article
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Open AccessArticle
Molecular Basis for the Neutralization of Tumor Necrosis Factor α by Certolizumab Pegol in the Treatment of Inflammatory Autoimmune Diseases
Int. J. Mol. Sci. 2017, 18(1), 228; https://doi.org/10.3390/ijms18010228 - 23 Jan 2017
Cited by 8
Abstract
Monoclonal antibodies against TNFα, including infliximab, adalimumab, golimumab, and certolizumab pegol, are widely used for the treatment of the inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Recently, the crystal structures of TNFα, in complex with the Fab fragments of infliximab [...] Read more.
Monoclonal antibodies against TNFα, including infliximab, adalimumab, golimumab, and certolizumab pegol, are widely used for the treatment of the inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Recently, the crystal structures of TNFα, in complex with the Fab fragments of infliximab and adalimumab, have revealed the molecular mechanisms of these antibody drugs. Here, we report the crystal structure of TNFα in complex with the Fab fragment of certolizumab pegol to clarify the precise antigen-antibody interactions and the structural basis for the neutralization of TNFα by this therapeutic antibody. The structural analysis and the mutagenesis study revealed that the epitope is limited to a single protomer of the TNFα trimer. Additionally, the DE loop and the GH loop of TNFα play critical roles in the interaction with certolizumab, suggesting that this drug exerts its effects by partially occupying the receptor binding site of TNFα. In addition, a conformational change of the DE loop was induced by certolizumab binding, thereby interrupting the TNFα-receptor interaction. A comprehensive comparison of the interactions of TNFα blockers with TNFα revealed the epitope diversity on the surface of TNFα, providing a better understanding of the molecular mechanism of TNFα blockers. The accumulation of these structural studies can provide a basis for the improvement of therapeutic antibodies against TNFα. Full article
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Review

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Open AccessReview
The Innate and Adaptive Immune System as Targets for Biologic Therapies in Inflammatory Bowel Disease
Int. J. Mol. Sci. 2017, 18(10), 2020; https://doi.org/10.3390/ijms18102020 - 21 Sep 2017
Cited by 9
Abstract
Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition causing inflammation of gastrointestinal and systemic cells, with an increasing prevalence worldwide. Many factors are known to trigger and maintain inflammation in IBD including the innate and adaptive immune systems, genetics, the gastrointestinal microbiome [...] Read more.
Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition causing inflammation of gastrointestinal and systemic cells, with an increasing prevalence worldwide. Many factors are known to trigger and maintain inflammation in IBD including the innate and adaptive immune systems, genetics, the gastrointestinal microbiome and several environmental factors. Our knowledge of the involvement of the immune system in the pathophysiology of IBD has advanced rapidly over the last two decades, leading to the development of several immune-targeted treatments with a biological source, known as biologic agents. The initial focus of these agents was directed against the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) leading to dramatic changes in the disease course for a proportion of patients with IBD. However, more recently, it has been shown that a significant proportion of patients do not respond to anti-TNF-α directed therapies, leading a shift to other inflammatory pathways and targets, including those of both the innate and adaptive immune systems, and targets linking both systems including anti-leukocyte trafficking agents-integrins and adhesion molecules. This review briefly describes the molecular basis of immune based gastrointestinal inflammation in IBD, and then describes how several current and future biologic agents work to manipulate these pathways, and their clinical success to date. Full article
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Open AccessReview
Anti-NKG2D mAb: A New Treatment for Crohn’s Disease?
Int. J. Mol. Sci. 2017, 18(9), 1997; https://doi.org/10.3390/ijms18091997 - 16 Sep 2017
Cited by 2
Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) are immunologically-mediated, debilitating conditions resulting from destructive inflammation of the gastrointestinal tract. The pathogenesis of IBD is incompletely understood, but is considered to be the result of an abnormal immune response with a wide range of [...] Read more.
Crohn’s disease (CD) and ulcerative colitis (UC) are immunologically-mediated, debilitating conditions resulting from destructive inflammation of the gastrointestinal tract. The pathogenesis of IBD is incompletely understood, but is considered to be the result of an abnormal immune response with a wide range of cell types and proteins involved. Natural Killer Group 2D (NKG2D) is an activating receptor constitutively expressed on human Natural Killer (NK), γδ T, mucosal-associated invariant T (MAIT), CD56+ T, and CD8+ T cells. Activation of NKG2D triggers cellular proliferation, cytokine production, and target cell killing. Research into the NKG2D mechanism of action has primarily been focused on cancer and viral infections where cytotoxicity evasion is a concern. In human inflammatory bowel disease (IBD) this system is less characterized, but the ligands have been shown to be highly expressed during intestinal inflammation and the following receptor activation may contribute to tissue degeneration. A recent phase II clinical trial showed that an antibody against NKG2D induced clinical remission of CD in some patients, suggesting NKG2D and its ligands to be of importance in the pathogenesis of CD. This review will describe the receptor and its ligands in intestinal tissues and the clinical potential of blocking NKG2D in Crohn’s disease. Full article
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Open AccessReview
Can We Predict the Efficacy of Anti-TNF-α Agents?
Int. J. Mol. Sci. 2017, 18(9), 1973; https://doi.org/10.3390/ijms18091973 - 14 Sep 2017
Cited by 13
Abstract
The use of biologic agents, particularly anti-tumor necrosis factor (TNF)-α, has revolutionized the treatment of inflammatory bowel diseases (IBD), modifying their natural history. Several data on the efficacy of these agents in inducing and maintaining clinical remission have been accumulated over the past [...] Read more.
The use of biologic agents, particularly anti-tumor necrosis factor (TNF)-α, has revolutionized the treatment of inflammatory bowel diseases (IBD), modifying their natural history. Several data on the efficacy of these agents in inducing and maintaining clinical remission have been accumulated over the past two decades: their use avoid the need for steroids therapy, promote mucosal healing, reduce hospitalizations and surgeries and therefore dramatically improve the quality of life of IBD patients. However, primary non-response to these agents or loss of response over time mainly due to immunogenicity or treatment-related side-effects are a frequent concern in IBD patients. Thus, the identification of predicting factors of efficacy is crucial to allow clinicians to efficiently use these therapies, avoiding them when they are ineffective and eventually shifting towards alternative biological therapies with the end goal of optimizing the cost-effectiveness ratio. In this review, we aim to identify the predictive factors of short- and long-term benefits of anti-TNF-α therapy in IBD patients. In particular, multiple patient-, disease- and treatment-related factors have been evaluated. Full article
Open AccessReview
PDE4 Inhibition and Inflammatory Bowel Disease: A Novel Therapeutic Avenue
Int. J. Mol. Sci. 2017, 18(6), 1276; https://doi.org/10.3390/ijms18061276 - 15 Jun 2017
Cited by 11
Abstract
Background. In the last few decades, a better knowledge of the inflammatory pathways involved in the pathogenesis of Inflammatory Bowel Disease (IBD) has promoted biological therapy as an important tool to treat IBD patients. However, in spite of a wider spectrum of biological [...] Read more.
Background. In the last few decades, a better knowledge of the inflammatory pathways involved in the pathogenesis of Inflammatory Bowel Disease (IBD) has promoted biological therapy as an important tool to treat IBD patients. However, in spite of a wider spectrum of biological drugs, a significant proportion of patients is unaffected by or lose their response to these compounds, along with increased risks of infections and malignancies. For these reasons there is an urgent need to look for new pharmacological targets. The novel Phosphodiesterase 4 (PDE4) inhibitors have been recently introduced as new modulators of intracellular signals and gene transcription for the treatment of IBD. Aim. To discuss and describe the state of the art of this new class of compounds in the IBD field, with particular attention to apremilast. Methods. Published articles selected from PubMed were comprehensively reviewed, with key words including apremilast, inflammatory disease, IBD, psoriasis, psoriatic arthritis, pathogenesis, therapies, and treatment. Results. PDE4 inhibitors generate elevated intracellular levels of cyclic Adenosine Monophosphate (cAMP), that consequently down-regulate the release of pro-inflammatory cytokines in the mucosa of IBD patients. The newly developed apremilast is one of these drugs and has already been approved for the treatment of dermatologic/rheumatologic inflammatory conditions; studies in psoriasis and psoriatic arthritis have in fact demonstrated its clinical activity. However, no clinical trials have yet been published on the use of apremilast in IBD. Conclusion. In light of the similarity of pro-inflammatory signaling pathways across the gut, the skin, and joints, apremilast is likely supposed to show its efficacy also in IBD. Full article
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