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Kaur P, Karuppuchamy T, Chilukuri A, Kim M, Urrete J, Shen Z, Saxon L, Lundborg LR, Mikulski Z, Jedlicka P, Rivera-Nieves J. S1P Lyase Inhibition Increased Intestinal S1P, Disrupted the Intestinal Barrier and Aggravated DSS-Induced Colitis. Inflamm Bowel Dis 2025:izaf030. [PMID: 39960746 DOI: 10.1093/ibd/izaf030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Indexed: 04/02/2025]
Abstract
BACKGROUND Sphingosine-1-phospate (S1P) receptor agonists (eg, ozanimod) desensitize migrating lymphocytes by irreversibly binding to S1P receptors (S1PR) and triggering their proteasomal degradation. Desensitized lymphocytes cannot sense S1P, therefore, halting lymphocyte recirculation. The S1P lyase (SPL) irreversibly degrades S1P and its inhibition disrupts the S1P gradient. We previously found that systemic SPL inhibitors induce central immunosuppression. Here, we examined whether SPL inhibition may attenuate colitis without systemic immunotoxicity. METHODS We first analyzed SPL expression and localization in mice using qRT-PCR and immunohistochemistry. SPL inhibitors 4-deoxypyridoxine hydrochloride (DOP) and 2-acetyl-4-(tetrahydroxybutyl) imidazole (THI) were used to inhibit SPL systemically, whereas a conditional intestinal epithelial cell (IEC)-specific SPL-deficient mouse was used to evaluate the effects of IEC-specific SPL inhibition on survival, disease activity, histological severity of dextran sulfate sodium-induced colitis, S1P levels, and intestinal permeability. RESULTS Sgpl1 mRNA transcripts and protein were ubiquitously expressed in gastrointestinal (GI) tract leukocytes and IEC. Systemic SPL inhibitors did not induce colitis by themselves but depleted CD4+ and CD8+ T cells from blood. However, contrary to its therapeutic effects on ileitis, systemic inhibition reduced survival, accelerated weight loss, worsened histopathological inflammation indices, and tissue damage. We then examined the effects of IEC-specific inhibition on peripheral cell counts and severity of colitis. We found that while it spared peripheral immunity, it similarly hastened colitis. Finally, we examined whether colitis acceleration was due to epithelial barrier compromise after disruption of the S1P gradient. We found that not only systemic but also IEC-specific SPL inhibition increased local S1P levels and led to IEC barrier compromise. CONCLUSION Homeostatic intestinal S1P levels are critical for the regulation of IEC barrier function. Further studies using adaptive immunity-based inflammatory bowel diseases (IBD) models are required to assess the translational value of IEC-specific SPL inhibition as a therapeutic target for human IBD.
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Affiliation(s)
- Prabhdeep Kaur
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
| | - Thangaraj Karuppuchamy
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA 92161, USA
| | - Amruth Chilukuri
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
| | - Margaret Kim
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA 92161, USA
| | - Josef Urrete
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
| | - Zining Shen
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
| | - Leo Saxon
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA 92161, USA
| | - Luke R Lundborg
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA 92161, USA
| | - Zbigniew Mikulski
- Histology and Microscopy Core, La Jolla Institute for Immunology, La Jolla, CA, USA
| | - Paul Jedlicka
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Jesús Rivera-Nieves
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA 92161, USA
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Vieujean S, Jairath V, Peyrin-Biroulet L, Dubinsky M, Iacucci M, Magro F, Danese S. Understanding the therapeutic toolkit for inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2025:10.1038/s41575-024-01035-7. [PMID: 39891014 DOI: 10.1038/s41575-024-01035-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/19/2024] [Indexed: 02/03/2025]
Abstract
Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is a group of chronic, immune-mediated disorders of the gastrointestinal tract that present substantial clinical challenges owing to their complex pathophysiology and tendency to relapse. A treat-to-target approach is recommended, involving iterative treatment adjustments to achieve clinical response, reduce inflammatory markers and achieve long-term goals such as mucosal healing. Lifelong medication is often necessary to manage the disease, maintain remission and prevent complications. The therapeutic landscape for IBD has evolved substantially; however, a ceiling on therapeutic efficacy remains and surgery is sometimes required (owing to uncontrolled disease activity or complications). Effective IBD management involves comprehensive care, including medication adherence and a collaborative clinician-patient relationship. This Review discusses current therapeutic options for IBD, detailing mechanisms of action, efficacy, safety profiles and guidelines for use of each drug class. We also explore emerging therapies and the role of surgery. Additionally, the importance of a multidisciplinary team and personalized care in managing IBD is emphasized, advocating for patient empowerment and involvement in treatment decisions. By synthesizing current knowledge and emerging trends, this Review aims to equip healthcare professionals with a thorough understanding of therapeutic options for IBD, enhancing informed, evidence-based decisions in clinical practice.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
- Department of Gastroenterology, INFINY Institute, CHRU Nancy, Vandœuvre-lès-Nancy, France
| | - Vipul Jairath
- Division of Gastroenterology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, INFINY Institute, CHRU Nancy, Vandœuvre-lès-Nancy, France
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Marla Dubinsky
- Department of Paediatrics, Susan and Leonard Feinstein IBD Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Marietta Iacucci
- APC Microbiome Ireland, College of Medicine and Health, University College of Cork, Cork, Ireland
| | - Fernando Magro
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milano, Italy.
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Chilukuri A, Kim M, Mitra T, Gubatan JM, Urrete J, Saxon LD, Ablack A, Mikulski Z, Dobaczewska K, Shen Z, Keir M, Yi T, Kaur P, Oliveira P, Murillo-Saich J, Chang EY, Steiner CA, Jedlicka P, Guma M, Rivera-Nieves J. A Similar Mutation in the AAUU-Rich Elements of the Mouse TNF Gene Results in a Distinct Ileocolitic Phenotype: A New Strain of TNF-Overexpressing Mice. Inflamm Bowel Dis 2025:izae307. [PMID: 39756463 DOI: 10.1093/ibd/izae307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Indexed: 01/07/2025]
Abstract
BACKGROUND Tumor necrosis factor (TNF) is a pleiotropic cytokine that plays a critical role in the pathogenesis of immune-mediated diseases including inflammatory bowel disease (IBD). The stability of its mRNA transcript, determined in part by destabilizing sequences in its AAUU repeats (ARE) gene region, is an important regulator of its tissue and systemic levels. A deletion in the ARE region of the gene resulted in IBD and arthritis in mice and pigs, supporting a critical role for the cytokine in human IBD and several human arthritides. A mutation in the same area of the mouse genome by Genentech scientists (T.Y., M.K.) resulted in a similar but not identical phenotype. METHODS Here, we compare histopathological, cellular, and molecular features of the strains and propose reasons for their distinct phenotypes. First, while homozygous TNFΔARE mice develop severe arthritis and die after weaning, homozygous Genentech TNFΔARE (ΔG/ΔG) mice have normal lifespans, and males are often fertile. RESULTS We found that while the ileitic phenotype had peaked at 12 weeks of age in all mice, colitis progressed mostly after 20 weeks of age in heterozygous mice. Their variably penetrant arthritic phenotype progressed mostly after 20 weeks, also in heterozygous mice from both strains. There was expansion of central memory T and B cells in lymphoid organs of TNF-overproducing strains and their transcriptional profile shared well-known pathogenetic pathways with human IBD. Finally, we found differences in the mutated sequences within the ARE regions of the TNF gene and in their microbiota composition and genetic background. These differences likely explain their phenotypic differences. CONCLUSIONS In summary, we describe a different strain of TNF-overproducing mice with an overlapping, yet not identical phenotype, which may have differential applications than the original strain.
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Affiliation(s)
- Amruth Chilukuri
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - Margaret Kim
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA, USA
| | - Taniya Mitra
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA, USA
| | - John M Gubatan
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Josef Urrete
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - Leo D Saxon
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA, USA
| | - Amber Ablack
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - Zbigniew Mikulski
- Microscopy and Histology Core, La Jolla Institute of Allergy and Immunology, La Jolla, CA, USA
| | - Katarzyna Dobaczewska
- Microscopy and Histology Core, La Jolla Institute of Allergy and Immunology, La Jolla, CA, USA
| | - Zining Shen
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - Mary Keir
- Genentech Pharmaceuticals, South San Francisco, CA, USA
| | - Tangsheng Yi
- Genentech Pharmaceuticals, South San Francisco, CA, USA
| | - Prabhdeep Kaur
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA, USA
| | - Patricia Oliveira
- Rheumatology Division, University of California San Diego, La Jolla, CA, USA
| | | | - Eric Y Chang
- Radiology Department, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA, USA
| | - Calen A Steiner
- Division of Gastroenterology, University of Colorado, Denver, CO, USA
| | - Paul Jedlicka
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Mónica Guma
- Rheumatology Division, University of California San Diego, La Jolla, CA, USA
| | - Jesús Rivera-Nieves
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA, USA
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Kitsou K, Kokkotis G, Rivera-Nieves J, Bamias G. Targeting the Sphingosine-1-Phosphate Pathway: New Opportunities in Inflammatory Bowel Disease Management. Drugs 2024; 84:1179-1197. [PMID: 39322927 DOI: 10.1007/s40265-024-02094-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2024] [Indexed: 09/27/2024]
Abstract
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC) are chronic immune-mediated diseases which primarily target the intestines. In recent years, the development and regulatory approval of various immunotherapies, both biological agents and small molecules, that target specific pathways of the IBD-associated inflammatory cascade have revolutionized the treatment of IBD. Small molecules offer the advantages of oral administration and short wash-out times. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of ceramide, which exerts its functions after binding to five G-protein-coupled receptors (S1PR1-S1PR5). Concerning IBD, S1P participates in the egress of lymphocytes from the secondary lymphoid tissue and their re-circulation to sites of inflammation, mainly through S1PR1 binding. In addition, this system facilitates the differentiation of T-helper cells towards proinflammatory immunophenotypes. Recently, S1P modulators have offered a valuable addition to the IBD treatment armamentarium. They exert their anti-inflammatory function via sequestration of T cell subsets in the lymphoid tissues and prevention of gut homing. In this review, we revisit the role of the S1P/S1PR axis in the pathogenesis of IBD and discuss efficacy and safety data from clinical trials and real-world reports on the two S1PR modulators, ozanimod and etrasimod, that are currently approved for IBD treatment, and comment on their potential positioning in the IBD day-to-day management. We also present recent data on emerging S1P modulators. Finally, based on the successes and failures of S1PR modulators in IBD, we discuss future avenues of IBD treatments targeting the S1P/S1PR axis.
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Affiliation(s)
| | - Georgios Kokkotis
- GI-Unit, 3rd Department of Internal Medicine, Sotiria Hospital, 152 Mesogeion Av., 11528, Athens, Greece
| | - Jesús Rivera-Nieves
- San Diego VA Medical Center (SDVAMC), San Diego, CA, USA
- Division of Gastroenterology, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA, USA
| | - Giorgos Bamias
- GI-Unit, 3rd Department of Internal Medicine, Sotiria Hospital, 152 Mesogeion Av., 11528, Athens, Greece.
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Vieujean S, Peyrin-Biroulet L. Pharmacokinetics of S1P receptor modulators in the treatment of ulcerative colitis. Expert Opin Drug Metab Toxicol 2024; 20:881-892. [PMID: 39252206 DOI: 10.1080/17425255.2024.2402931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 07/17/2024] [Accepted: 09/06/2024] [Indexed: 09/11/2024]
Abstract
INTRODUCTION Ulcerative colitis is a chronic inflammatory bowel disease, affecting the colorectal mucosae, with a relapsing-remitting course, characterized by the trafficking and gathering of lymphocytes in the inflammatory intestinal mucosa. Sphingosine-1-phosphate (S1P) receptor modulators preventing lymphocytes egress from lymphoid tissues to the active inflammation site is an alternative therapeutic option in this condition. AREA COVERED We carried out a comprehensive review of the literature available on Medline, Scopus and Embase regarding the pharmacokinetics of S1P receptor modulators. For each compound, we reviewed the mechanism of action, pharmacokinetic data and efficacy and safety data from phase 3 studies and real-life studies when available. EXPERT OPINION S1P receptor modulators, including ozanimod and etrasimod (both currently on the market) as well as VTX002 (under development), are a new class of drugs for the treatment of moderate to severe ulcerative colitis, inducing and maintaining the remission. Due to its pharmacokinetic features, this class of drugs has certain advantages such as an oral administration, a short half-life, a high volume of distribution, and no immunogenicity. On the other hand, there are risks of cardiological and ophthalmological side-effects, as well as drug-drug interactions risk, that require special attention from the healthcare providers.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, INFINY Institute, INSERM NGERE, CHRU Nancy, Vandœuvre-lès-Nancy, France
- Groupe Hospitalier privé Ambroise Paré - Hartmann, Paris IBD center, Neuilly sur Seine, France
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
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Dai YG, Sun D, Liu J, Wei X, Chi L, Wang H. Efficacy and safety of etrolizumab in the treatment of inflammatory bowel disease: a meta-analysis. PeerJ 2024; 12:e17945. [PMID: 39193512 PMCID: PMC11348897 DOI: 10.7717/peerj.17945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 07/29/2024] [Indexed: 08/29/2024] Open
Abstract
Background To explore the efficacy and safety of etrolizumab in treating inflammatory bowel disease (IBD) through meta-analysis. Method A comprehensive exploration encompassed randomized controlled trials examining the efficacy of etrolizumab in treating IBD across PubMed, Embase, Cochrane library, and Web of Science, with a search deadline of 1 December 2023. Quality assessment leaned on the Cochrane manual's risk-of-bias evaluation, while Stata 15 undertook the data analysis. Result Five randomized controlled studies involving 1682 individuals were finally included, Meta-analysis results suggested that compared with placebo, etrolizumab could improve clinical response (RR = 1.26, 95% CI [1.04-1.51]), clinical remission (RR = 1.26, 95% CI [1.04-1.51]) in IBD patients. Endoscopic alleviate (RR = 2.10, 95% CI [1.56-2.82]), endoscopic improvement (RR = 2.10, 95% CI [1.56-2.82]), endoscopic remission (RR = 2.10, 95% CI [1.56-2.82]), Endoscopic improvement (RR = 1.56, 95% CI [1.30-1.89]), histological remission (RR = 1.62, 95% CI [1.26-2.08]), and did not increase any adverse events (RR = 0.95, 95% CI [0.90-1.01]) and serious adverse events (RR = 0.94, 95% CI [0.68-1.31]). Conclusion According to our current study, etrolizumab is a promising drug in IBD.
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Affiliation(s)
- Yong gang Dai
- Shandong University of Traditional Chinese Medicine, Shandong, China
- Shandong Provincial Third Hospital, Shandong, China
| | - Dajuan Sun
- Shandong University of Traditional Chinese Medicine, Shandong, China
| | - Jiahui Liu
- Shandong University of Traditional Chinese Medicine, Shandong, China
| | - Xiunan Wei
- Shandong University of Traditional Chinese Medicine, Shandong, China
| | - Lili Chi
- Shandong University of Traditional Chinese Medicine, Shandong, China
| | - Hongya Wang
- Shandong Provincial Third Hospital, Shandong, China
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Darpo B, Connor K, Cabell CH, Grundy JS. Cardiovascular Evaluation of Etrasimod, a Selective Sphingosine 1-phosphate Receptor Modulator, in Healthy Adults: Results of a Randomized, Thorough QT/QTc Study. Clin Pharmacol Drug Dev 2024; 13:326-340. [PMID: 38441346 DOI: 10.1002/cpdd.1388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 01/25/2024] [Indexed: 04/05/2024]
Abstract
Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator used as an oral treatment option for immune-mediated inflammatory disorders. This randomized, double-blind, placebo- and positive-controlled, parallel-group, healthy adult study investigated etrasimod's effect on the QT interval and other electrocardiogram parameters. All participants received etrasimod-matched placebo on day 1. Group A received once-daily, multiple ascending doses of etrasimod (2-4 mg) on days 1-14 and moxifloxacin-matched placebo on days 1 and 15. Group B received etrasimod-matched placebo on days 1-14 and either moxifloxacin 400 mg or moxifloxacin-matched placebo on days 1 and 15. The primary analysis was a concentration-QTc analysis using a corrected QT interval by Fridericia (QTcF). The etrasimod concentration-QTc analysis predicted placebo-corrected change from baseline QTcF (ΔΔQTcF) values and associated 90% confidence intervals remained <10 milliseconds over the observed etrasimod plasma concentration range (≤279 ng/mL). Etrasimod was associated with mild, transient, asymptomatic heart rate slowing that was most pronounced on day 1 (2 mg, first dose). The largest-by-time point mean placebo-corrected changes in heart rate from time-matched day -1 baseline (∆∆HR) on days 1, 7 (2 mg, last dose), and 14 (4 mg, last dose) were -15.1, -8.5, and -6.0 bpm, respectively. Etrasimod's effects on PR interval were small, with the largest least squares mean placebo-corrected change from baseline in PR interval (∆∆PR) being 6.6 milliseconds. No episodes of atrioventricular block were observed. Thus, multiple ascending doses of etrasimod were not associated with clinically relevant QT/QTc effects in healthy adults and only had a mild, transient, and asymptomatic impact on heart rate.
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Affiliation(s)
| | | | - Christopher H Cabell
- Arena Pharmaceuticals, San Diego, CA, USA, a wholly-owned subsidiary of Pfizer Inc, New York, NY, USA
| | - John S Grundy
- Arena Pharmaceuticals, San Diego, CA, USA, a wholly-owned subsidiary of Pfizer Inc, New York, NY, USA
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Velikova T, Sekulovski M, Peshevska-Sekulovska M. Immunogenicity and Loss of Effectiveness of Biologic Therapy for Inflammatory Bowel Disease Patients Due to Anti-Drug Antibody Development. Antibodies (Basel) 2024; 13:16. [PMID: 38534206 DOI: 10.3390/antib13010016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 02/12/2024] [Accepted: 02/21/2024] [Indexed: 03/28/2024] Open
Abstract
Many patients with inflammatory bowel disease (IBD) experience a loss of effectiveness to biologic therapy (i.e., anti-TNF therapy, etc.). Therefore, in addition to the adverse effects of the treatment, these patients also face failure to achieve and maintain remission. Immunogenicity, the process of production of antibodies to biological agents, is fundamental to the evolution of loss of response to treatment in IBD patients. The presence of these antibodies in patients is linked to decreased serum drug levels and inhibited biological activity. However, immunogenicity rates exhibit significant variability across inflammatory disease states, immunoassay formats, and time periods. In this review, we aimed to elucidate the immunogenicity and immune mechanisms of antibody formation to biologics, the loss of therapy response, clinical results of biological treatment for IBD from systematic reviews and meta-analyses, as well as to summarize the most recent strategies for overcoming immunogenicity and approaches for managing treatment failure in IBD.
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Affiliation(s)
- Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
| | - Metodija Sekulovski
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Anesthesiology and Intensive Care, University Hospital Lozenetz, 1 Kozyak Str., 1407 Sofia, Bulgaria
| | - Monika Peshevska-Sekulovska
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Gastroenterology, University Hospital Lozenetz, 1407 Sofia, Bulgaria
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Suilik HA, Jaber F, Abuelazm M, Ramadan A, Elzeftawy MA, Elrosasy A, Youssef RA, Abdelazeem B, Hashash JG, Farraye FA, Ghoz H. Sphingosine 1-phosphate (S1P) receptor modulators as an induction and maintenance therapy for ulcerative colitis: a systematic review and meta-analysis of randomized controlled trials. Inflamm Res 2024; 73:183-198. [PMID: 38153524 DOI: 10.1007/s00011-023-01829-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 09/02/2023] [Accepted: 11/27/2023] [Indexed: 12/29/2023] Open
Abstract
BACKGROUND AND OBJECTIVE One sphingosine-1-phosphate (S1P) receptor modulator is approved (ozanimod) and another (etrasimod) is under investigation for the induction and maintenance of remission of ulcerative colitis (UC). We aim to evaluate the efficacy and safety of S1P modulators in patients with active UC. METHODS We conducted a systematic review and meta-analysis synthesizing randomized controlled trials (RCTs), which were retrieved by systematically searching: PubMed, Web of Science, SCOPUS, and Cochrane through May 13th, 2023. We used the fixed-effect model to pool dichotomous data using risk ratio (RR) with a 95% confidence interval (CI). RESULTS Five RCTs with a total of 1990 patients were included. S1P receptor modulators were significantly associated with increased clinical response during both the induction (RR 1.71 with 95% CI [1.50, 1.94], P = 0.00001) and maintenance phases (RR 1.89 with 95% CI [1.33, 2.69], P = 0.0004); clinical remission rates during both induction (RR 2.76 with 95% CI [1.88, 4.05], P = 0.00001) and maintenance phases (RR 3.34 with 95% CI [1.41, 7.94], P = 0.006); endoscopic improvement during both induction (RR 2.15 with 95% CI [1.71, 2.70], P = 0.00001) and maintenance phases (RR 2.41 with 95% CI [1.15, 5.05], P = 0.02); and histologic remission during both induction (RR 2.60 with 95% CI [1.89, 3.57] [1.17, 2.10], P = 0.00001) and maintenance phases (RR 2.52 with 95% CI [1.89, 3.37], P = 0.00001). Finally, there was no difference regarding safety outcomes as compared to placebo in both the induction and maintenance phases. CONCLUSION S1P receptor modulators are effective in inducing and maintaining remission in patients with moderate to severe UC.
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Affiliation(s)
| | - Fouad Jaber
- Department of Internal Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.
| | | | - Alaa Ramadan
- Faculty of Medicine, South Valley University, Qena, Egypt
| | | | - Amr Elrosasy
- Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Basel Abdelazeem
- West Virginia University, Morgantown, WV, USA
- Michigan State University, East Lansing, MI, USA
| | - Jana G Hashash
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Francis A Farraye
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Hassan Ghoz
- Division of Gastroenterology and Hepatology, University of Missouri-Kansas City, Kansas City, MO, USA
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Schulze LL, Becker E, Dedden M, Liu LJ, van Passen C, Mohamed-Abdou M, Müller TM, Wiendl M, Ullrich KAM, Atreya I, Leppkes M, Ekici AB, Kirchner P, Stürzl M, Sexton D, Palliser D, Atreya R, Siegmund B, Neurath MF, Zundler S. Differential Effects of Ontamalimab Versus Vedolizumab on Immune Cell Trafficking in Intestinal Inflammation and Inflammatory Bowel Disease. J Crohns Colitis 2023; 17:1817-1832. [PMID: 37208197 DOI: 10.1093/ecco-jcc/jjad088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 03/16/2023] [Accepted: 05/16/2023] [Indexed: 05/21/2023]
Abstract
BACKGROUND AND AIMS The anti-MAdCAM-1 antibody ontamalimab demonstrated efficacy in a phase II trial in ulcerative colitis and results of early terminated phase III trials are pending, but its precise mechanisms of action are still unclear. Thus, we explored the mechanisms of action of ontamalimab and compared it to the anti-α4β7 antibody vedolizumab. METHODS We studied MAdCAM-1 expression with RNA sequencing and immunohistochemistry. The mechanisms of action of ontamalimab were assessed with fluorescence microscopy, dynamic adhesion and rolling assays. We performed in vivo cell trafficking studies in mice and compared ontamalimab and vedolizumab surrogate [-s] antibodies in experimental models of colitis and wound healing. We analysed immune cell infiltration under anti-MAdCAM-1 and anti-α4β7 treatment by single-cell transcriptomics and studied compensatory trafficking pathways. RESULTS MAdCAM-1 expression was increased in active inflammatory bowel disease. Binding of ontamalimab to MAdCAM-1 induced the internalization of the complex. Functionally, ontamalimab blocked T cell adhesion similar to vedolizumab, but also inhibited L-selectin-dependent rolling of innate and adaptive immune cells. Despite conserved mechanisms in mice, the impact of ontamalimab-s and vedolizumab-s on experimental colitis and wound healing was similar. Single-cell RNA sequencing demonstrated enrichment of ontamalimab-s-treated lamina propria cells in specific clusters, and in vitro experiments indicated that redundant adhesion pathways are active in these cells. CONCLUSIONS Ontamalimab has unique and broader mechanisms of action compared to vedolizumab. However, this seems to be compensated for by redundant cell trafficking circuits and leads to similar preclinical efficacy of anti-α4β7 and anti-MAdCAM-1 treatment. These results will be important for the interpretation of pending phase III data.
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Affiliation(s)
- Lisa Lou Schulze
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Emily Becker
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Mark Dedden
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Li-Juan Liu
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Chiara van Passen
- Department of Surgery, Division of Molecular and Experimental Surgery, University Hospital Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Germany
| | - Mariam Mohamed-Abdou
- Department of Surgery, Division of Molecular and Experimental Surgery, University Hospital Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Germany
| | - Tanja M Müller
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany
| | - Maximilian Wiendl
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Karen A M Ullrich
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Imke Atreya
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany
| | - Moritz Leppkes
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany
| | - Arif B Ekici
- Institute of Human Genetics, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Philipp Kirchner
- Institute of Human Genetics, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Michael Stürzl
- Department of Surgery, Division of Molecular and Experimental Surgery, University Hospital Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Germany
| | - Dan Sexton
- Shire HGT, a Takeda company, Cambridge, MA, USA
| | | | - Raja Atreya
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany
| | - Britta Siegmund
- Division of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Markus F Neurath
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany
| | - Sebastian Zundler
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany
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Passeron T, King B, Seneschal J, Steinhoff M, Jabbari A, Ohyama M, Tobin DJ, Randhawa S, Winkler A, Telliez JB, Martin D, Lejeune A. Inhibition of T-cell activity in alopecia areata: recent developments and new directions. Front Immunol 2023; 14:1243556. [PMID: 38022501 PMCID: PMC10657858 DOI: 10.3389/fimmu.2023.1243556] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 10/05/2023] [Indexed: 12/01/2023] Open
Abstract
Alopecia areata (AA) is an autoimmune disease that has a complex underlying immunopathogenesis characterized by nonscarring hair loss ranging from small bald patches to complete loss of scalp, face, and/or body hair. Although the etiopathogenesis of AA has not yet been fully characterized, immune privilege collapse at the hair follicle (HF) followed by T-cell receptor recognition of exposed HF autoantigens by autoreactive cytotoxic CD8+ T cells is now understood to play a central role. Few treatment options are available, with the Janus kinase (JAK) 1/2 inhibitor baricitinib (2022) and the selective JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitor ritlecitinib (2023) being the only US Food and Drug Administration-approved systemic medications thus far for severe AA. Several other treatments are used off-label with limited efficacy and/or suboptimal safety and tolerability. With an increased understanding of the T-cell-mediated autoimmune and inflammatory pathogenesis of AA, additional therapeutic pathways beyond JAK inhibition are currently under investigation for the development of AA therapies. This narrative review presents a detailed overview about the role of T cells and T-cell-signaling pathways in the pathogenesis of AA, with a focus on those pathways targeted by drugs in clinical development for the treatment of AA. A detailed summary of new drugs targeting these pathways with expert commentary on future directions for AA drug development and the importance of targeting multiple T-cell-signaling pathways is also provided in this review.
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Affiliation(s)
- Thierry Passeron
- University Côte d’Azur, Centre Hospitalier Universitaire Nice, Department of Dermatology, Nice, France
- University Côte d’Azur, INSERM, U1065, C3M, Nice, France
| | - Brett King
- Department of Dermatology, Yale University School of Medicine, New Haven, CT, United States
| | - Julien Seneschal
- Department of Dermatology and Paediatric Dermatology, National Reference Centre for Rare Skin Diseases, Saint-André Hospital, University of Bordeaux, Bordeaux, France
- Bordeaux University, Centre national de la recherche scientifique (CNRS), ImmunoConcept, UMR5164, Bordeaux, France
| | - Martin Steinhoff
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
- Department of Dermatology and Venereology, Weill Cornell Medicine-Qatar, Doha, Qatar
- College of Medicine, Qatar University, Doha, Qatar
- Department of Dermatology, Weill Cornell Medicine, New York, NY, United States
- College of Health and Life Sciences, Hamad Bin Khalifa University-Qatar, Doha, Qatar
| | - Ali Jabbari
- Department of Dermatology, University of Iowa, Iowa City, IA, United States
- Iowa City VA Medical Center, Iowa City, IA, United States
| | - Manabu Ohyama
- Department of Dermatology, Kyorin University Faculty of Medicine, Tokyo, Japan
| | - Desmond J. Tobin
- Charles Institute of Dermatology, UCD School of Medicine, University College Dublin, Dublin, Ireland
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Bencardino S, D’Amico F, Faggiani I, Bernardi F, Allocca M, Furfaro F, Parigi TL, Zilli A, Fiorino G, Peyrin-Biroulet L, Danese S. Efficacy and Safety of S1P1 Receptor Modulator Drugs for Patients with Moderate-to-Severe Ulcerative Colitis. J Clin Med 2023; 12:5014. [PMID: 37568417 PMCID: PMC10419826 DOI: 10.3390/jcm12155014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 07/24/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that negatively impacts patients' quality of life. In the last decades, the therapeutic options available for the management of patients with moderate to severe UC have increased significantly, including not only biological drugs but also small molecules. However, there is a persistent need to develop new drugs that act on new targets while minimizing the risk of adverse events. Sphingosine-1-phosphate (S1P) is a membrane-derived lysophospholipid. The S1P gradient between tissues and the circulatory system has a key role in regulating the trafficking of immune cells as autoreactive B and T lymphocytes. S1P receptor modulators could be a safe and efficacious alternative mechanism for reducing inflammation in immune-mediated disorders, including UC, by reducing lymphocyte egress from the lymph nodes to the bloodstream. Several S1P receptor modulators have been developed and tested in UC. Ozanimod is already approved by Food and Drug Administration (FDA) and European Medical Agency (EMA), while etrasimod and VTX002 are still under approval. Oral administration route, rapidity and reliable safety profile are the main advantages of this class of drugs. The aim of this review is to summarize the available evidence for the efficacy, safety, and pharmacokinetics of ozanimod, etrasimod, and VTX002 in UC.
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Affiliation(s)
- Sarah Bencardino
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, 20132 Milan, Italy; (S.B.); (F.D.); (I.F.); (F.B.); (M.A.); (F.F.); (T.L.P.); (A.Z.); (G.F.)
| | - Ferdinando D’Amico
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, 20132 Milan, Italy; (S.B.); (F.D.); (I.F.); (F.B.); (M.A.); (F.F.); (T.L.P.); (A.Z.); (G.F.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
| | - Ilaria Faggiani
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, 20132 Milan, Italy; (S.B.); (F.D.); (I.F.); (F.B.); (M.A.); (F.F.); (T.L.P.); (A.Z.); (G.F.)
| | - Francesca Bernardi
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, 20132 Milan, Italy; (S.B.); (F.D.); (I.F.); (F.B.); (M.A.); (F.F.); (T.L.P.); (A.Z.); (G.F.)
| | - Mariangela Allocca
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, 20132 Milan, Italy; (S.B.); (F.D.); (I.F.); (F.B.); (M.A.); (F.F.); (T.L.P.); (A.Z.); (G.F.)
| | - Federica Furfaro
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, 20132 Milan, Italy; (S.B.); (F.D.); (I.F.); (F.B.); (M.A.); (F.F.); (T.L.P.); (A.Z.); (G.F.)
| | - Tommaso Lorenzo Parigi
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, 20132 Milan, Italy; (S.B.); (F.D.); (I.F.); (F.B.); (M.A.); (F.F.); (T.L.P.); (A.Z.); (G.F.)
| | - Alessandra Zilli
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, 20132 Milan, Italy; (S.B.); (F.D.); (I.F.); (F.B.); (M.A.); (F.F.); (T.L.P.); (A.Z.); (G.F.)
| | - Gionata Fiorino
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, 20132 Milan, Italy; (S.B.); (F.D.); (I.F.); (F.B.); (M.A.); (F.F.); (T.L.P.); (A.Z.); (G.F.)
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, University of Lorraine, CHRU-Nancy, F-54000 Nancy, France;
- Department of Gastroenterology, Nancy University Hospital, F-54500 Vandœuvre-lès-Nancy, France
- INSERM, NGERE, University of Lorraine, F-54000 Nancy, France
- INFINY Institute, Nancy University Hospital, F-54500 Vandœuvre-lès-Nancy, France
- FHU-CURE, Nancy University Hospital, F-54500 Vandœuvre-lès-Nancy, France
- Groupe Hospitalier privé Ambroise Paré-Hartmann, Paris IBD Center, F-92200 Neuilly sur Seine, France
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, 20132 Milan, Italy; (S.B.); (F.D.); (I.F.); (F.B.); (M.A.); (F.F.); (T.L.P.); (A.Z.); (G.F.)
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Zou F, Wang S, Xu M, Wu Z, Deng F. The role of sphingosine-1-phosphate in the gut mucosal microenvironment and inflammatory bowel diseases. Front Physiol 2023; 14:1235656. [PMID: 37560160 PMCID: PMC10407793 DOI: 10.3389/fphys.2023.1235656] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 07/17/2023] [Indexed: 08/11/2023] Open
Abstract
Sphingosine-1-phosphate (S1P), a type of bioactive sphingolipid, can regulate various cellular functions of distinct cell types in the human body. S1P is generated intracellularly by the catalysis of sphingosine kinase 1/2 (SphK1/2). S1P is transferred to the extracellular environment via the S1P transporter, binds to cellular S1P receptors (S1PRs) and subsequently activates S1P-S1PR downstream signaling. Dysbiosis of the intestinal microbiota, immune dysregulation and damage to epithelial barriers are associated with inflammatory bowel disease (IBD). Generally, S1P mainly exerts a proinflammatory effect by binding to S1PR1 on lymphocytes to facilitate lymphocyte migration to inflamed tissues, and increased S1P was found in the intestinal mucosa of IBD patients. Notably, there is an interaction between the distribution of gut bacteria and SphK-S1P signaling in the intestinal epithelium. S1P-S1PR signaling can also regulate the functions of intestinal epithelial cells (IECs) in mucosa, including cell proliferation and apoptosis. Additionally, increased S1P in immune cells of the lamina propria aggravates the inflammatory response by increasing the production of proinflammatory cytokines. Several novel drugs targeted at S1PRs have recently been used for IBD treatment. This review provides an overview of the S1P-S1PR signaling pathway and, in particular, summarizes the various roles of S1P in the gut mucosal microenvironment to deeply explore the function of S1P-S1PR signaling during intestinal inflammation and, more importantly, to identify potential therapeutic targets for IBD in the SphK-S1P-S1PR axis.
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Affiliation(s)
- Fei Zou
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Su Wang
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Mengmeng Xu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Zengrong Wu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
| | - Feihong Deng
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, Hunan, China
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Liu J, Di B, Xu LL. Recent advances in the treatment of IBD: Targets, mechanisms and related therapies. Cytokine Growth Factor Rev 2023; 71-72:1-12. [PMID: 37455149 DOI: 10.1016/j.cytogfr.2023.07.001] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/08/2023] [Accepted: 07/10/2023] [Indexed: 07/18/2023]
Abstract
Inflammatory bowel disease (IBD), as a representative inflammatory disease, currently has multiple effective treatment options available and new therapeutic strategies are being actively explored to further increase the treatment options for patients with IBD. Furthermore, biologic agents and small molecule drugs developed for ulcerative colitis (UC) and Crohn's disease (CD) have evolved toward fewer side effects and more accurate targeting. Novel inhibitors that target cytokines (such as IL-12/23 inhibitors, PDE4 inhibitors), integrins (such as integrin inhibitors), cytokine signaling pathways (such as JAK inhibitors, SMAD7 blocker) and cell signaling receptors (such as S1P receptor modulator) have become the preferred treatment choice for many IBD patients. Conventional therapies such as 5-aminosalicylic acid, corticosteroids, immunomodulators and anti-tumor necrosis factor agents continue to demonstrate therapeutic efficacy, particularly in combination with drug therapy. This review integrates research from chemical, biological and adjuvant therapies to evaluate current and future IBD therapies, highlighting the mechanism of action of each therapy and emphasizing the potential of development prospects.
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Affiliation(s)
- Juan Liu
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China
| | - Bin Di
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.
| | - Li-Li Xu
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.
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Intestinal Barrier Dysfunction and Microbial Translocation in Patients with First-Diagnosed Atrial Fibrillation. Biomedicines 2023; 11:biomedicines11010176. [PMID: 36672684 PMCID: PMC9856173 DOI: 10.3390/biomedicines11010176] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/03/2023] [Accepted: 01/06/2023] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND According to the leaky gut concept, microbial products (e.g., lipopolysaccharide, LPS) enter the circulation and mediate pro-inflammatory immunological responses. Higher plasma LPS levels have been reported in patients with various cardiovascular diseases, but not specifically during early atrial fibrillation (AF). METHODS We studied data and blood samples from patients presenting with first-diagnosed AF (FDAF) (n = 80) and 20 controls. RESULTS Circulating biomarkers that are suggestive of mucosal inflammation (zonulin, mucosal adhesion molecule MAdCAM-1) and intestinal epithelium damage (intestinal fatty acid binding protein, IFABP) were increased in the plasma of patients with FDAF when compared to patients with chronic cardiovascular diseases but without AF. Surrogate plasma markers of increased intestinal permeability (LPS, CD14, LPS-binding protein, gut-derived LPS-neutralising IgA antibodies, EndoCAbs) were detected during early AF. A reduced ratio of IgG/IgM EndoCAbs titres indicated chronic endotoxaemia. Collagen turnover biomarkers, which corresponded to the LPS values, suggested an association of gut-derived low-grade endotoxaemia with adverse structural remodelling. The LPS concentrations were higher in FDAF patients who experienced a major adverse cardiovascular event. CONCLUSIONS Intestinal barrier dysfunction and microbial translocation accompany FDAF. Improving gut permeability and low-grade endotoxaemia might be a potential therapeutic approach to reducing the disease progression and cardiovascular complications in FDAF.
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Tourkochristou E, Mouzaki A, Triantos C. Unveiling the biological role of sphingosine-1-phosphate receptor modulators in inflammatory bowel diseases. World J Gastroenterol 2023; 29:110-125. [PMID: 36683721 PMCID: PMC9850947 DOI: 10.3748/wjg.v29.i1.110] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/16/2022] [Accepted: 12/14/2022] [Indexed: 01/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide. The increasing disease burden worldwide, lack of response to current biologic therapeutics, and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy. Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effective therapeutics. Sphingosine-1-phosphate (S1P) receptor (S1PR) modulators form a class of oral small molecule drugs currently in clinical development for IBD have shown promising effects on disease improvement. S1P is a sphingosine-derived phospholipid that acts by binding to its receptor S1PR and is involved in the regulation of several biological processes including cell survival, differentiation, migration, proliferation, immune response, and lymphocyte trafficking. T lymphocytes play an important role in regulating inflammatory responses. In inflamed IBD tissue, an imbalance between T helper (Th) and regulatory T lymphocytes and Th cytokine levels was found. The S1P/S1PR signaling axis and metabolism have been linked to inflammatory responses in IBD. S1P modulators targeting S1PRs and S1P metabolism have been developed and shown to regulate inflammatory responses by affecting lymphocyte trafficking, lymphocyte number, lymphocyte activity, cytokine production, and contributing to gut barrier function.
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Affiliation(s)
- Evanthia Tourkochristou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
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Sheikholeslami A, Fazaeli H, Kalhor N, Khoshandam M, Eshagh Hoseini SJ, Sheykhhasan M. Use of Mesenchymal Stem Cells in Crohn's Disease and Perianal Fistulas: A Narrative Review. Curr Stem Cell Res Ther 2023; 18:76-92. [PMID: 34530720 DOI: 10.2174/1574888x16666210916145717] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/08/2021] [Accepted: 06/15/2021] [Indexed: 11/22/2022]
Abstract
Crohn's Disease (CD), which usually leads to anal fistulas among patients, is the most important inflammatory bowel disease that causes morbidity in many people around the world. This review article proposes using MSCs as a hopeful therapeutic strategy for CD and anal fistula treatment in both preclinical and clinical conditions. Finally, darvadstrocel, a cell-based medication to treat complex anal fistulas in adults, as the only European Medicines Agency (EMA)-approved product for the treatment of anal fistulas in CD is addressed. Although several common therapies, such as surgery and anti-tumor necrosis factor-alpha (TNF-α) drugs as well as a combination of these methods is used to improve this disease, however, due to the low effectiveness of these treatments, the use of new strategies with higher efficiency is still recommended. Cell therapy is among the new emerging therapeutic strategies that have attracted great attention from clinicians due to its unique capabilities. One of the most widely used cell sources administrated in cell therapy is mesenchymal stem cell (MSC). This review article will discuss preclinical and clinical studies about MSCs as a potent and promising therapeutic option in the treatment of CD and anal fistula.
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Affiliation(s)
- Azar Sheikholeslami
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Hoda Fazaeli
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom,Iran
| | - Naser Kalhor
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Mohadeseh Khoshandam
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | | | - Mohsen Sheykhhasan
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran.,Department of Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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Mousavi T, Hassani S, Baeeri M, Rahimifard M, Vakhshiteh F, Gholami M, Ghafour-Broujerdi E, Abdollahi M. Comparison of the safety and efficacy of fingolimod and tofacitinib in the zebrafish model of colitis. Food Chem Toxicol 2022; 170:113509. [DOI: 10.1016/j.fct.2022.113509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 10/27/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022]
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Dhillon S. Carotegrast Methyl: First Approval. Drugs 2022; 82:1011-1016. [PMID: 35723803 DOI: 10.1007/s40265-022-01732-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Carotegrast methyl (Carogra®) is a small-molecule α4 integrin antagonist being developed by EA Pharma (formerly Ajinomoto Pharmaceuticals) and Kissei Pharmaceutical for the treatment of ulcerative colitis. The active metabolite of carotegrast methyl exerts an anti-inflammatory effect by blocking the interaction of α4β1 or α4β7 integrins and their ligands, VCAM-1 and MAd-CAM-1, thereby inhibiting the adhesion of inflammatory cells, including T cells, to vascular endothelial cells and extravasation into inflammatory sites. In March 2022, carotegrast methyl received its first approval in Japan for the treatment of moderate ulcerative colitis in patients who had inadequate response to 5-aminosalicylic acid. This article summarizes the milestones in the development of carotegrast methyl leading to this first approval for the treatment of moderate ulcerative colitis.
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Affiliation(s)
- Sohita Dhillon
- Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
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20
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Bamias G, Kokkotis G, Gizis M, Kapizioni C, Karmiris K, Koureta E, Kyriakos N, Leonidakis G, Makris K, Markopoulos P, Michalopoulos G, Michopoulos S, Papaconstantinou I, Polymeros D, Siakavellas SI, Triantafyllou K, Tsironi E, Tsoukali E, Tzouvala M, Viazis N, Xourafas V, Zacharopoulou E, Zampeli E, Zografos K, Papatheodoridis G, Mantzaris G. Predictors of Response to Vedolizumab in Patients with Ulcerative Colitis: Results from the Greek VEDO-IBD Cohort. Dig Dis Sci 2022; 67:1007-1017. [PMID: 33751325 PMCID: PMC7942521 DOI: 10.1007/s10620-021-06907-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 02/19/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND Optimization of treatment with biologics is currently an unmet need for patients with ulcerative colitis (UC). Real-world studies provide neutral estimates of drug efficacy and safety within unselected patient populations and allow for the recognition of specific characteristics that affect response to therapy. AIMS We aimed to depict the efficacy of vedolizumab in patients with UC in a real-world setting and identify prognosticators of improved outcomes. METHODS Patients with active UC who commenced treatment with vedolizumab were prospectively followed up. Patient-reported outcomes (PROs) and clinical/endoscopic-reported outcomes were recorded at baseline and at weeks 14 and 54. Predefined endpoints of early and persistent efficacy were analyzed against clinical characteristics to identify prognostic factors for response. RESULTS We included 96 patients (anti-TNF-exposed = 38.5%). At week 14, 73 patients (76%) had clinical response and 54 (56.3%) clinical remission. At week 54, the primary endpoint of vedolizumab persistence was met by 72 patients (75%), whereas steroid-free clinical remission by 59.4%. Among patients who had endoscopy, rates for mucosal healing (Mayo endoscopic score of 0) were 29.8% at week 14 and 44.6% at week 54, respectively. Vedolizumab treatment led to significant improvements in quality of life. Corticosteroid-refractory or anti-TNF-refractory disease, articular manifestations, and high baseline UC-PRO2 were associated with decreased efficacy of vedolizumab in the primary and secondary outcomes. CONCLUSIONS Vedolizumab is characterized by high efficacy and long-term treatment persistence in UC. More aggressive disease, as indicated by refractoriness to steroids or anti-TNFs and elevated baseline PROs, may predict suboptimal response and help pre-treatment prognostic stratification of patients.
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Affiliation(s)
- Giorgos Bamias
- GI Unit, 3Rd Department of Internal Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Messogeion 152, 11527 Athens, Greece
| | - Georgios Kokkotis
- GI Unit, 3Rd Department of Internal Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Messogeion 152, 11527 Athens, Greece
| | - Michalis Gizis
- GI Unit, 3Rd Department of Internal Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Messogeion 152, 11527 Athens, Greece
| | - Christina Kapizioni
- Department of Gastroenterology, Tzaneion General Hospital, Leoforos Afentouli, 18536 Piraeus, Greece
| | - Konstantinos Karmiris
- Department of Gastroenterology, Venizeleio General Hospital, Leoforos Knosou 44, 71409 Heraklion, Greece
| | - Evgenia Koureta
- Department of Gastroenterology, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Agiou Thoma 17, 11527 Athens, Greece
| | - Nikolaos Kyriakos
- Department of Gastroenterology, 401 General Military Hospital of Athens, Leoforos Panagioti Kanellopoulou, 11525 Athens, Greece
| | - Georgios Leonidakis
- Department of Gastroenterology, Alexandra General Hospital, Lourou 4-2, 11528 Athens, Greece
| | - Konstantinos Makris
- Department of Gastroenterology, Tzaneion General Hospital, Leoforos Afentouli, 18536 Piraeus, Greece
| | - Panagiotis Markopoulos
- Department of Gastroenterology, Metaxa Memorial General Hospital, Mpotasi 51, 18537 Piraeus, Greece
| | - Georgios Michalopoulos
- Department of Gastroenterology, Tzaneion General Hospital, Leoforos Afentouli, 18536 Piraeus, Greece
| | - Spyridon Michopoulos
- Department of Gastroenterology, Alexandra General Hospital, Lourou 4-2, 11528 Athens, Greece
| | - Ioannis Papaconstantinou
- Second Department of Surgery, National and Kapodistrian University of Athens, Medical School, Aretaieion University Hospital, Leoforos Vasilissis Sofias 76, 11528 Athens, Greece
| | - Dimitrios Polymeros
- Hepatogastroenterology Unit, Second Department of Internal Medicine-Propaedeutic, Medical School, National and Kapodistrian University of Athens, Attikon University General Hospital, Rimini 1, 12462 Athens, Greece
| | - Spyros I. Siakavellas
- Department of Gastroenterology, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Agiou Thoma 17, 11527 Athens, Greece
| | - Konstantinos Triantafyllou
- Hepatogastroenterology Unit, Second Department of Internal Medicine-Propaedeutic, Medical School, National and Kapodistrian University of Athens, Attikon University General Hospital, Rimini 1, 12462 Athens, Greece
| | - Eftychia Tsironi
- Department of Gastroenterology, Metaxa Memorial General Hospital, Mpotasi 51, 18537 Piraeus, Greece
| | - Emmanouela Tsoukali
- Department of Gastroenterology, GHA Evaggelismos- Opthalmiatreion Athinon-Polykliniki, Ipsilantou 45-47, 10676 Athens, Greece
| | - Maria Tzouvala
- Department of Gastroenterology, General Hospital Nikaias-Piraeus “Agios Panteleimon” -General Hospital Dytikis Attikis “Agia Varvara”, Dim. Mantouvalou 3, 18454 Athens, Greece
| | - Nikos Viazis
- Department of Gastroenterology, GHA Evaggelismos- Opthalmiatreion Athinon-Polykliniki, Ipsilantou 45-47, 10676 Athens, Greece
| | - Vassileios Xourafas
- GI Unit, 3Rd Department of Internal Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Messogeion 152, 11527 Athens, Greece
| | - Eirini Zacharopoulou
- Department of Gastroenterology, General Hospital Nikaias-Piraeus “Agios Panteleimon” -General Hospital Dytikis Attikis “Agia Varvara”, Dim. Mantouvalou 3, 18454 Athens, Greece
| | - Evanthia Zampeli
- Department of Gastroenterology, Alexandra General Hospital, Lourou 4-2, 11528 Athens, Greece
| | - Konstantinos Zografos
- GI Unit, 3Rd Department of Internal Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Messogeion 152, 11527 Athens, Greece
| | - George Papatheodoridis
- Department of Gastroenterology, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Agiou Thoma 17, 11527 Athens, Greece
| | - Gerasimos Mantzaris
- Department of Gastroenterology, GHA Evaggelismos- Opthalmiatreion Athinon-Polykliniki, Ipsilantou 45-47, 10676 Athens, Greece
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Campillo-Gimenez L, Rios-Covian D, Rivera-Nieves J, Kiyono H, Chu H, Ernst PB. Microbial-Driven Immunological Memory and Its Potential Role in Microbiome Editing for the Prevention of Colorectal Cancer. Front Cell Infect Microbiol 2021; 11:752304. [PMID: 34869061 PMCID: PMC8633303 DOI: 10.3389/fcimb.2021.752304] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 10/12/2021] [Indexed: 12/13/2022] Open
Abstract
Over the last several years, many advances have been made in understanding the role of bacteria in the pathogenesis of gastrointestinal cancers. Beginning with Helicobacter pylori being recognized as the first bacterial carcinogen and the causative agent of most gastric cancers, more recent studies have examined the role of enteric microbes in colorectal cancer. In the digestive tract, these communities are numerous and have a complex interrelationship with local immune/inflammatory responses that impact the health of the host. As modifying the microbiome in the stomach has decreased the risk of gastric cancer, modifying the distal microbiome may decrease the risk of colorectal cancers. To date, very few studies have considered the notion that mucosal lymphocyte-dependent immune memory may confound attempts to change the microbial components in these communities. The goal of this review is to consider some of the factors impacting host-microbial interactions that affect colorectal cancer and raise questions about how immune memory responses to the local microbial consortium affect any attempt to modify the composition of the intestinal microbiome.
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Affiliation(s)
- Laure Campillo-Gimenez
- Department of Pathology, University of California San Diego, San Diego, CA, United States
| | - David Rios-Covian
- Department of Pathology, University of California San Diego, San Diego, CA, United States
| | - Jesus Rivera-Nieves
- Department of Medicine, Division of Gastroenterology, University of California San Diego, San Diego, CA, United States
- San Diego Veterans Affairs (VA) Medical Center, San Diego, CA, United States
| | - Hiroshi Kiyono
- Department of Medicine, Division of Gastroenterology, University of California San Diego, San Diego, CA, United States
- CU-UCSD, Center for Mucosal Immunology, Allergy and Vaccine Development, University of California San Diego, San Diego, CA, United States
- Future Medicine Education and Research Organization, Chiba University, Chiba, Japan
| | - Hiutung Chu
- Department of Pathology, University of California San Diego, San Diego, CA, United States
- CU-UCSD, Center for Mucosal Immunology, Allergy and Vaccine Development, University of California San Diego, San Diego, CA, United States
| | - Peter B. Ernst
- Department of Pathology, University of California San Diego, San Diego, CA, United States
- San Diego Veterans Affairs (VA) Medical Center, San Diego, CA, United States
- CU-UCSD, Center for Mucosal Immunology, Allergy and Vaccine Development, University of California San Diego, San Diego, CA, United States
- Division of Comparative Pathology and Medicine, University of California San Diego, San Diego, CA, United States
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22
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Ruiz-Rivera MB, Gómez-Icazbalceta G, Lamoyi E, Huerta L. Host membrane proteins in the HIV-induced membrane fusion: Role in pathogenesis and therapeutic potential of autoantibodies. Curr Opin Pharmacol 2021; 60:241-248. [PMID: 34481334 DOI: 10.1016/j.coph.2021.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 06/11/2021] [Accepted: 07/12/2021] [Indexed: 11/27/2022]
Abstract
Host proteins such as receptors, adhesion and signaling molecules, promote virus-cell fusion, virus cell-cell transmission, and formation of multinucleated cells with outstanding properties. These events are implicated in virus dissemination and the induction of pathological effects such as the infection of the gut-associated lymphoid tissue, placenta infection, and neurological complications. Antibodies directed to the host membrane proteins are produced during the natural HIV infection and may contribute significantly to virus inhibition. Antibodies against the HIV receptor have been approved for therapy and others targeting additional host membrane proteins are currently under evaluation. This review emphasizes the relevance of the different pathways of HIV spreading between cells and of antibodies directed to host membrane components in the development of broad-range therapeutics against HIV.
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Affiliation(s)
- Mirna B Ruiz-Rivera
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | | | - Edmundo Lamoyi
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Leonor Huerta
- Department of Immunology, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
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Misselwitz B, Juillerat P, Sulz MC, Siegmund B, Brand S. Emerging Treatment Options in Inflammatory Bowel Disease: Janus Kinases, Stem Cells, and More. Digestion 2021; 101 Suppl 1:69-82. [PMID: 32570252 DOI: 10.1159/000507782] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 04/07/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Treatment of inflammatory bowel diseases (IBD) has tremendously improved during the last 20 years; however, a substantial fraction of patients does not respond to available therapies or lose response, and new strategies are needed. SUMMARY Two pharmacological principles have been successfully used for IBD treatment: inhibition of cellular signaling and interference with leukocyte trafficking. Besides tumor necrosis factor, interleukin (IL)-23 is a promising drug target, and antibodies for the combined inhibition of IL-23 and IL-12 (ustekinumab and briakinumab) or selective IL-23 inhibition (brazikumab, risankizumab, and mirikizumab) seem to be effective in Crohn's disease (CD) with emerging evidence also for ulcerative colitis (UC). Janus kinase (JAK) mediates intracellular signaling of a large number of cytokines. Tofacitinib is the first JAK inhibitor approved for UC, and the JAK inhibitors filgotinib and upadacitinib showed potential in CD. Leukocyte trafficking can be inhibited by interference with lymphocyte integrin-α4β7 or endothelial MadCAM-1. The α4β7 integrin inhibitor vedolizumab is an established treatment in IBD, and long-term data of pivotal studies are now available. Additional molecules with therapeutic potential are α4β7-specific abrilumab, β7-specific etrolizumab, and the α4-specific small molecule AJM300. PF-00547659, an antibody against endothelial MadCAM-1, also showed therapeutic potential in UC. Modulation of sphingosine-1-phosphate receptor (S1PR) activity is necessary for the egress of lymphocytes into the circulation, and S1PR modulation results in lymphocyte trapping in lymphatic organs. Ozanimod, an S1PR1 and S1PR5 inhibitor, has been successfully tested in initial studies in UC. Mesenchymal stem cell therapy has been approved for the treatment of complex, active CD fistula, and mesenchymal stem cell therapy might be a paradigm shift for this condition. Autologous stem cell transplantation (ASCT) has been successfully used in CD case series; however, in a randomized trial, a highly stringent endpoint was not met. However, considering positive effects in secondary endpoints, ASCT might be a future treatment of last resort in severe, refractory CD cases, provided that safer protocols can be provided. Key messages: New IBD treatments are successful for a significant fraction of patients. However, new strategies for patient selection, treatment combinations, and/or additional therapies must be developed to serve the need of all IBD patients.
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Affiliation(s)
- Benjamin Misselwitz
- Gastroenterology, Department of Visceral Surgery and Medicine, Inselspital Bern and Bern University, Bern, Switzerland,
| | - Pascal Juillerat
- Gastroenterology, Department of Visceral Surgery and Medicine, Inselspital Bern and Bern University, Bern, Switzerland
| | - Michael Christian Sulz
- Department of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Britta Siegmund
- Medical Department (Gastroenterology, Infectious Diseases, Rheumatology), Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Stephan Brand
- Department of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
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24
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Biological Treatments in Inflammatory Bowel Disease: A Complex Mix of Mechanisms and Actions. BIOLOGICS 2021. [DOI: 10.3390/biologics1020012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic disease that requires lifelong medication and whose incidence is increasing over the world. There is currently no cure for IBD, and the current therapeutic objective is to control the inflammatory process. Approximately one third of treated patients do not respond to treatment and refractoriness to treatment is common. Therefore, pharmacological treatments, such as monoclonal antibodies, are urgently needed, and new treatment guidelines are regularly published. Due to the extremely important current role of biologics in the therapy of IBD, herein we have briefly reviewed the main biological treatments currently available. In addition, we have focused on the mechanisms of action of the most relevant groups of biological agents in IBD therapy, which are not completely clear but are undoubtfully important for understanding both their therapeutic efficacy and the adverse side effects they may have. Further studies are necessary to better understand the action mechanism of these drugs, which will in turn help us to understand how to improve their efficacy and safety. These studies will hopefully pave the path for a personalized medicine.
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Matsuoka K, Naganuma M, Hibi T, Tsubouchi H, Oketani K, Katsurabara T, Hojo S, Takenaka O, Kawano T, Imai T, Kanai T. Phase 1 study on the safety and efficacy of E6011, antifractalkine antibody, in patients with Crohn's disease. J Gastroenterol Hepatol 2021; 36:2180-2186. [PMID: 33599356 PMCID: PMC8451784 DOI: 10.1111/jgh.15463] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 11/16/2020] [Accepted: 12/23/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIM E6011 is a humanized monoclonal antibody targeting fractalkine (FKN), a CX3C chemokine, which regulates leukocyte trafficking during inflammation. We evaluated the safety and pharmacokinetic profile of E6011 in patients with Crohn's disease (CD) and also performed preliminary pharmacodynamic (PD) and efficacy assessments. METHODS This study included a 12-week multiple ascending dose (MAD) phase (2, 5, 10, and 15 mg/kg intravenously every 2 weeks, n = 6, 8, 7, and 7, respectively) and a 40-week Extension phase (n = 12) at the same dose as the MAD phase. Serum E6011, serum total FKN (free soluble FKN and E6011-FKN complex) as a PD marker and CD activity index were evaluated. The primary outcome was safety assessment in the MAD phase. RESULTS Twenty-seven (96%) of 28 patients had previously been treated with anti-tumor necrosis factor α agents. During the MAD phase, adverse events (AEs) occurred in 18 (64%). The most common AE was nasopharyngitis (five patients, 18%). No severe AEs occurred. Serious AEs occurred in three patients, progression of CD in two, and anemia in one. Serum E6011 concentrations increased dose-dependently after infusion and reached a plateau around 4-6 weeks. Serum total FKN rose simultaneously. Five (18%) patients developed anti-E6011 antibodies during the study. Overall, clinical response and clinical remission were observed at Week 12 in 40% (10/25) and 16% (4/25) of active CD patients, respectively. CONCLUSION E6011 was well-tolerated and might be effective in CD patients. These findings need to be clarified in a randomized controlled study.
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Affiliation(s)
- Katsuyoshi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Internal MedicineKeio University School of MedicineTokyoJapan
| | - Makoto Naganuma
- Division of Gastroenterology and Hepatology, Department of Internal MedicineKeio University School of MedicineTokyoJapan
| | - Toshifumi Hibi
- Center for Advanced IBD Research and TreatmentKitasato University Kitasato Institute HospitalTokyoJapan
| | | | - Kiyoshi Oketani
- Clinical Development DepartmentEA Pharma Co., Ltd.TokyoJapan
| | | | - Seiichiro Hojo
- Clinical Data Science DepartmentMedicine Development Center, Eisai Co., Ltd.TokyoJapan
| | - Osamu Takenaka
- Clinical Pharmacology Science DepartmentMedicine Development Center, Eisai Co., Ltd.TokyoJapan
| | - Tetsu Kawano
- Research and DevelopmentKAN Research Institute, Inc.TokyoJapan
| | - Toshio Imai
- Research and DevelopmentKAN Research Institute, Inc.TokyoJapan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal MedicineKeio University School of MedicineTokyoJapan
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Giménez-Bastida JA, González-Sarrías A, Laparra-Llopis JM, Schneider C, Espín JC. Targeting Mammalian 5-Lipoxygenase by Dietary Phenolics as an Anti-Inflammatory Mechanism: A Systematic Review. Int J Mol Sci 2021; 22:7937. [PMID: 34360703 PMCID: PMC8348464 DOI: 10.3390/ijms22157937] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/20/2021] [Accepted: 07/21/2021] [Indexed: 12/15/2022] Open
Abstract
5-Lipoxygenase (5-LOX) plays a key role in inflammation through the biosynthesis of leukotrienes and other lipid mediators. Current evidence suggests that dietary (poly)phenols exert a beneficial impact on human health through anti-inflammatory activities. Their mechanisms of action have mostly been associated with the modulation of pro-inflammatory cytokines (TNF-α, IL-1β), prostaglandins (PGE2), and the interaction with NF-κB and cyclooxygenase 2 (COX-2) pathways. Much less is known about the 5-lipoxygenase (5-LOX) pathway as a target of dietary (poly)phenols. This systematic review aimed to summarize how dietary (poly)phenols target the 5-LOX pathway in preclinical and human studies. The number of studies identified is low (5, 24, and 127 human, animal, and cellular studies, respectively) compared to the thousands of studies focusing on the COX-2 pathway. Some (poly)phenolics such as caffeic acid, hydroxytyrosol, resveratrol, curcumin, nordihydroguaiaretic acid (NDGA), and quercetin have been reported to reduce the formation of 5-LOX eicosanoids in vitro. However, the in vivo evidence is inconclusive because of the low number of studies and the difficulty of attributing effects to (poly)phenols. Therefore, increasing the number of studies targeting the 5-LOX pathway would largely expand our knowledge on the anti-inflammatory mechanisms of (poly)phenols.
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Affiliation(s)
- Juan Antonio Giménez-Bastida
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain;
| | - Antonio González-Sarrías
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain;
| | - José Moisés Laparra-Llopis
- Group of Molecular Immunonutrition in Cancer, Madrid Institute for Advanced Studies in Food (IMDEA-Food), 28049 Madrid, Spain;
| | - Claus Schneider
- Division of Clinical Pharmacology, Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, TN 37232, USA;
| | - Juan Carlos Espín
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Department Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Campus de Espinardo, 30100 Murcia, Spain;
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Ben Ghezala I, Charkaoui M, Michiels C, Bardou M, Luu M. Small Molecule Drugs in Inflammatory Bowel Diseases. Pharmaceuticals (Basel) 2021; 14:ph14070637. [PMID: 34209234 PMCID: PMC8308576 DOI: 10.3390/ph14070637] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 12/22/2022] Open
Abstract
Inflammatory bowel diseases (IBDs), mainly represented by Crohn’s disease (CD) and Ulcerative Colitis (UC), are chronic disorders with an unclear pathogenesis. This incurable and iterative intestinal mucosal inflammation requires the life-long use of anti-inflammatory drugs to prevent flares or relapses, which are the major providers of complications, such as small bowel strictures and intestinal perforations. The introduction of tumor necrosis factor (TNF)-alpha inhibitors and other compounds, such as anti-IL12/23 and anti-alpha4/beta7 integrin monoclonal antibodies, has considerably improved the clinical management of IBDs. They are now the standard of care, being the first-line therapy in patients with aggressive disease and in patients with moderate to severe disease with an inadequate response to conventional therapy. However, for approximately one third of all patients, their efficacy remains insufficient by a lack or loss of response due to the formation of anti-drug antibodies or compliance difficulties with parenteral formulations. To address these issues, orally administered Small Molecules Drugs (SMDs) that use a broad range of novel pharmacological pathways, such as JAK inhibitors, sphingosine-1-phosphate receptor modulators, and phosphodiesterase 4 inhibitors, have been developed for CD and UC. This article provides an updated and complete review of the most recently authorized SMDs and SMDs in phase II/III development.
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Affiliation(s)
- Inès Ben Ghezala
- INSERM, CIC1432, Plurithematic Unit, 21079 Dijon, France; (I.B.G.); (M.B.)
- Clinical Investigation Center, Plurithematic Unit, Dijon Bourgogne University Hospital, 21079 Dijon, France
- Ophthalmology Department, Dijon Bourgogne University Hospital, 21079 Dijon, France
| | - Maëva Charkaoui
- Gastroenterology Department, Dijon Bourgogne University Hospital, 21079 Dijon, France; (M.C.); (C.M.)
| | - Christophe Michiels
- Gastroenterology Department, Dijon Bourgogne University Hospital, 21079 Dijon, France; (M.C.); (C.M.)
| | - Marc Bardou
- INSERM, CIC1432, Plurithematic Unit, 21079 Dijon, France; (I.B.G.); (M.B.)
- Clinical Investigation Center, Plurithematic Unit, Dijon Bourgogne University Hospital, 21079 Dijon, France
- Gastroenterology Department, Dijon Bourgogne University Hospital, 21079 Dijon, France; (M.C.); (C.M.)
| | - Maxime Luu
- INSERM, CIC1432, Plurithematic Unit, 21079 Dijon, France; (I.B.G.); (M.B.)
- Clinical Investigation Center, Plurithematic Unit, Dijon Bourgogne University Hospital, 21079 Dijon, France
- Correspondence:
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28
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Tong Xie Yao Fang: A Classic Chinese Medicine Prescription with Potential for the Treatment of Ulcerative Colitis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5548764. [PMID: 34211567 PMCID: PMC8208878 DOI: 10.1155/2021/5548764] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/05/2021] [Accepted: 05/21/2021] [Indexed: 02/06/2023]
Abstract
The prescription of Tong Xie Yao Fang (TXYF) was derived from the Yuan dynasty “Dan Brook Heart Law,” which was a representative formula for treating liver-spleen disharmony, diarrhea, and abdominal pain. The prescription is composed of four herbs for soothing the liver and strengthening the spleen. TXYF is reportedly capable of eliminating discomfort in ulcerative colitis (UC). This classic formula has been widely used for regulating gastrointestinal motor dysfunction and repairing colon mucosa. This review aims to provide current information on the pharmacology and clinical research of TXYF in the treatment of UC, and to critically appraise that information, in order to guide the future clinical use and experimental study of TXYF in the treatment of UC. We searched online databases including PubMed, CNKI, and Google Scholar for research published between 2010 and 2020 on TXYF and its efficacy in the treatment of UC. The findings indicated that TXYF has anti-inflammatory and immunomodulatory effects, regulates cell signal transduction, brain-gut axis, and intestinal flora in UC, and may promote targeting of bone mesenchymal stem cells (BMSCs) to the colonic mucosa and accelerate healing of the colonic mucosal barrier. In addition, the results of clinical studies showed that TXYF has good efficacy and few adverse reactions in the treatment of UC. Although it has achieved some success, the research is limited by deficiencies; there is a lack of unified standards for the construction of UC animal models and for administration regimen. In addition, the dosage of TXYF is not consistent and lacks pharmacological verification, and clinical trial data are not detailed or sufficiently rigorous. Therefore, a more rigorous, comprehensive, and in-depth study of TXYF in the treatment of UC is needed.
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Wiendl M, Becker E, Müller TM, Voskens CJ, Neurath MF, Zundler S. Targeting Immune Cell Trafficking - Insights From Research Models and Implications for Future IBD Therapy. Front Immunol 2021; 12:656452. [PMID: 34017333 PMCID: PMC8129496 DOI: 10.3389/fimmu.2021.656452] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 04/16/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC) are multifactorial diseases with still unknown aetiology and an increasing prevalence and incidence worldwide. Despite plentiful therapeutic options for IBDs, the lack or loss of response in certain patients demands the development of further treatments to tackle this unmet medical need. In recent years, the success of the anti-α4β7 antibody vedolizumab highlighted the potential of targeting the homing of immune cells, which is now an important pillar of IBD therapy. Due to its complexity, leukocyte trafficking and the involved molecules offer a largely untapped resource for a plethora of potential therapeutic interventions. In this review, we aim to summarise current and future directions of specifically interfering with immune cell trafficking. We will comment on concepts of homing, retention and recirculation and particularly focus on the role of tissue-derived chemokines. Moreover, we will give an overview of the mode of action of drugs currently in use or still in the pipeline, highlighting their mechanisms and potential to reduce disease burden.
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Affiliation(s)
- Maximilian Wiendl
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Emily Becker
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Tanja M. Müller
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Caroline J. Voskens
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Sebastian Zundler
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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Kneusels J, Kaehler M, Cascorbi I, Wedel T, Neunlist M, Lucius R, Cossais F. Limited Impact of 6-Mercaptopurine on Inflammation-Induced Chemokines Expression Profile in Primary Cultures of Enteric Nervous System. Neurochem Res 2021; 46:1781-1793. [PMID: 33864170 PMCID: PMC8187225 DOI: 10.1007/s11064-021-03324-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/04/2021] [Accepted: 04/09/2021] [Indexed: 01/09/2023]
Abstract
Increasing evidences indicate that the enteric nervous system (ENS) and enteric glial cells (EGC) play important regulatory roles in intestinal inflammation. Mercaptopurine (6-MP) is a cytostatic compound clinically used for the treatment of inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease. However, potential impacts of 6-MP on ENS response to inflammation have not been evaluated yet. In this study, we aimed to gain deeper insights into the profile of inflammatory mediators expressed by the ENS and on the potential anti-inflammatory impact of 6-MP in this context. Genome-wide expression analyses were performed on ENS primary cultures exposed to lipopolysaccharide (LPS) and 6-MP alone or in combination. Differential expression of main hits was validated by quantitative real-time PCR (qPCR) using a cell line for EGC. ENS cells expressed a broad spectrum of cytokines and chemokines of the C-X-C motif ligand (CXCL) family under inflammatory stress. Induction of Cxcl5 and Cxcl10 by inflammatory stimuli was confirmed in EGC. Inflammation-induced protein secretion of TNF-α and Cxcl5 was partly inhibited by 6-MP in ENS primary cultures but not in EGC. Further work is required to identify the cellular mechanisms involved in this regulation. These findings extend our knowledge of the anti-inflammatory properties of 6-MP related to the ENS and in particular of the EGC-response to inflammatory stimuli.
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Affiliation(s)
- Jan Kneusels
- Institute of Anatomy, Kiel University, Kiel, Germany.
| | - Meike Kaehler
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel University, Kiel, Germany
| | - Ingolf Cascorbi
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel University, Kiel, Germany
| | - Thilo Wedel
- Institute of Anatomy, Kiel University, Kiel, Germany
| | | | - Ralph Lucius
- Institute of Anatomy, Kiel University, Kiel, Germany
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Rosen H. The Role of Small Molecule Inhibition of Leukocyte Trafficking in Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y) 2021; 17:175-177. [PMID: 34035777 PMCID: PMC8132633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Affiliation(s)
- Hugh Rosen
- Professor of Molecular Medicine Scripps Research La Jolla, California
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Ruiz F, Wyss A, Rossel JB, Sulz MC, Brand S, Moncsek A, Mertens JC, Roth R, Clottu AS, Burri E, Juillerat P, Biedermann L, Greuter T, Rogler G, Pot C, Misselwitz B. A single nucleotide polymorphism in the gene for GPR183 increases its surface expression on blood lymphocytes of patients with inflammatory bowel disease. Br J Pharmacol 2021; 178:3157-3175. [PMID: 33511653 DOI: 10.1111/bph.15395] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Affiliation(s)
- Florian Ruiz
- Laboratories of Neuroimmunology, Neuroscience Research Center and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Annika Wyss
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Jean-Benoît Rossel
- Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland
| | - Michael Christian Sulz
- Department of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Stephan Brand
- Department of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Anja Moncsek
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Joachim C Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - René Roth
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Aurélie S Clottu
- Laboratories of Neuroimmunology, Neuroscience Research Center and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Emanuel Burri
- Department of Gastroenterology and Hepatology, University Medical Clinic, Kantonsspital Baselland, Liestal, Switzerland
| | - Pascal Juillerat
- Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Luc Biedermann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Thomas Greuter
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Caroline Pot
- Laboratories of Neuroimmunology, Neuroscience Research Center and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Benjamin Misselwitz
- Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
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Lasa JS, Olivera PA, Bonovas S, Danese S, Peyrin-Biroulet L. Safety of S1P Modulators in Patients with Immune-Mediated Diseases: A Systematic Review and Meta-Analysis. Drug Saf 2021; 44:645-660. [PMID: 33666900 DOI: 10.1007/s40264-021-01057-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/15/2021] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Sphingosine-1-phosphate modulators are approved for the treatment of multiple sclerosis and are under development for other immune-mediated conditions; however, safety concerns have arisen. OBJECTIVE The objective of this systematic review was to investigate the safety profile of S1P modulators in patients with multiple sclerosis, ulcerative colitis, Crohn's disease, psoriasis, and systemic lupus erythematosus. METHODS We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from 1 January, 1990 through 1 April, 2020. We also performed a manual review of conference databases from 2017 through 2020. The primary outcome was the occurrence of adverse events and serious adverse events. We also estimated the occurrence of serious infections, herpes zoster infection, malignancy, bradycardia, atrio-ventricular block, and macular edema. We performed a meta-analysis of controlled studies to assess the risks of such events. RESULTS We identified 3843 citations; of these, 26 studies were finally included, comprising 9604 patients who were exposed to a sphingosine-1-phosphate modulator. A meta-analysis of randomized controlled trials showed an increased risk in herpes zoster infection [risk ratio, 1.75 (95% confidence interval 1.09-2.80)], bradycardia [2.64 (1.77-3.96)], and atrio-ventricular block [1.73 (1.03-2.91)] among subjects exposed to sphingosine-1-phosphate modulators as compared with a placebo or an active comparator. CONCLUSIONS We found an increased risk of herpes zoster infection, and transient cardiovascular events among patients treated with sphingosine-1-phosphate modulators. CLINICAL TRIAL REGISTRATION PROSPERO CRD42020172575.
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Affiliation(s)
- Juan S Lasa
- IBD Unit, Gastroenterology Section, Department of Internal Medicine, Centro de Educación Médica e Investigación Clínica (CEMIC), Buenos Aires, Argentina.,Gastroenterology Department, Hospital Británico de Buenos Aires, Buenos Aires, Argentina
| | - Pablo A Olivera
- IBD Unit, Gastroenterology Section, Department of Internal Medicine, Centro de Educación Médica e Investigación Clínica (CEMIC), Buenos Aires, Argentina
| | - Stefanos Bonovas
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IBD Unit, Humanitas Clinical and Research Center-IRCCS, Milan, Italy
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IBD Unit, Humanitas Clinical and Research Center-IRCCS, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Hepatogastroenterology, INSERM NGERE, Nancy University Hospital, Lorraine University, Allée du Morvan, 54511, Vandoeuvre-lès-Nancy, France.
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Wang X, Chen S, Xiang H, Liang Z, Lu H. Role of sphingosine-1-phosphate receptors in vascular injury of inflammatory bowel disease. J Cell Mol Med 2021; 25:2740-2749. [PMID: 33595873 PMCID: PMC7957208 DOI: 10.1111/jcmm.16333] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 01/12/2021] [Accepted: 01/18/2021] [Indexed: 12/14/2022] Open
Abstract
Sphingosine‐1‐phosphate receptors (S1PRs) have an impact on the intestinal inflammation of inflammatory bowel disease (IBD) by regulating lymphocyte migration and differentiation. S1PR modulators as an emerging therapeutic approach are being investigated for the treatment of IBD. However, the role of S1PRs in intestinal vessels has not drawn much attention. Intestinal vascular damage is one of the major pathophysiological features of IBD, characterized by increased vascular density and impaired barrier function. S1PRs have pleiotropic effects on vascular endothelial cells, including proliferation, migration, angiogenesis and barrier homeostasis. Mounting evidence shows that S1PRs are abnormally expressed on intestinal vascular endothelial cells in IBD. Unexpectedly, S1PR modulators may damage intestinal vasculature, for example increase intestinal bleeding; therefore, S1PRs are thought to be involved in the regulation of intestinal vascular function in IBD. However, little is understood about how S1PRs regulate intestinal vascular function and participate in the initiation and progression of IBD. In this review, we summarize the pathogenic role of S1PRs in and the underlying mechanisms behind the intestinal vascular injury in IBD in order for improving IBD practice including S1PR‐targeted therapies.
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Affiliation(s)
- Xuewen Wang
- Center for Experimental Medicine, the Third Xiangya Hospital of Central South University, Changsha, China.,Department of Cardiology, the Third Xiangya Hospital of Central South University, Changsha, China
| | - Shuhua Chen
- Department of Biochemistry, School of Life Sciences of Central South University, Changsha, China
| | - Hong Xiang
- Center for Experimental Medicine, the Third Xiangya Hospital of Central South University, Changsha, China
| | - Ziwei Liang
- Department of Clinical laboratory, Yueyang Hospital Affiliated to Hunan Normal University, Yueyang, China
| | - Hongwei Lu
- Center for Experimental Medicine, the Third Xiangya Hospital of Central South University, Changsha, China.,Department of Cardiology, the Third Xiangya Hospital of Central South University, Changsha, China
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35
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Misselwitz B, Wyss A, Raselli T, Cerovic V, Sailer AW, Krupka N, Ruiz F, Pot C, Pabst O. The oxysterol receptor GPR183 in inflammatory bowel diseases. Br J Pharmacol 2021; 178:3140-3156. [PMID: 33145756 DOI: 10.1111/bph.15311] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 09/29/2020] [Accepted: 10/12/2020] [Indexed: 12/15/2022] Open
Abstract
Immune cell trafficking is an important mechanism for the pathogenesis of inflammatory bowel disease (IBD). The oxysterol receptor GPR183 and its ligands, dihydroxylated oxysterols, can mediate positioning of immune cells including innate lymphoid cells. GPR183 has been mapped to an IBD risk locus, however another gene, Ubac2 is encoded on the reverse strand and associated with Behçet's disease, therefore the role of GPR183 as a genetic risk factor requires validation. GPR183 and production of its oxysterol ligands are up-regulated in human IBD and murine colitis. Gpr183 inactivation reduced severity of colitis in group 3 innate lymphoid cells-dependent colitis and in IL-10 colitis but not in dextran sodium sulphate colitis. Irrespectively, Gpr183 knockout strongly reduced accumulation of intestinal lymphoid tissue in health and all colitis models. In conclusion, genetic, translational and experimental studies implicate GPR183 in IBD pathogenesis and GPR183-dependent cell migration might be a therapeutic drug target for IBD. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.
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Affiliation(s)
- Benjamin Misselwitz
- Gastroenterology, University Hospital of Visceral Surgery and Medicine, Inselspital Bern and Bern University, Bern, Switzerland
| | - Annika Wyss
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Tina Raselli
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Vuk Cerovic
- Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany
| | - Andreas W Sailer
- Disease Area X, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Niklas Krupka
- Gastroenterology, University Hospital of Visceral Surgery and Medicine, Inselspital Bern and Bern University, Bern, Switzerland
| | - Florian Ruiz
- Service of Neurology, University of Lausanne, Lausanne, Switzerland.,Department of Clinical Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Caroline Pot
- Service of Neurology, University of Lausanne, Lausanne, Switzerland.,Department of Clinical Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Oliver Pabst
- Institute of Molecular Medicine, RWTH Aachen University, Aachen, Germany
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An integrin αEβ7-dependent mechanism of IgA transcytosis requires direct plasma cell contact with intestinal epithelium. Mucosal Immunol 2021; 14:1347-1357. [PMID: 34417548 PMCID: PMC8528714 DOI: 10.1038/s41385-021-00439-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/09/2021] [Accepted: 07/31/2021] [Indexed: 02/04/2023]
Abstract
Efficient IgA transcytosis is critical for the maintenance of a homeostatic microbiota. In the canonical model, locally-secreted dimeric (d)IgA reaches the polymeric immunoglobulin receptor (pIgR) on intestinal epithelium via simple diffusion. A role for integrin αE(CD103)β7 during transcytosis has not been described, nor its expression by intestinal B cell lineage cells. We found that αE-deficient (αE-/-) mice have a luminal IgA deficit, despite normal antibody-secreting cells (ASC) recruitment, local IgA production and increased pIgR expression. This deficit was not due to dendritic cell (DC)-derived retinoic acid (RA) nor class-switching defects, as stool from RAG-/- mice reconstituted with αE-/- B cells was also IgA deficient. Flow cytometric, ultrastructural and transcriptional profiling showed that αEβ7-expressing ASC represent an undescribed subset of terminally-differentiated intestinal plasma cells (PC) that establishes direct cell to cell contact with intestinal epithelium. We propose that IgA not only reaches pIgR through diffusion, but that αEβ7+ PC dock with E-cadherin-expressing intestinal epithelium to directly relay IgA for transcytosis into the intestinal lumen.
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Zobeiri M, Momtaz S, Parvizi F, Tewari D, Farzaei MH, Nabavi SM. Targeting Mitogen-Activated Protein Kinases by Natural Products: A Novel Therapeutic Approach for Inflammatory Bowel Diseases. Curr Pharm Biotechnol 2020; 21:1342-1353. [PMID: 31840607 DOI: 10.2174/1389201021666191216122555] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 08/01/2019] [Accepted: 11/21/2019] [Indexed: 12/11/2022]
Abstract
An increase in the prevalence of Inflammatory Bowel Diseases (IBD) as a multifactorial intestinal chronic inflammation as well as the absence of a certain cure, has created an innovative era in the management of IBD by molecule/pathway-based anti-inflammatory approaches. There are credible documentations that demonstrate Mitogen-Activated Protein Kinases (MAPK) acts as IBD regulator. Upon the activation of MAPK signalling pathway, the transcription and expression of various encoding inflammatory molecules implicated in IBD are altered, thereby exacerbating the inflammation development. The current pharmacological management of IBD, including drug and biological therapies are expensive, possess temporary relief and some adverse effects. In this context, a variety of dietary fruits or medicinal herbs have received worldwide attention versus the development of IBD. Infact, natural ingredients, such as Flavaglines, Fisetin, Myricitrin, Cardamonin, Curcumin, Octacosanol and Mangiferin possess protective and therapeutic effects against IBD via modulation of different segments of MAPK signaling pathway. This review paper calls attention to the role of MAPK signaling triggered by natural products in the prevention and treatment of IBD.
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Affiliation(s)
- Mehdi Zobeiri
- Internal Medicine Department, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran,Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran,Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Fatemeh Parvizi
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Devesh Tewari
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144 411, India
| | - Mohammad H Farzaei
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Seyed M Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Gilardi D, Gabbiadini R, Allocca M, Correale C, Fiorino G, Furfaro F, Zilli A, Peyrin-Biroulet L, Danese S. PK, PD, and interactions: the new scenario with JAK inhibitors and S1P receptor modulators, two classes of small molecule drugs, in IBD. Expert Rev Gastroenterol Hepatol 2020; 14:797-806. [PMID: 32571107 DOI: 10.1080/17474124.2020.1785868] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Inflammatory bowel diseases (IBDs) are immune-mediated chronic inflammatory disorders of the gastrointestinal tract whose pathogenesis is not yet fully understood. Despite the advent of biological agents, there are still unmet needs for IBD patients, due to suboptimal rate of sustained remission achieved. Small molecule drugs (SMDs), the next generation of selective drugs in IBD, show promising results in ongoing trials. AREAS COVERED We describe the pharmacodynamics and pharmacokinetic features of novel SMDs and their main differences with biologic agents. EXPERT OPINION Small molecule drugs are a promising class of drugs for the treatment of ulcerative colitis and Crohn's disease with good results in inducing and maintaining remission. Hence, over the next few years physicians will have numerous options of small molecule drugs for the treatment of patients with IBD. This group of drugs are potentially easier to use over biological agents due to pharmacokinetic features such as oral administration, short half-life, high volume of distribution, and lack of immunogenicity. On the other hand, drug-drug interactions can happen with small-molecule drugs, principally due to competitive metabolic and clearance mechanisms.
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Affiliation(s)
- Daniela Gilardi
- Humanitas Clinical and Research Center - IRCCS , Milan, Italy
| | | | - Mariangela Allocca
- Humanitas Clinical and Research Center - IRCCS , Milan, Italy.,Department of Biomedical Sciences, Humanitas University , Milan, Italy
| | - Carmen Correale
- Humanitas Clinical and Research Center - IRCCS , Milan, Italy
| | - Gionata Fiorino
- Humanitas Clinical and Research Center - IRCCS , Milan, Italy.,Department of Biomedical Sciences, Humanitas University , Milan, Italy
| | | | | | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm U954, Nancy University Hospital, Lorraine University , Vandoeuvre, France
| | - Silvio Danese
- Humanitas Clinical and Research Center - IRCCS , Milan, Italy.,Department of Biomedical Sciences, Humanitas University , Milan, Italy
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Rivera-Nieves J. Targeting Beta-7 Integrins for the Treatment of Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y) 2020; 16:367-369. [PMID: 34035742 PMCID: PMC8132642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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40
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Han Q, Tang HZ, Zou M, Zhao J, Wang L, Bian ZX, Li YH. Anti-inflammatory Efficacy of Combined Natural Alkaloid Berberine and S1PR Modulator Fingolimod at Low Doses in Ulcerative Colitis Preclinical Models. JOURNAL OF NATURAL PRODUCTS 2020; 83:1939-1949. [PMID: 32432470 DOI: 10.1021/acs.jnatprod.0c00175] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
The natural alkaloid berberine is being studied as a drug candidate for the treatment of ulcerative colitis (UC). Fingolimod is an immunomodulator approved for the treatment of multiple sclerosis. Whether fingolimod use can be extended to UC and how it interacts with berberine remain unclear. In the present study, the anti-inflammatory efficacies of berberine, fingolimod, and a combination of half-doses of them was examined in mice with dextran sulfate sodium-induced colitis. In mice with subchronic colitis, 14-day oral administration of fingolimod had greater efficacy than berberine in ameliorating the disease clinical severity and colon shortening. However, in mice with chronic colitis, 30-day oral administration of berberine was more effective than fingolimod except on splenic swelling. Notably, the combination of half-doses of each drug was equally effective as the superior single drugs for two models and resulted in reduced splenic swelling in the chronic colitis model. The inhibition of cytokine expression and STAT3 activation, as well as binding to the sphingosine 1-phosphate receptor by both drugs, contributed to the combination efficacy. Our findings suggest that fingolimod in combination with berberine at reduced doses represents a novel therapy for UC that attains satisfactory efficacy with reduced potentials for adverse effects.
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Affiliation(s)
- Qian Han
- School of Medicine, South China University of Technology, Guangzhou 510641, China
| | - Hua-Zheng Tang
- School of Medicine, South China University of Technology, Guangzhou 510641, China
| | - Min Zou
- School of Medicine, South China University of Technology, Guangzhou 510641, China
| | - Jie Zhao
- School of Medicine, South China University of Technology, Guangzhou 510641, China
| | - Ling Wang
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510641, China
| | - Zhao-Xiang Bian
- Lab of Brain and Gut Research, Hong Kong Chinese Medicine Research Center, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Yan-Hong Li
- School of Medicine, South China University of Technology, Guangzhou 510641, China
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, United States
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Giménez-Bastida JA, González-Sarrías A, Espín JC, Schneider C. Inhibition of 5-Lipoxygenase-Derived Leukotrienes and Hemiketals as a Novel Anti-Inflammatory Mechanism of Urolithins. Mol Nutr Food Res 2020; 64:e2000129. [PMID: 32306507 DOI: 10.1002/mnfr.202000129] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 03/27/2020] [Indexed: 12/20/2022]
Abstract
SCOPE Urolithins (Uro), gut microbial metabolites derived from ellagic acid (EA), reach significant concentrations in the human colon. Uro-A exerts anti-inflammatory activity in animal models of inflammatory bowel diseases (IBDs). It is hypothesized that Uro can modulate the biosynthesis of leukocyte-derived inflammatory eicosanoids from the 5-lipoxygenase (5-LOX), cyclooxygenase-2 (COX-2), and 5-LOX/COX-2 pathways, relevant in the onset and progression of IBDs, including 5-hydroxyeicosatetraenoic acids (5-HETEs), leukotriene-B4 (LTB4 ), prostaglandin E2 (PGE2 ), and hemiketals (HKE2 and HKD2 ). METHODS AND RESULTS Leukocytes, obtained from six healthy donors, are stimulated with lipopolysaccharide and calcium ionophore A23187. Uro, at concentrations found in the human colon (1-15 µm), decrease eicosanoid biosynthesis and COX-2 levels in the activated leukocytes. In contrast, EA and conjugated Uro (glucuronides and sulfates) are inactive. Uro-A and isourolithin-A reduce the formation of the 5-LOX/COX-2 products HKE2 and HKD2 through the COX-2 pathway (down-regulation of COX-2 and PGE2), whereas Uro-C reduces 5-HETE and LTB4 via inhibition of 5-LOX. CONCLUSIONS The results show that physiologically relevant colonic Uro target eicosanoid biosynthetic pathways. The effect on HKs and LTB4 formation is unprecedented and expands the knowledge on anti-inflammatory mechanisms of Uro against IBDs.
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Affiliation(s)
- Juan Antonio Giménez-Bastida
- Department of Pharmacology and Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, TN, 37232, USA.,Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Dept. Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Murcia, Campus de Espinardo, 30100, Spain
| | - Antonio González-Sarrías
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Dept. Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Murcia, Campus de Espinardo, 30100, Spain
| | - Juan Carlos Espín
- Laboratory of Food and Health, Research Group on Quality, Safety and Bioactivity of Plant Foods, Dept. Food Science and Technology, CEBAS-CSIC, P.O. Box 164, Murcia, Campus de Espinardo, 30100, Spain
| | - Claus Schneider
- Department of Pharmacology and Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, TN, 37232, USA
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Tyler CJ, Guzman M, Lundborg LR, Yeasmin S, Perez-Jeldres T, Yarur A, Behm B, Dulai PS, Patel D, Bamias G, Rivera-Nieves J. Inherent Immune Cell Variation Within Colonic Segments Presents Challenges for Clinical Trial Design. J Crohns Colitis 2020; 14:1364-1377. [PMID: 32239151 PMCID: PMC7533898 DOI: 10.1093/ecco-jcc/jjaa067] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Intestinal biopsy sampling during IBD trials represents a valuable adjunct strategy for understanding drug responses at the tissue level. Given the length and distinctive embryonic origins of the proximal and distal colon, we investigated whether inherent regional differences of immune cell composition could introduce confounders when sampling different disease stages, or pre/post drug administration. Here, we capitalise on novel mass cytometry technology to perform deep immunophenotyping of distinct healthy colonic segments, using the limited numbers of biopsies that can be harvested from patients. METHODS Biopsies [2.8 mm] were collected from the caecum, transverse colon, descending colon, and rectum of normal volunteers. Intestinal leukocytes were isolated, stained with a panel of 37 antibodies, and mass cytometry data acquired. RESULTS Site-specific patterns of leukocyte localisation were observed. The proximal colon featured increased CD8+ T cells [particularly resident memory], monocytes, and CD19+ B cells. Conversely, the distal colon and rectum tissues exhibited enrichment for CD4+ T cells and antibody-secreting cells. The transverse colon displayed increased abundance of both γδ T cells and NK cells. Subsets of leukocyte lineages also displayed gradients of expression along the colon length. CONCLUSIONS Our results show an inherent regional immune cell variation within colonic segments, indicating that regional mucosal signatures must be considered when assessing disease stages or the prospective effects of trial drugs on leukocyte subsets. Precise protocols for intestinal sampling must be implemented to allow for the proper interpretation of potential differences observed within leukocyte lineages present in the colonic lamina propria.
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Affiliation(s)
- Christopher J Tyler
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA,San Diego VA Medical Center, San Diego, CA, USA
| | - Mauricio Guzman
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA,San Diego VA Medical Center, San Diego, CA, USA
| | - Luke R Lundborg
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA,San Diego VA Medical Center, San Diego, CA, USA
| | - Shaila Yeasmin
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA,San Diego VA Medical Center, San Diego, CA, USA
| | - Tamara Perez-Jeldres
- Universidad Católica de Chile, Santiago, Chile,Hospital San Borja Arriarán, Santiago, Chile
| | - Andres Yarur
- Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Brian Behm
- Division of Gastroenterology, University of Virginia, Charlottesville, VI, USA
| | | | - Derek Patel
- San Diego VA Medical Center, San Diego, CA, USA
| | - Giorgos Bamias
- GI Unit, 3rd Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece
| | - Jesús Rivera-Nieves
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA,San Diego VA Medical Center, San Diego, CA, USA,Corresponding author: Jesús Rivera-Nieves, MD, Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, 9500 Gilman Drive Bldg. BRF-II Rm. 4A32, San Diego, CA 92093-0063. Tel.: 858.534.5495; fax: 858.246.1788;
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Sandborn WJ, Peyrin-Biroulet L, Zhang J, Chiorean M, Vermeire S, Lee SD, Kühbacher T, Yacyshyn B, Cabell CH, Naik SU, Klassen P, Panés J. Efficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients With Ulcerative Colitis. Gastroenterology 2020; 158:550-561. [PMID: 31711921 DOI: 10.1053/j.gastro.2019.10.035] [Citation(s) in RCA: 159] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 10/25/2019] [Accepted: 10/29/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Etrasimod (APD334) is an oral, selective sphingosine 1-phosphate receptor modulator in development for immune-mediated inflammatory disorders. We assessed the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis (UC). METHODS In a phase 2, proof-of-concept, double-blind, parallel-group study, adult outpatients with modified Mayo Clinic scores (MCSs) (stool frequency, rectal bleeding, and endoscopy findings) of 4-9, endoscopic subscores of 2 or more, and rectal bleeding subscores of 1 or more were randomly assigned to groups given once-daily etrasimod 1 mg (n = 52), etrasimod 2 mg (n = 50), or placebo (n = 54) for 12 weeks. The study was performed from October 15, 2015, through February 14, 2018, at 87 centers in 17 countries. The primary endpoint was an increase in the mean improvement in modified MCS from baseline to week 12. Secondary endpoints included the proportion of patients with endoscopic improvement (subscores of 1 or less) from baseline to week 12. Exploratory endpoints, including clinical remission, are reported in the article, although the study was statistically powered to draw conclusions only on the primary endpoint. RESULTS At week 12, the etrasimod 2 mg group met the primary and all secondary endpoints. Etrasimod 2 mg led to a significantly greater increase in mean improvement in modified MCS from baseline than placebo (difference from placebo, 0.99 points; 90% confidence interval, 0.30-1.68; P = .009), and etrasimod 1 mg led to an increase in mean improvement from baseline in modified MCS of 0.43 points more than placebo (90% confidence interval, reduction of 0.24 to increase of 1.11; nominal P = .15). Endoscopic improvement occurred in 41.8% of patients receiving etrasimod 2 mg vs 17.8% receiving placebo (P = .003). Most adverse events were mild to moderate. Three patients had a transient, asymptomatic, low-grade atrioventricular block that resolved spontaneously all patients had evidence of atrioventricular block before etrasimod exposure. CONCLUSIONS In patients with moderately to severely active ulcerative colitis, etrasimod 2 mg was more effective than placebo in producing clinical and endoscopic improvements. Further clinical development is warranted. Clinicaltrials.gov, Number: NCT02447302.
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Affiliation(s)
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Jinkun Zhang
- Arena Pharmaceuticals, Inc, San Diego, California
| | - Michael Chiorean
- Division of Gastroenterology, Virginia Mason Medical Center, Seattle, Washington
| | - Séverine Vermeire
- Department of Gastroenterology & Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Scott D Lee
- University of Washington Medical Center, Seattle, Washington
| | - Tanja Kühbacher
- Asklepios Westklinikum Hamburg and Christian Albrechts University, Hamburg, Germany
| | - Bruce Yacyshyn
- Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio
| | | | | | | | - Julián Panés
- Hospital Clinic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
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Shimano K, Maeda Y, Kataoka H, Murase M, Mochizuki S, Utsumi H, Oshita K, Sugahara K. Amiselimod (MT-1303), a novel sphingosine 1-phosphate receptor-1 functional antagonist, inhibits progress of chronic colitis induced by transfer of CD4+CD45RBhigh T cells. PLoS One 2019; 14:e0226154. [PMID: 31805144 PMCID: PMC6894856 DOI: 10.1371/journal.pone.0226154] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 11/20/2019] [Indexed: 02/07/2023] Open
Abstract
Amiselimod (MT-1303) is a novel sphingosine 1-phosphate receptor-1 (S1P1 receptor) modulator with a more favorable cardiac safety profile than other S1P1 receptor modulators. MT-1303 phosphate (MT-1303-P), an active metabolite of MT-1303, exhibits S1P1 receptor agonism at a lower EC50 value than other S1P1 receptor modulators currently being developed. We aimed to evaluate the efficacy of MT-1303 and its mode of action in chronic colitis using an inflammatory bowel disease (IBD) model. Oral administration of MT-1303 (0.3 mg/kg) once daily for 3 days to mice almost completely abolished S1P1 receptor expression on CD4+ T cells from mesenteric lymph nodes, which corresponded to a marked decrease in CD4+ T cell count in peripheral blood, indicating that MT-1303-P acts as a functional antagonist of the S1P1 receptor. The potential benefit of MT-1303 for IBD was assessed using immunodeficient SCID mice with chronic colitis induced by adoptive transfer of CD4+CD45RBhigh T cells from BALB/c mice. An oral dose of 0.1 and 0.3 mg/kg MT-1303 administered daily one week after the cell transfer inhibited the development of chronic colitis with an efficacy comparable to that of an anti-mTNF-α mAb (250 μg/mouse). In addition, MT-1303 administration significantly reduced the number of infiltrating Th1 and Th17 cells into the lamina propria of the colon in colitis mice. Our results suggest that MT-1303 acts as a functional antagonist of the S1P1 receptor on lymphocytes, regulates lymphocyte trafficking, and inhibits infiltration of colitogenic Th1 and Th17 cells into the colon to inhibit the development of chronic colitis.
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Affiliation(s)
- Kyoko Shimano
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
| | - Yasuhiro Maeda
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
| | - Hirotoshi Kataoka
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
| | - Mikako Murase
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
| | - Sachiko Mochizuki
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
| | - Hiroyuki Utsumi
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
| | - Koichi Oshita
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
| | - Kunio Sugahara
- Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan
- * E-mail:
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Lin E, Lin K, Katz S. Serious and Opportunistic Infections in Elderly Patients With Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y) 2019; 15:593-605. [PMID: 31802985 PMCID: PMC6883733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Inflammatory bowel disease (IBD) is often treated with biologics and immunomodulators, which can place elderly IBD patients at risk for serious and opportunistic infections. This article provides an updated account of research on therapies in IBD that are associated with an increased infection risk. Relevant serious and opportunistic infections in the elderly population are discussed along with methods for prevention and treatment. The incidence of infection increases with age and the degree of immunosuppression. Emphasis should be placed on performing vaccinations at the time of IBD diagnosis. Additionally, patients receiving immunosuppressive therapy should avoid live vaccines. Physicians should have a greater awareness of the increased risk of infection in elderly adults and the need for screening for infection prior to initiation of immunosuppressive IBD therapies.
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Affiliation(s)
- Elissa Lin
- Dr Elissa Lin is a resident in the Department of Internal Medicine at NYU Langone Medical Center in New York, New York
- Mr Kevin Lin is a medical student and Dr Katz is a clinical professor of medicine at NYU School of Medicine in New York, New York
| | - Kevin Lin
- Dr Elissa Lin is a resident in the Department of Internal Medicine at NYU Langone Medical Center in New York, New York
- Mr Kevin Lin is a medical student and Dr Katz is a clinical professor of medicine at NYU School of Medicine in New York, New York
| | - Seymour Katz
- Dr Elissa Lin is a resident in the Department of Internal Medicine at NYU Langone Medical Center in New York, New York
- Mr Kevin Lin is a medical student and Dr Katz is a clinical professor of medicine at NYU School of Medicine in New York, New York
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Yang JHM, Khatri L, Mickunas M, Williams E, Tatovic D, Alhadj Ali M, Young P, Moyle P, Sahni V, Wang R, Kaur R, Tannahill GM, Beaton AR, Gerlag DM, Savage COS, Napolitano Rosen A, Waldron-Lynch F, Dayan CM, Tree TIM. Phenotypic Analysis of Human Lymph Nodes in Subjects With New-Onset Type 1 Diabetes and Healthy Individuals by Flow Cytometry. Front Immunol 2019; 10:2547. [PMID: 31749806 PMCID: PMC6842967 DOI: 10.3389/fimmu.2019.02547] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 10/14/2019] [Indexed: 12/18/2022] Open
Abstract
Background: Ultrasound guided sampling of human lymph node (LN) combined with advanced flow cytometry allows phenotypic analysis of multiple immune cell subsets. These may provide insights into immune processes and responses to immunotherapies not apparent from analysis of the blood. Methods: Ultrasound guided inguinal LN samples were obtained by both fine needle aspiration (FNA) and core needle biopsy in 10 adults within 8 weeks of diagnosis of type 1 diabetes (T1D) and 12 age-matched healthy controls at two study centers. Peripheral blood mononuclear cells (PBMC) were obtained on the same occasion. Samples were transported same day to the central laboratory and analyzed by multicolour flow cytometry. Results: LN sampling was well-tolerated and yielded sufficient cells for analysis in 95% of cases. We confirmed the segregation of CD69+ cells into LN and the predominance of CD8+ Temra cells in blood previously reported. In addition, we demonstrated clear enrichment of CD8+ naïve, FOXP3+ Treg, class-switched B cells, CD56bright NK cells and plasmacytoid dendritic cells (DC) in LNs as well as CD4+ T cells of the Th2 phenotype and those expressing Helios and Ki67. Conventional NK cells were virtually absent from LNs as were Th22 and Th1Th17 cells. Paired correlation analysis of blood and LN in the same individuals indicated that for many cell subsets, especially those associated with activation: such as CD25+ and proliferating (Ki67+) T cells, activated follicular helper T cells and class-switched B cells, levels in the LN compartment could not be predicted by analysis of blood. We also observed an increase in Th1-like Treg and less proliferating (Ki67+) CD4+ T cells in LN from T1D compared to control LNs, changes which were not reflected in the blood. Conclusions: LN sampling in humans is well-tolerated. We provide the first detailed “roadmap” comparing immune subsets in LN vs. blood emphasizing a role for differentiated effector T cells in the blood and T cell regulation, B cell activation and memory in the LN. For many subsets, frequencies in blood, did not correlate with LN, suggesting that LN sampling would be valuable for monitoring immuno-therapies where these subsets may be impacted.
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Affiliation(s)
- Jennie H M Yang
- Department of Immunobiology, School of Immunology & Microbial Sciences (SIMS), King's College London, London, United Kingdom.,NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, United Kingdom
| | - Leena Khatri
- Department of Immunobiology, School of Immunology & Microbial Sciences (SIMS), King's College London, London, United Kingdom.,NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, United Kingdom
| | - Marius Mickunas
- Department of Immunobiology, School of Immunology & Microbial Sciences (SIMS), King's College London, London, United Kingdom.,NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, United Kingdom
| | - Evangelia Williams
- Department of Immunobiology, School of Immunology & Microbial Sciences (SIMS), King's College London, London, United Kingdom.,NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, United Kingdom
| | - Danijela Tatovic
- Diabetes/Autoimmunity Research Group, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Mohammad Alhadj Ali
- Diabetes/Autoimmunity Research Group, Cardiff University School of Medicine, Cardiff, United Kingdom
| | | | - Penelope Moyle
- Experimental Medicine and Immunotherapeutics (EMIT), Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Vishal Sahni
- GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom
| | - Ryan Wang
- GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom
| | - Rejbinder Kaur
- GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom
| | | | - Andrew R Beaton
- GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom
| | - Danielle M Gerlag
- GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom
| | | | | | - Frank Waldron-Lynch
- Experimental Medicine and Immunotherapeutics (EMIT), Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Colin M Dayan
- Diabetes/Autoimmunity Research Group, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Timothy I M Tree
- Department of Immunobiology, School of Immunology & Microbial Sciences (SIMS), King's College London, London, United Kingdom.,NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, United Kingdom
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Target-Specific Fluorescence-Mediated Tomography for Non-Invasive and Dynamic Assessment of Early Neutrophil Infiltration in Murine Experimental Colitis. Cells 2019; 8:cells8111328. [PMID: 31661876 PMCID: PMC6912230 DOI: 10.3390/cells8111328] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 10/18/2019] [Accepted: 10/26/2019] [Indexed: 12/13/2022] Open
Abstract
The role of neutrophils in the pathogenesis of inflammatory bowel disease (IBD) is still only incompletely understood. Here, we evaluated target-specific fluorescence-mediated tomography (FMT) for visualization of neutrophil infiltration in murine experimental DSS-induced colitis. Colitis was assessed using clinical, endoscopic, and histopathological parameters. Intestinal neutrophil infiltration was determined at day 0, 4, and 10 by targeted FMT after injection of a neutrophil-specific fluorescence-labelled monoclonal antibody (Gr-1). Complementary, immunofluorescence tissue sections with Gr-1 and ELISA-based assessment of tissue myeloperoxidase (MPO) served as the gold standard for the quantification of neutrophil infiltration. Colitic animals showed decreasing body weight, presence of fecal occult blood, and endoscopic signs of inflammation. FMT revealed a significantly increased level of fluorescence only four days after colitis induction as compared to pre-experimental conditions (pmol tracer 73.2 ± 18.1 versus 738.6 ± 80.7; p < 0.05), while neither body weight nor endoscopic assessment showed significant changes at this early time. Confirmatory, post-mortem immunofluorescence studies and measurements of tissue MPO confirmed the presence of increased neutrophil infiltration in colitic mice compared to controls. Concluding, Gr-1 targeted FMT can detect early colonic infiltration of neutrophils in experimental colitis even before clinical symptoms or endoscopic alterations occur. Therefore, FMT might be an important tool for repetitive and non-invasive monitoring of inflammatory cell infiltrate in intestinal inflammation.
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Zundler S, Becker E, Schulze LL, Neurath MF. Immune cell trafficking and retention in inflammatory bowel disease: mechanistic insights and therapeutic advances. Gut 2019; 68:1688-1700. [PMID: 31127023 DOI: 10.1136/gutjnl-2018-317977] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/01/2019] [Accepted: 05/03/2019] [Indexed: 12/12/2022]
Abstract
Intestinal immune cell trafficking has been identified as a central event in the pathogenesis of inflammatory bowel diseases (IBD). Intensive research on different aspects of the immune mechanisms controlling and controlled by T cell trafficking and retention has led to the approval of the anti-α4β7 antibody vedolizumab, the ongoing development of a number of further anti-trafficking agents (ATAs) such as the anti-β7 antibody etrolizumab or the anti-MAdCAM-1 antibody ontamalimab and the identification of potential future targets like G-protein coupled receptor 15. However, several aspects of the biology of immune cell trafficking and regarding the mechanism of action of ATAs are still unclear, for example, which impact these compounds have on the trafficking of non-lymphocyte populations like monocytes and how precisely these therapies differ with regard to their effect on immune cell subpopulations. This review will summarise recent advances of basic science in the field of intestinal immune cell trafficking and discuss these findings with regard to different pharmacological approaches from a translational perspective.
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Affiliation(s)
- Sebastian Zundler
- Department of Medicine 1, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Emily Becker
- Department of Medicine 1, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Lisa Lou Schulze
- Department of Medicine 1, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
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49
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Roosenboom B, Wahab PJ, Smids C, Groenen MJM, van Koolwijk E, van Lochem EG, Horjus Talabur Horje CS. Intestinal CD103+CD4+ and CD103+CD8+ T-Cell Subsets in the Gut of Inflammatory Bowel Disease Patients at Diagnosis and During Follow-up. Inflamm Bowel Dis 2019; 25:1497-1509. [PMID: 30918941 PMCID: PMC6701511 DOI: 10.1093/ibd/izz049] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND The integrin CD103 is proposed to be a potential therapeutical target in inflammatory bowel disease (IBD), as it can form a heterodimeric integrin with β7 (Etrolizumab, anti-β7 integrin) on epithelial T cells. Therefore, we aimed to study the frequencies of different intestinal CD103+T-cell subsets, both CD4+ and CD8+, in newly diagnosed, untreated IBD patients at baseline and during follow-up, compared with healthy controls. METHODS Intestinal biopsies from inflamed segments during colonoscopy and peripheral blood samples were prospectively taken from IBD patients at diagnosis and during follow-up. Blood and single cell suspensions from biopsies were analyzed for CD103+ T-cell subpopulations by flow cytometry and expressed as median percentages of the total T-cell population. RESULTS In total, 75 Crohn's disease (CD) patients, 49 ulcerative colitis (UC) patients, and 16 healthy controls were included. At presentation, IBD patients displayed lower percentages of CD103+T-cell subsets in inflamed biopsies: 3% (1 to 5) CD103+CD4+ in IBD vs 5% (5 to 7) in healthy controls (P = 0.007) and 9% (4 to 15) CD103+CD8+ compared with 42% (23 to 57) in healthy controls (P = 0.001). The majority of intestinal T cells was composed of CD103-CD4+ T cells (65% [52 to 74]) in IBD compared with 30% (21 to 50) in healthy controls (P = 0.001). In patients with endoscopic remission during follow-up (n = 27), frequencies of CD103+ and CD103-T-cell subsets were comparable with healthy controls. CONCLUSION At diagnosis, active inflammation in IBD was associated with decreased percentages of both CD103+CD4+ and CD103+CD8+T-cell subsets in colon and ileum biopsies. In active disease during follow-up, these T-cell populations remained low but increased in remission to values comparable with healthy controls. A shift toward more CD103-T cells was observed during active inflammation.
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Affiliation(s)
- Britt Roosenboom
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, the Netherlands,Address correspondence to: B. Roosenboom, Department of Gastroenterology and Hepatology, Rijnstate Hospital, Wagnerlaan 55, 6815 AD Arnhem, the Netherlands. E-mail:
| | - Peter J Wahab
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, the Netherlands
| | - Carolijn Smids
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, the Netherlands
| | - Marcel J M Groenen
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, the Netherlands
| | - Elly van Koolwijk
- Department of Microbiology and Immunology, Rijnstate Hospital, Arnhem, the Netherlands
| | - Ellen G van Lochem
- Department of Microbiology and Immunology, Rijnstate Hospital, Arnhem, the Netherlands
| | - Carmen S Horjus Talabur Horje
- Crohn & Colitis Centre Rijnstate, Department of Gastroenterology and Hepatology, Rijnstate Hospital, Arnhem, the Netherlands
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Yoon H. Subcutaneous integrin inhibitors may provide more treatment options for patients with moderate-to-severe ulcerative colitis. Intest Res 2019; 17:283-284. [PMID: 31352773 PMCID: PMC6667369 DOI: 10.5217/ir.2019.00070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 06/09/2019] [Indexed: 11/28/2022] Open
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