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Kulig P, Brazauskas P, Suffiotti M, Raoult E, Babilonski U, Renault B, Grieder U, Vezzali E, Blattmann P, Martinic MM, Murphy MJ. Efficacy of IDOR-1117-2520, a novel, orally available CCR6 antagonist in preclinical models of skin dermatitis. Br J Pharmacol 2025. [PMID: 40156059 DOI: 10.1111/bph.70025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 01/22/2025] [Accepted: 02/11/2025] [Indexed: 04/01/2025] Open
Abstract
BACKGROUND AND PURPOSE The chemokine receptor CCR6 guides pathogenic T17 cells, implicated in autoimmune diseases including psoriasis, to sites of inflammation via the chemokine CCL20. Therefor, pharmacological inhibition of CCR6+ immune cell migration provides a novel therapeutic approach. Translatability of such an intervention has not yet been assessed in detail. We evaluated the translatability of the Aldara® mouse model induced skin inflammation to psoriasis, with particular focus on immune cell trafficking and assessed the efficacy of IDOR-1117-2520, a highly selective, potent and orally available CCR6 small inhibitor. EXPERIMENTAL APPROACH Effects of IDOR-1117-2520 were investigated in the Aldara® and IL23 mouse models of skin inflammation using flow cytometry, RNA sequencing and transcriptome-based cell type deconvolution approaches to characterise immune cell migration patterns. These results were compared to human psoriasis transcriptomics data. KEY RESULTS IDOR-1117-2520 dose dependently reduced infiltration of CCR6+ immune cells into inflamed skin, and was equally efficacious as IL-17 and IL-23 inhibition in models of skin inflammation. Pathway analysis showed molecular similarities in the immune response between human psoriasis and the Aldara® mouse model. IL-17/IL-23 pathway genes were expressed in both human psoriasis and the mouse model. CCR6 inhibition modulated multiple pathways associated with inflammation beyond the proximal IL-17/IL-23 pathway. A chemokine-chemokine receptor interaction map implicated CCL20-CCR6 as the dominant axis in recruiting pathogenic T17 cells in both the model and in human psoriasis. CONCLUSION AND IMPLICATIONS IDOR-1117-2520 could provide a promising novel targeted approach to treating psoriasis and, potentially, other autoimmune diseases involving the CCR6/CCL20 axis and the IL-17/IL-23 pathway. IDOR-1117-2520 is currently being evaluated in a clinical phase 1 trial (ISRCTN28892128).
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Affiliation(s)
- Paulina Kulig
- Department of Translational and Pharmacological Science, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Pijus Brazauskas
- Department of Translational and Pharmacological Science, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Madeleine Suffiotti
- Department of Translational and Pharmacological Science, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Emilie Raoult
- Department of Translational and Pharmacological Science, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Ulrike Babilonski
- Department of Translational and Pharmacological Science, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Bérengère Renault
- Department of Translational and Pharmacological Science, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Ursula Grieder
- Department of Translational and Pharmacological Science, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Enrico Vezzali
- Department of Translational and Pharmacological Science, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Peter Blattmann
- Department of Translational and Pharmacological Science, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Marianne M Martinic
- Department of Translational and Pharmacological Science, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - Mark J Murphy
- Department of Translational and Pharmacological Science, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
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Irwandi RA, Marruganti C, Collins G, Carvalho JDS, Gilroy D, D’Aiuto F. The translational potential of inflammation-induced skin blister human models in exploring the pathogenesis of periodontitis and its systemic health implications. Front Immunol 2024; 15:1469828. [PMID: 39737182 PMCID: PMC11682961 DOI: 10.3389/fimmu.2024.1469828] [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: 07/24/2024] [Accepted: 12/02/2024] [Indexed: 01/01/2025] Open
Abstract
Periodontitis is a highly prevalent chronic disease. Despite decades of extensive research on the topic, a complete understanding of its immunopathogenesis, especially when linked to other inflammatory comorbidities, is lacking. Ex vivo human and in vivo animal experiments have shown the host inflammatory response's crucial role in both the disease's onset and its systemic implications. These approaches, however, remain questionable when translating these findings into real-world scenarios linked to periodontitis. A clear need for new in vivo human models is discussed, especially within the context of understanding the host response to key pathogens linked to periodontitis, such as Porphyromonas gingivalis (P. gingivalis). Therefore, a skin blister model was employed to describe the stages of the host immune response in humans after challenges by microbial and/or sterile insults. A novel human challenge model using UV-killed P. gingivalis holds promise in producing new evidence and bridging the gap of the host response to periodontitis and its links with other common chronic diseases.
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Affiliation(s)
- Rizky Aditya Irwandi
- Periodontology Unit, UCL Eastman Dental Institute, University College London, London, United Kingdom
- Department of Oral Biology, Faculty of Dentistry, Universitas Indonesia, Jakarta, Indonesia
| | - Crystal Marruganti
- Periodontology Unit, UCL Eastman Dental Institute, University College London, London, United Kingdom
- Unit of Periodontology, Endodontology and Restorative Dentistry, Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - George Collins
- Department of Ageing, Rheumatology and Regenerative Medicine, Division of Medicine, University College London, London, United Kingdom
- Department of Cardiology, St Bartholomew’s Hospital, Barts Health NHS Trust, London, United Kingdom
| | - Jhonatan de Souza Carvalho
- Department of Ageing, Rheumatology and Regenerative Medicine, Division of Medicine, University College London, London, United Kingdom
- Department of Diagnosis and Surgery, São Paulo State University (UNESP), School of Dentistry, Araraquara, Brazil
| | - Derek Gilroy
- Department of Ageing, Rheumatology and Regenerative Medicine, Division of Medicine, University College London, London, United Kingdom
| | - Francesco D’Aiuto
- Periodontology Unit, UCL Eastman Dental Institute, University College London, London, United Kingdom
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Giovenzana A, Codazzi V, Pandolfo M, Petrelli A. T cell trafficking in human chronic inflammatory diseases. iScience 2024; 27:110528. [PMID: 39171290 PMCID: PMC11338127 DOI: 10.1016/j.isci.2024.110528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024] Open
Abstract
Circulating T cells, which migrate from the periphery to sites of tissue inflammation, play a crucial role in the development of various chronic inflammatory conditions. Recent research has highlighted subsets of tissue-resident T cells that acquire migratory capabilities and re-enter circulation, referred to here as "recirculating T cells." In this review, we examine recent advancements in understanding the biology of T cell trafficking in diseases where T cell infiltration is pivotal, such as multiple sclerosis and inflammatory bowel diseases, as well as in metabolic disorders where the role of T cell migration is less understood. Additionally, we discuss current insights into therapeutic strategies aimed at modulating T cell circulation across tissues and the application of state-of-the-art technologies for studying recirculation in humans. This review underscores the significance of investigating T trafficking as a novel potential target for therapeutic interventions across a spectrum of human chronic inflammatory diseases.
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Affiliation(s)
- Anna Giovenzana
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Valentina Codazzi
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Michele Pandolfo
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
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Xin R. Inflammatory Gene Panel Guiding the Study of Genetics in Inflammatory Bowel Disease. Mol Diagn Ther 2024; 28:389-401. [PMID: 38635139 DOI: 10.1007/s40291-024-00709-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2024] [Indexed: 04/19/2024]
Abstract
Inflammatory bowel disease (IBD) is a complex disease that develops through a sequence of molecular events that are still poorly defined. This process is driven by a multitude of context-dependent genes that play different roles based on their environment. The complexity and multi-faceted nature of these genes make it difficult to study the genetic basis of IBD. The goal of this article is to review the key genes in the pathophysiology of IBD and highlight new technology that can be used in further research. This paper examines Nanostring RNA probe technology, which uses tissue analyzed without the use of enzymes, transcription, or amplification. Nanostring offers several panels of genes to test, including an inflammation panel of 234 genes. This article analyzes this panel and reviews the literature for each gene's effect in IBD for use as a framework to review the pathophysiology of the disease. The panel was narrowed to 26 genes with significant evidence of mechanistic potential in IBD, which were then categorized into specific areas of pathogenesis. These include gut barrier breakdown, inappropriate recognition of commensal bacteria, immune cell activation, proinflammatory cytokine release, and subsequent impairment of the anti-inflammatory response. The eventual goal of this paper is the creation of a customized panel of IBD genes that can be used to better understand the genetic mechanism of IBD and aid in the development of future therapies in IBD.
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Affiliation(s)
- Ryan Xin
- Columbia University Irving Medical Center, 177 Fort Washington Avenue, New York, NY, 10032, USA.
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He Y, Ruan S, Liang G, Hao J, Zhou X, Li Z, Mu L, Wu J, Yang H. A Nonbactericidal Anionic Antimicrobial Peptide Provides Prophylactic and Therapeutic Efficacies against Bacterial Infections in Mice by Immunomodulatory-Antithrombotic Duality. J Med Chem 2024; 67:7487-7503. [PMID: 38688020 DOI: 10.1021/acs.jmedchem.4c00342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2024]
Abstract
Although bactericidal cationic antimicrobial peptides (AMPs) have been well characterized, less information is available about the antibacterial properties and mechanisms of action of nonbactericidal AMPs, especially nonbactericidal anionic AMPs. Herein, a novel anionic antimicrobial peptide (Gy-CATH) with a net charge of -4 was identified from the skin of the frog Glyphoglossus yunnanensis. Gy-CATH lacks direct antibacterial effects but exhibits significantly preventive and therapeutic capacities in mice that are infected with Staphylococcus aureus, Enterobacteriaceae coli, methicillin-resistant Staphylococcus aureus (MRSA), or carbapenem-resistant E. coli (CREC). In vitro and in vivo investigations proved the regulation of Gy-CATH on neutrophils and macrophages involved in the host immune defense against infection. Moreover, Gy-CATH significantly reduced the extent of pulmonary fibrin deposition and prevented thrombosis in mice, which was attributed to the regulatory role of Gy-CATH in physiological anticoagulants and platelet aggregation. These findings show that Gy-CATH is a potential candidate for the treatment of bacterial infection.
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Affiliation(s)
- Yanmei He
- School of Basic Medical Sciences, Kunming Medical University, Kunming 650500, Yunnan, China
| | - Shimei Ruan
- School of Basic Medical Sciences, Kunming Medical University, Kunming 650500, Yunnan, China
| | - Guozhu Liang
- School of Basic Medical Sciences, Kunming Medical University, Kunming 650500, Yunnan, China
| | - Jing Hao
- School of Basic Medical Sciences, Kunming Medical University, Kunming 650500, Yunnan, China
| | - Xiaoyan Zhou
- School of Basic Medical Sciences, Kunming Medical University, Kunming 650500, Yunnan, China
| | - Zhuorui Li
- School of Basic Medical Sciences, Kunming Medical University, Kunming 650500, Yunnan, China
| | - Lixian Mu
- School of Basic Medical Sciences, Kunming Medical University, Kunming 650500, Yunnan, China
| | - Jing Wu
- School of Basic Medical Sciences, Kunming Medical University, Kunming 650500, Yunnan, China
| | - Hailong Yang
- School of Basic Medical Sciences, Kunming Medical University, Kunming 650500, Yunnan, China
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Mehandru S, Colombel JF, Juarez J, Bugni J, Lindsay JO. Understanding the molecular mechanisms of anti-trafficking therapies and their clinical relevance in inflammatory bowel disease. Mucosal Immunol 2023; 16:859-870. [PMID: 37574127 PMCID: PMC11141405 DOI: 10.1016/j.mucimm.2023.08.001] [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] [Received: 07/27/2023] [Accepted: 08/06/2023] [Indexed: 08/15/2023]
Abstract
In patients with inflammatory bowel disease (IBD), a combination of dysbiosis, increased intestinal permeability, and insufficient regulatory responses facilitate the development of chronic inflammation, which is driven by a complex interplay between the mucosal immune system and the environment and sustained by immune priming and ongoing cellular recruitment to the gut. The localization of immune cells is mediated by their expression of chemokine receptors and integrins, which bind to chemokines and adhesion molecules, respectively. In this article, we review the mechanisms of action of anti-trafficking therapies for IBD and consider clinical observations in the context of the different mechanisms of action. Furthermore, we discuss the evolution of molecular resistance to anti-cytokines, in which the composition of immune cells in the gut changes in response to treatment, and the potential implications of this for treatment sequencing. Lastly, we discuss the relevance of mechanism of action to combination therapy for IBD.
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Affiliation(s)
- Saurabh Mehandru
- The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Jean-Frederic Colombel
- The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Julius Juarez
- Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA, USA
| | - James Bugni
- Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA, USA
| | - James O Lindsay
- Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK; Department of Gastroenterology, Royal London Hospital, Barts Health NHS Trust, London, UK
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Pool ES, Kooy-Winkelaar Y, van Unen V, Falkenburg JF, Koning F, Heemskerk MHM, Tjon JML. Mass cytometric analysis unveils a disease-specific immune cell network in the bone marrow in acquired aplastic anemia. Front Immunol 2023; 14:1274116. [PMID: 38094307 PMCID: PMC10716190 DOI: 10.3389/fimmu.2023.1274116] [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: 08/07/2023] [Accepted: 11/14/2023] [Indexed: 12/18/2023] Open
Abstract
Idiopathic acquired aplastic anemia (AA) is considered an immune-mediated syndrome of bone marrow failure since approximately 70% of patients respond to immunosuppressive therapy (IST) consisting of a course of anti-thymocyte globulin (ATG) followed by long-term use of ciclosporin. However, the immune response that underlies the pathogenesis of AA remains poorly understood. In this study, we applied high-dimensional mass cytometry on bone marrow aspirates of AA patients pre-ATG, AA patients post-ATG and healthy donors to decipher which immune cells may be implicated in the pathogenesis of AA. We show that the bone marrow of AA patients features an immune cell composition distinct from healthy donors, with significant differences in the myeloid, B-cell, CD4+ and CD8+ T-cells lineages. Specifically, we discovered that AA pre-ATG is characterized by a disease-specific immune cell network with high frequencies of CD16+ myeloid cells, CCR6++ B-cells, Th17-like CCR6+ memory CD4+ T-cells, CD45RA+CCR7+CD38+ CD8+ T-cells and KLRG1+ terminally differentiated effector memory (EMRA) CD8+ T-cells, compatible with a state of chronic inflammation. Successful treatment with IST strongly reduced the levels of CD16+ myeloid cells and showed a trend toward normalization of the frequencies of CCR6++ B-cells, CCR6+ memory CD4+ T-cells and KLRG1+EMRA CD8+ T-cells. Altogether, our study provides a unique overview of the immune landscape in bone marrow in AA at a single-cell level and proposes CCR6 as a potential new therapeutic target in AA.
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Affiliation(s)
- Emma S. Pool
- Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
| | | | - Vincent van Unen
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
- Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA, United States
| | | | - Frits Koning
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
| | | | - Jennifer M-L. Tjon
- Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
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8
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Shi ZR, Mabuchi T, Riutta SJ, Wu X, Peterson FC, Volkman BF, Hwang ST. The Chemokine, CCL20, and Its Receptor, CCR6, in the Pathogenesis and Treatment of Psoriasis and Psoriatic Arthritis. JOURNAL OF PSORIASIS AND PSORIATIC ARTHRITIS 2023; 8:107-117. [PMID: 39296310 PMCID: PMC11361516 DOI: 10.1177/24755303231159106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/21/2024]
Abstract
Background Chemokines represent a superfamily of immune-modulatory small protein molecules that regulate leukocyte migration to inflammatory sites through their chemoattractant and cell signaling properties. This review focuses on the immunological functions of the CCR6 chemokine receptor and is chemokine ligand, CCL20, that contribute to it role in inflammation in human psoriasis. Methods Peer-reviewed relevant articles are searched and selected from 2000 to 2022 using the search engines including PubMed and Google Scholar. Results After selectively reviewing and evaluating over seventy articles, a comprehensive overview on the immunology of CCL20-CCR6 axis in psoriasis and psoriatic arthritis, the X-ray crystal structures of CCL20 monomers, and the potential of developing clinical therapies targeting this axis is summarized. Conclusions Over the past decade, preclinical studies carried out in animal models of psoriasis involving agents targeting CCL20-CCR6 axis have yielded promising results. Other studies that this axis may play a role in a number of other autoimmune diseases, including rheumatoid arthritis, suggesting a rationale for further investigation into this key signaling/migratory pathway.
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Affiliation(s)
- Zhen-Rui Shi
- Department of Dermatology, Sun Yat-sen Memorial Hospital, Guang-zhou, China
| | - Tomotaka Mabuchi
- Department of Dermatology, Tokai University School of Medicine, Isehara, Japan
| | - Sarah J Riutta
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Xuesong Wu
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Francis C Peterson
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Brian F Volkman
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Sam T Hwang
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA, USA
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Herrnstadt GR, Niehus CB, Ramcke T, Hagenstein J, Ehnold LI, Nosko A, Warkotsch MT, Feindt FC, Melderis S, Paust HJ, Sivayoganathan V, Jauch-Speer SL, Wong MN, Indenbirken D, Krebs CF, Huber TB, Panzer U, Puelles VG, Kluger MA, Steinmetz OM. The CCR6/CCL20 axis expands RORγt + Tregs to protect from glomerulonephritis. Kidney Int 2023; 104:74-89. [PMID: 36924892 DOI: 10.1016/j.kint.2023.02.027] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 03/17/2023]
Abstract
Previous studies have identified a unique Treg population, which expresses the Th17 characteristic transcription factor RORγt. These RORγt+ Tregs possess enhanced immunosuppressive capacity, which endows them with great therapeutic potential. However, as a caveat, they are also capable of secreting pro-inflammatory IL-17A. Since the sum function of RORγt+ Tregs in glomerulonephritis (GN) remains unknown, we studied the effects of their absence. Purified CD4+ T cell populations, containing or lacking RORγt+ Tregs, were transferred into immunocompromised RAG1 knockout mice and the nephrotoxic nephritis model of GN was induced. Absence of RORγt+ Tregs significantly aggravated kidney injury, demonstrating overall kidney-protective properties. Analyses of immune responses showed that RORγt+ Tregs were broadly immunosuppressive with no preference for a particular type of T cell response. Further characterization revealed a distinct functional and transcriptional profile, including enhanced production of IL-10. Expression of the chemokine receptor CCR6 marked a particularly potent subset, whose absence significantly worsened GN. As an underlying mechanism, we found that chemokine CCL20 acting through receptor CCR6 signaling mediated expansion and activation of RORγt+ Tregs. Finally, we also detected an increase of CCR6+ Tregs in kidney biopsies, as well as enhanced secretion of chemokine CCL20 in 21 patients with anti-neutrophil cytoplasmic antibody associated GN compared to that of 31 healthy living donors, indicating clinical relevance. Thus, our data characterize RORγt+ Tregs as anti-inflammatory mediators of GN and identify them as promising target for Treg directed therapies.
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Affiliation(s)
- Georg R Herrnstadt
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph B Niehus
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Torben Ramcke
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julia Hagenstein
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Laura-Isabell Ehnold
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anna Nosko
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Matthias T Warkotsch
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frederic C Feindt
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Simon Melderis
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hans-Joachim Paust
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Varshi Sivayoganathan
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Milagros N Wong
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Christian F Krebs
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tobias B Huber
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ulf Panzer
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Victor G Puelles
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Malte A Kluger
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Oliver M Steinmetz
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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10
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Zundler S, Schulze LL, Neurath MF. Controlling in and out - the future of interfering with immune cell trafficking in inflammatory bowel disease. Expert Rev Clin Immunol 2023; 19:155-167. [PMID: 36427088 DOI: 10.1080/1744666x.2023.2152794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Immune cell trafficking is a key requirement in the pathogenesis of inflammatory bowel diseases. Consistently, therapeutic strategies to target immune cell trafficking have been established and continue to be developed for the treatment of ulcerative colitis and Crohn's disease. AREAS COVERED In this review, we briefly summarize the most important checkpoints of intestinal immune cell trafficking and their importance during IBD. Moreover, we provide an overview of associated therapeutic targets and previous as well as current efforts on treatment strategies related to these targets. EXPERT OPINION Finally, we comment on potential future developments that might shape the field of immune cell trafficking in the context of IBD.
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Affiliation(s)
- Sebastian Zundler
- Department of Medicine 1 and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Lisa Lou Schulze
- Department of Medicine 1 and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1 and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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11
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Martina MG, Giorgio C, Allodi M, Palese S, Barocelli E, Ballabeni V, Szpakowska M, Chevigne A, Piet van Hamburg J, Davelaar N, Lubberts E, Bertoni S, Radi M. Discovery of small-molecules targeting the CCL20/CCR6 axis as first-in-class inhibitors for inflammatory bowel diseases. Eur J Med Chem 2022; 243:114703. [DOI: 10.1016/j.ejmech.2022.114703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/18/2022] [Accepted: 08/19/2022] [Indexed: 11/03/2022]
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Yamamoto-Furusho JK, Parra-Holguín NN. Emerging therapeutic options in inflammatory bowel disease. World J Gastroenterol 2021; 27:8242-8261. [PMID: 35068868 PMCID: PMC8717021 DOI: 10.3748/wjg.v27.i48.8242] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/04/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic disease that requires chronic treatment throughout the evolution of the disease, with a complex physiopathology that entails great challenges for the development of new and specific treatments for ulcerative colitis and Crohn´s disease. The anti-tumor necrosis factor alpha therapy has impacted the clinical course of IBD in those patients who do not respond to conventional treatment, so there is a need to develop new therapies and markers of treatment response. Various pathways involved in the development of the disease are known and the new therapies have focused on blocking the inflammatory process at the gastrointestinal level by oral, intravenous, subcutaneous, and topical route. All these new therapies can lead to more personalized treatments with higher success rates and fewer relapses. These treatments have not only focused on clinical remission, but also on achieving macroscopic changes at the endoscopic level and microscopic changes by achieving mucosal healing. These treatments are mainly based on modifying signaling pathways, by blocking receptors or ligands, reducing cell migration and maintaining the integrity of the epithelial barrier. Therefore, this review presents the efficacy and safety of the new treatments that are currently under study and the advances that have been made in this area in recent years.
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Affiliation(s)
- Jesus K Yamamoto-Furusho
- Gastroenterology Unit, Inflammatory Bowel Disease Clinic, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City 14080, Mexico
| | - Norma N Parra-Holguín
- Gastroenterology Unit, Inflammatory Bowel Disease Clinic, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City 14080, Mexico
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Camba-Gómez M, Arosa L, Gualillo O, Conde-Aranda J. Chemokines and chemokine receptors in inflammatory bowel disease: Recent findings and future perspectives. Drug Discov Today 2021; 27:1167-1175. [PMID: 34896626 DOI: 10.1016/j.drudis.2021.12.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 11/11/2021] [Accepted: 12/06/2021] [Indexed: 11/03/2022]
Abstract
Despite the benefits of current therapeutic options for treating inflammatory bowel disease (IBD), there are still patients who are refractory to these therapies. Moreover, the relapses caused by incomplete intestinal mucosa healing are frequent. Therefore, there is a need for novel pharmacological targets that can improve the existing IBD therapeutic armamentarium. Chemokine and chemokine receptors have emerged as appealing options to this end. As well as controlling leukocyte trafficking to inflamed tissues, these proteins regulate many other processes related to the development of intestinal inflammation. In this review, we summarise the most recent preclinical studies, along with the putative application of chemokine-based therapies in patients with IBD.
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Affiliation(s)
- Miguel Camba-Gómez
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Laura Arosa
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Oreste Gualillo
- SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Javier Conde-Aranda
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
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14
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Kfoury Y, Baryawno N, Severe N, Mei S, Gustafsson K, Hirz T, Brouse T, Scadden EW, Igolkina AA, Kokkaliaris K, Choi BD, Barkas N, Randolph MA, Shin JH, Saylor PJ, Scadden DT, Sykes DB, Kharchenko PV. Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment. Cancer Cell 2021; 39:1464-1478.e8. [PMID: 34719426 PMCID: PMC8578470 DOI: 10.1016/j.ccell.2021.09.005] [Citation(s) in RCA: 139] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 07/15/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023]
Abstract
Bone metastases are devastating complications of cancer. They are particularly common in prostate cancer (PCa), represent incurable disease, and are refractory to immunotherapy. We seek to define distinct features of the bone marrow (BM) microenvironment by analyzing single cells from bone metastatic prostate tumors, involved BM, uninvolved BM, and BM from cancer-free, orthopedic patients, and healthy individuals. Metastatic PCa is associated with multifaceted immune distortion, specifically exhaustion of distinct T cell subsets, appearance of macrophages with states specific to PCa bone metastases. The chemokine CCL20 is notably overexpressed by myeloid cells, as is its cognate CCR6 receptor on T cells. Disruption of the CCL20-CCR6 axis in mice with syngeneic PCa bone metastases restores T cell reactivity and significantly prolongs animal survival. Comparative high-resolution analysis of PCa bone metastases shows a targeted approach for relieving local immunosuppression for therapeutic effect.
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Affiliation(s)
- Youmna Kfoury
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Ninib Baryawno
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Childhood Cancer Research Unit, Department of Women's Health and Children's, Karolinska Institutet, Stockholm, Sweden.
| | - Nicolas Severe
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Shenglin Mei
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Karin Gustafsson
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Taghreed Hirz
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Thomas Brouse
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Elizabeth W Scadden
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Anna A Igolkina
- St. Petersburg Polytechnical University, St. Petersburg, Russia
| | - Konstantinos Kokkaliaris
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Bryan D Choi
- Department of Neurosurgery, Harvard Medical School, Boston, MA, USA
| | - Nikolas Barkas
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Mark A Randolph
- Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - John H Shin
- Department of Neurosurgery, Harvard Medical School, Boston, MA, USA
| | - Philip J Saylor
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA
| | - David T Scadden
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - David B Sykes
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Peter V Kharchenko
- Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
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15
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Orsmond A, Bereza-Malcolm L, Lynch T, March L, Xue M. Skin Barrier Dysregulation in Psoriasis. Int J Mol Sci 2021; 22:10841. [PMID: 34639182 PMCID: PMC8509518 DOI: 10.3390/ijms221910841] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 10/01/2021] [Accepted: 10/05/2021] [Indexed: 02/07/2023] Open
Abstract
The skin barrier is broadly composed of two elements-a physical barrier mostly localised in the epidermis, and an immune barrier localised in both the dermis and epidermis. These two systems interact cooperatively to maintain skin homeostasis and overall human health. However, if dysregulated, several skin diseases may arise. Psoriasis is one of the most prevalent skin diseases associated with disrupted barrier function. It is characterised by the formation of psoriatic lesions, the aberrant differentiation and proliferation of keratinocytes, and excessive inflammation. In this review, we summarize recent discoveries in disease pathogenesis, including the contribution of keratinocytes, immune cells, genetic and environmental factors, and how they advance current and future treatments.
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Affiliation(s)
- Andreas Orsmond
- Sutton Arthritis Research Laboratory, Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (A.O.); (L.B.-M.)
- The Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (T.L.); (L.M.)
| | - Lara Bereza-Malcolm
- Sutton Arthritis Research Laboratory, Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (A.O.); (L.B.-M.)
- The Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (T.L.); (L.M.)
| | - Tom Lynch
- The Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (T.L.); (L.M.)
| | - Lyn March
- The Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (T.L.); (L.M.)
| | - Meilang Xue
- Sutton Arthritis Research Laboratory, Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (A.O.); (L.B.-M.)
- The Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (T.L.); (L.M.)
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16
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Kapitanov GI, Chabot JR, Narula J, Roy M, Neubert H, Palandra J, Farrokhi V, Johnson JS, Webster R, Jones HM. A Mechanistic Site-Of-Action Model: A Tool for Informing Right Target, Right Compound, And Right Dose for Therapeutic Antagonistic Antibody Programs. FRONTIERS IN BIOINFORMATICS 2021; 1:731340. [DOI: 10.3389/fbinf.2021.731340] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/23/2021] [Indexed: 11/13/2022] Open
Abstract
Quantitative modeling is increasingly utilized in the drug discovery and development process, from the initial stages of target selection, through clinical studies. The modeling can provide guidance on three major questions–is this the right target, what are the right compound properties, and what is the right dose for moving the best possible candidate forward. In this manuscript, we present a site-of-action modeling framework which we apply to monoclonal antibodies against soluble targets. We give a comprehensive overview of how we construct the model and how we parametrize it and include several examples of how to apply this framework for answering the questions postulated above. The utilities and limitations of this approach are discussed.
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17
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Shi Z, Garcia-Melchor E, Wu X, Getschman AE, Nguyen M, Rowland DJ, Wilson M, Sunzini F, Akbar M, Huynh M, Law T, Kundu-Raychaudhuri SK, Raychaudhuri SP, Volkman BF, Millar NL, Hwang ST. Targeting the CCR6/CCL20 axis in entheseal and cutaneous inflammation. Arthritis Rheumatol 2021; 73:2271-2281. [PMID: 34081845 DOI: 10.1002/art.41882] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 05/18/2021] [Indexed: 11/12/2022]
Abstract
OBJECTIVES To assess the involvement of the CCR6/CCL20 axis in psoriatic arthritis (PsA) and psoriasis (PsO) and to evaluate its potential as a therapeutic target. METHODS First, we quantified CCL20 levels in peripheral blood and synovial fluid of PsA patients and the presence of CCR6+ cells in synovial and tendon tissue. Utilizing an IL-23 minicircle DNA (MC) mouse model exhibiting key features of both PsO and PsA, we investigated CCR6 and CCL20 expression and the preventive and therapeutical effect of CCL20 blockade. Healthy tendon stromal cells were stimulated in vitro with IL-1β to assess the production of CCL20 by qPCR and ELISA. The effect of conditioned media from stimulated tenocytes in inducing T cell migration was interrogated with a transwell system. RESULTS We observed an upregulation of both CCR6 and CCL20 in the enthesis of IL-23 MC-treated mice, which was confirmed in human biopsies. Specific targeting of the CCR6/CCL20 axis with a CCL20 locked dimer (CCL20LD) blocked entheseal inflammation, leading to profound reductions in clinical and proinflammatory markers in the joints and skin of IL-23 MC-treated mice. The stromal compartment in the tendon was the main source of CCL20 in this model and accordingly, in vitro activated human tendon cells were able to produce this chemokine and to induce CCR6+ T cell migration, the latter of which could be blocked by CCL20LD. CONCLUSIONS Our studies highlight the pathogenic role of CCR6-CCL20 axis in enthesitis and raise the prospect of a novel therapeutic approach for treating patients with PsO and PsA.
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Affiliation(s)
- Zhenrui Shi
- Department of Dermatology, University of California, Davis, Sacramento, CA, USA.,Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, China
| | - Emma Garcia-Melchor
- Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, UK
| | - Xuesong Wu
- Department of Dermatology, University of California, Davis, Sacramento, CA, USA
| | | | - Mimi Nguyen
- Department of Dermatology, University of California, Davis, Sacramento, CA, USA
| | - Douglas J Rowland
- Center for Molecular and Genomic Imaging, University of California, Davis, Sacramento, CA, USA
| | - Machelle Wilson
- Division of Biostatistics, Clinical and Translational Science Center, University of California, Davis, Sacramento, CA, USA
| | - Flavia Sunzini
- Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, UK
| | - Moeed Akbar
- Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, UK
| | - Mindy Huynh
- Department of Dermatology, University of California, Davis, Sacramento, CA, USA
| | - Timothy Law
- Department of Dermatology, University of California, Davis, Sacramento, CA, USA
| | - Smriti K Kundu-Raychaudhuri
- Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, CA, USA
| | - Siba P Raychaudhuri
- Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, CA, USA
| | - Brian F Volkman
- Department of Biochemistry, Medical College of Wisconsin, WI, USA
| | - Neal L Millar
- Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, UK
| | - Sam T Hwang
- Department of Dermatology, University of California, Davis, Sacramento, CA, USA
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18
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Meitei HT, Jadhav N, Lal G. CCR6-CCL20 axis as a therapeutic target for autoimmune diseases. Autoimmun Rev 2021; 20:102846. [PMID: 33971346 DOI: 10.1016/j.autrev.2021.102846] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 03/15/2021] [Accepted: 03/23/2021] [Indexed: 12/11/2022]
Abstract
Chemokine receptor CCR6 is expressed on various cells such as B cells, immature dendritic cells, innate lymphoid cells (ILCs), regulatory CD4 T cells, and Th17 cells. CCL20 is the only known high-affinity ligand that binds to CCR6 and drives CCR6+ cells' migration in tissues. CCL20 is mainly produced by epithelial cells, and its expression is increased by several folds under inflammatory conditions. Genome-wide association studies (GWAS) in patients with inflammatory bowel disease (IBD), psoriasis (PS), rheumatoid arthritis (RA), and multiple sclerosis (MS) showed a very strong correlation between the expression of CCR6 and disease severity. It has been shown that disruption of CCR6-CCL20 interaction by using antibodies or antagonists prevents the migration of CCR6 expressing immune cells at the site of inflammation and reduces the severity of the disease. This review discussed the importance of the CCR6-CCL20 axis in IBD, PS, RA, and MS, and recent advances in targeting the CCR6-CCL20 in controlling these autoimmune diseases.
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Affiliation(s)
| | - Nandadeep Jadhav
- National Centre for Cell Science, Ganeshkhind, Pune MH-411007, India
| | - Girdhari Lal
- National Centre for Cell Science, Ganeshkhind, Pune MH-411007, India.
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19
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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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20
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Thomson AS, Mai SH, Bouma G, Herdman M, Byrne M, Hottenstein CS, Minetti J, Trulli S, Taylor JD, White JR, Chen S. Structure and Functional Characterization of a Humanized Anti-CCL20 Antibody following Exposure to Serum Reveals the Formation of Immune Complex That Leads to Toxicity. THE JOURNAL OF IMMUNOLOGY 2021; 206:1067-1076. [PMID: 33483346 DOI: 10.4049/jimmunol.2000336] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 12/18/2020] [Indexed: 02/02/2023]
Abstract
mAbs have revolutionized the treatment of autoimmune disorders. Even though mAbs have shown impressive efficacy in blocking T cell or B cell activation and/or recruitment to sites of inflammation, this group of biologicals are not devoid of adverse effects. The most serious adverse effects include infusion reactions, including the activation of the complement pathway. In this study, we present a detailed structure-function study of an anti-CCL20 humanized IgG1 mAb that neutralizes CCL20 chemokine and prevents the recruitment of Th17 cells to sites of inflammation. We demonstrate that the anti-CCL20 Ab changes significantly following administration to humans and monkeys and exposure to human serum. Analysis of the drug product revealed that the anti-CCL20 Ab has unexpectedly high C1q binding. This high binding was linked to immune complex formation in vivo but not during in vitro serum incubation. The immune complex contained multiple complement components. Anti-CCL20 Ab-mediated, complement-dependent cytotoxicity occurred when the Ab bound to CCL20 tethered to the cell membrane of target cells. Taken together, these results provide a likely cause for the animal toxicity observed. In addition, anti-CCL20 revealed progressive acidification because of N100 (located in CDR) deamidation over time, which did not directly impact Ag binding. Our study demonstrates that the safety profiling of mAbs should include the evaluation of effector functions in addition to typical stressed conditions.
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Affiliation(s)
- Andrew S Thomson
- Biopharm Analytical Sciences, Biopharm Product Development and Supply, GlaxoSmithKline, Collegeville, PA 19426;
| | - Shing H Mai
- Biopharm Analytical Sciences, Biopharm Product Development and Supply, GlaxoSmithKline, Collegeville, PA 19426
| | - Gerben Bouma
- Adaptive Immunity Research Unit, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom
| | - Michael Herdman
- Clinical Pharmacology and Experimental Medicine, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom
| | - Michael Byrne
- Biopharm Analytical Sciences, Biopharm Product Development and Supply, GlaxoSmithKline, Collegeville, PA 19426
| | - Charles S Hottenstein
- Bioanalysis, Immunogenicity, and Biomarkers, In Vitro/In Vivo Translation, GlaxoSmithKline, Collegeville, PA 19426; and
| | - Joseph Minetti
- Biopharm Analytical Sciences, Biopharm Product Development and Supply, GlaxoSmithKline, Collegeville, PA 19426
| | - Stephen Trulli
- Biopharm Analytical Sciences, Biopharm Product Development and Supply, GlaxoSmithKline, Collegeville, PA 19426
| | - J David Taylor
- Protein, Cellular and Structural Sciences, Medicine Design, GlaxoSmithKline, Collegeville, PA 19426
| | - John R White
- Biopharm Analytical Sciences, Biopharm Product Development and Supply, GlaxoSmithKline, Collegeville, PA 19426
| | - Shugui Chen
- Biopharm Analytical Sciences, Biopharm Product Development and Supply, GlaxoSmithKline, Collegeville, PA 19426
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21
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van Hoogdalem EJ, van Iersel MT, Winter E, Constant J, Kappler M. Pharmacology-Guided Rule-Based Adaptive Dose Escalation in First-in-Human Studies. Clin Pharmacol Ther 2020; 109:1326-1333. [PMID: 33150581 DOI: 10.1002/cpt.2101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 10/14/2020] [Indexed: 11/06/2022]
Abstract
First-in-human (FIH) studies typically progress through cohorts of fixed, standard size throughout the escalation scheme. This work presents and tests a pharmacology-guided rule-based adaptive dose escalation design that aims at making "best use" of participants in early clinical drug evaluation; it is paper based, not requiring real-time access to computational methods. The design minimizes the number of participants exposed to dose levels with low likelihood of being therapeutically relevant. Using criteria based on dose-limiting adverse event rate and on target exposure or target pharmacodynamics, the design increases the sample size when approaching the dose range of potential clinical relevance. The adaptive escalation design was retrospectively tested on actual data from a sample of 40 recently executed FIH studies with novel small and large molecules, and it was evaluated by simulating trials with three compounds with different therapeutic windows, i.e., representing a promising, unacceptable, and dubious profile. In retrospective evaluation of the adaptive escalation design, none of the cases overshot the actually reported top dose; one case resulted in a top dose that was within 20% under the estimated maximum tolerated dose in the original study. The median reduction of total number of participants per study was 38%. Trial simulations confirmed the retrospective evaluation, showing a similar performance of the adaptive escalation design compared with the conventional 6 + 2 design, at a reduced study size for compounds with a presumed acceptable therapeutic window. The adaptive escalation design was shown to make "best use" of participants in FIH studies without compromising safety.
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Affiliation(s)
| | | | | | - John Constant
- PRA Health Sciences, Scientific Affairs, Victoria, British Columbia, Canada
| | - Martin Kappler
- PRA Health Sciences, Statistical Consulting Services, Levallois-Perret, France
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22
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Caligiuri A, Pastore M, Lori G, Raggi C, Di Maira G, Marra F, Gentilini A. Role of Chemokines in the Biology of Cholangiocarcinoma. Cancers (Basel) 2020; 12:cancers12082215. [PMID: 32784743 PMCID: PMC7463556 DOI: 10.3390/cancers12082215] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/03/2020] [Accepted: 08/05/2020] [Indexed: 02/07/2023] Open
Abstract
Cholangiocarcinoma (CCA), a heterogeneous tumor with poor prognosis, can arise at any level in the biliary tree. It may derive from epithelial cells in the biliary tracts and peribiliary glands and possibly from progenitor cells or even hepatocytes. Several risk factors are responsible for CCA onset, however an inflammatory milieu nearby the biliary tree represents the most common condition favoring CCA development. Chemokines play a key role in driving the immunological response upon liver injury and may sustain tumor initiation and development. Chemokine receptor-dependent pathways influence the interplay among various cellular components, resulting in remodeling of the hepatic microenvironment towards a pro-inflammatory, pro-fibrogenic, pro-angiogenic and pre-neoplastic setting. Moreover, once tumor develops, chemokine signaling may influence its progression. Here we review the role of chemokines in the regulation of CCA development and progression, and the modulation of angiogenesis, metastasis and immune control. The potential role of chemokines and their receptors as possible biomarkers and/or therapeutic targets for hepatobiliary cancer is also discussed.
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Affiliation(s)
| | | | | | | | | | - Fabio Marra
- Correspondence: (F.M.); (A.G.); Tel.: +39-055-2758095 or +39-055-2758498 or +39-055-2758499 (F.M.); +39-055-2751801 (A.G.)
| | - Alessandra Gentilini
- Correspondence: (F.M.); (A.G.); Tel.: +39-055-2758095 or +39-055-2758498 or +39-055-2758499 (F.M.); +39-055-2751801 (A.G.)
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23
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Kadomoto S, Izumi K, Mizokami A. The CCL20-CCR6 Axis in Cancer Progression. Int J Mol Sci 2020; 21:ijms21155186. [PMID: 32707869 PMCID: PMC7432448 DOI: 10.3390/ijms21155186] [Citation(s) in RCA: 160] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 12/14/2022] Open
Abstract
Chemokines, which are basic proteins that exert their effects via G protein-coupled receptors and a subset of the cytokine family, are mediators deeply involved in leukocyte migration during an inflammatory reaction. Chemokine (C-C motif) ligand 20 (CCL20), also known as macrophage inflammatory protein (MIP)-3α, liver activation regulated chemokine (LARC), and Exodus-1, is a small protein that is physiologically expressed in the liver, colon, and skin, is involved in tissue inflammation and homeostasis, and has a specific receptor C-C chemokine receptor 6 (CCR6). The CCL20-CCR6 axis has long been known to be involved in inflammatory and infectious diseases, such as rheumatoid arthritis and human immunodeficiency virus infections. Recently, however, reports have shown that the CCL20-CCR6 axis is associated with several cancers, including hepatocellular carcinoma, colorectal cancer, breast cancer, pancreatic cancer, cervical cancer, and kidney cancer. The CCL20-CCR6 axis promotes cancer progression directly by enhancing migration and proliferation of cancer cells and indirectly by remodeling the tumor microenvironment through immune cell control. The present article reviewed the role of the CCL20-CCR6 axis in cancer progression and its potential as a therapeutic target.
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Affiliation(s)
| | - Kouji Izumi
- Correspondence: ; Tel.: +81-76-265-2393; Fax: +81-76-234-4263
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Furue K, Ulzii D, Tanaka Y, Ito T, Tsuji G, Kido‐Nakahara M, Nakahara T, Furue M. Pathogenic implication of epidermal scratch injury in psoriasis and atopic dermatitis. J Dermatol 2020; 47:979-988. [DOI: 10.1111/1346-8138.15507] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/15/2020] [Accepted: 06/17/2020] [Indexed: 12/16/2022]
Affiliation(s)
- Kazuhisa Furue
- Department of Dermatology Graduate School of Medical Sciences Kyushu University Fukuoka Japan
| | - Dugarmaa Ulzii
- Department of Dermatology Graduate School of Medical Sciences Kyushu University Fukuoka Japan
| | - Yuka Tanaka
- Department of Dermatology Graduate School of Medical Sciences Kyushu University Fukuoka Japan
| | - Takamichi Ito
- Department of Dermatology Graduate School of Medical Sciences Kyushu University Fukuoka Japan
| | - Gaku Tsuji
- Department of Dermatology Graduate School of Medical Sciences Kyushu University Fukuoka Japan
- Research and Clinical Center for Yusho and Dioxin Kyushu University Hospital Fukuoka Japan
| | - Makiko Kido‐Nakahara
- Department of Dermatology Graduate School of Medical Sciences Kyushu University Fukuoka Japan
| | - Takeshi Nakahara
- Department of Dermatology Graduate School of Medical Sciences Kyushu University Fukuoka Japan
- Division of Skin Surface Sensing Department of Dermatology Graduate School of Medical Sciences Kyushu University Fukuoka Japan
| | - Masutaka Furue
- Department of Dermatology Graduate School of Medical Sciences Kyushu University Fukuoka Japan
- Research and Clinical Center for Yusho and Dioxin Kyushu University Hospital Fukuoka Japan
- Division of Skin Surface Sensing Department of Dermatology Graduate School of Medical Sciences Kyushu University Fukuoka Japan
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25
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Controlling leukocyte trafficking in IBD. Pharmacol Res 2020; 159:105050. [PMID: 32598943 DOI: 10.1016/j.phrs.2020.105050] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 06/24/2020] [Accepted: 06/24/2020] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel disease (IBD) is characterized by the accumulation of immune cells, myeloid cells and lymphocytes in the inflamed intestine. The presence and persistence of these cells, together with the production of pro-inflammatory mediators, perpetuate intestinal inflammation in both ulcerative colitis and Crohn's disease. Thus, blockade of leukocyte migration to the intestine is a main strategy used to control the disease and alleviate symptoms. Vedolizumab is the only anti-integrin drug approved for the treatment of IBD but several other drugs also targeting integrins, chemokines or receptors involved in leukocyte intestinal trafficking are under development and investigated for their efficacy and safety in IBD. The challenge now is to better understand the specific mechanism of action underlying each drug and to identify biomarkers that would guide drug selection in the individual patient.
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Laffan SB, Thomson AS, Mai S, Fishman C, Kambara T, Nistala K, Raymond JT, Chen S, Ramani T, Pageon L, Polsky R, Watkins M, Ottolangui G, White JR, Maier C, Herdman M, Bouma G. Immune complex disease in a chronic monkey study with a humanised, therapeutic antibody against CCL20 is associated with complement-containing drug aggregates. PLoS One 2020; 15:e0231655. [PMID: 32325480 PMCID: PMC7180069 DOI: 10.1371/journal.pone.0231655] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 03/27/2020] [Indexed: 12/18/2022] Open
Abstract
Despite the potential for the chemokine class as therapeutic targets in immune mediated disease, success has been limited. Many chemokines can bind to multiple receptors and many receptors have multiple ligands, with few exceptions. One of those exceptions is CCL20, which exclusively pairs to CCR6 and is associated with several immunologic conditions, thus providing a promising therapeutic target. Following successful evaluation in a single dose, first time in human clinical study, GSK3050002—a humanized IgG1 monoclonal antibody against human CCL20—was evaluated in a 26-week cynomolgus monkey toxicology study. A high incidence of unexpected vascular and organ inflammation was observed microscopically, leading to the decision to halt clinical development. Here we report a dose-responsive increase in the incidence and severity of inflammation in multiple organs from monkeys receiving 30 and 300 mg/kg/week by either subcutaneous or intravenous injection. Histomorphological changes resembled an immune complex-mediated pathology, which is often due to formation of anti-drug antibodies in monkeys receiving a human protein therapeutic and thus not predictive of clinical outcome. However, the presentation was atypical in that there was a clear dose response with a very high incidence of inflammation with a low incidence of ADA that did not correlate well individually. Additionally, the immunohistologic presentation was atypical in that the severity and distribution of tissue inflammation was greater than the numbers of associated immune complexes (i.e., granular deposits). An extensive ex vivo analysis of large molecular weight protein complexes in monkey serum from this study and in human serum samples demonstrated a time-dependent aggregation of GSK3050002, that was not predicted by in vitro assays. The aggregates also contained complement components. These findings support the hypothesis that immune complexes of drug aggregates, not necessarily including anti-drug antibodies, can fix complement, accumulate over time, and trigger immune complex disease. A situation which may have increased clinical relevance than typical anti-drug antibody-associated immune complex disease in monkeys administered human antibody proteins.
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Affiliation(s)
- Susan B. Laffan
- In vitro In vivo Translation (IVIVT), R&D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Andrew S. Thomson
- Biopharm Analytical Science, R&D Platform Technology and Science, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America
| | - Shing Mai
- Biopharm Analytical Science, R&D Platform Technology and Science, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America
| | - Cindy Fishman
- In vitro In vivo Translation (IVIVT), R&D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Takahito Kambara
- Pathology, IVIVT, R&D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Kiran Nistala
- Adaptive Immunity Research Unit, GlaxoSmithKline, Stevenage, United Kingdom
| | - James T. Raymond
- Charles River Laboratories, Inc., Frederick, Maryland, United States of America
| | - Shugui Chen
- Biopharm Analytical Science, R&D Platform Technology and Science, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America
| | - Thulasi Ramani
- Envigo CRS, Inc., Princeton, New Jersey, United States of America
| | - Laura Pageon
- Envigo CRS, Inc., Princeton, New Jersey, United States of America
| | - Rodd Polsky
- Biopharm Analytical Science, R&D Platform Technology and Science, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America
| | - Mark Watkins
- In vitro In vivo Translation (IVIVT), R&D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Gemma Ottolangui
- Biopharm Molecular Discovery, R&D Platform Technology and Science, GlaxoSmithKline, Stevenage, United Kingdom
| | - John R. White
- Biopharm Analytical Science, R&D Platform Technology and Science, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America
| | - Curtis Maier
- In vitro In vivo Translation (IVIVT), R&D, GlaxoSmithKline, Collegeville, Pennsylvania, United States of America
| | - Michael Herdman
- Clinical Pharmacology and Experimental Medicine, GlaxoSmithKline, Stevenage, United Kingdom
| | - Gerben Bouma
- Adaptive Immunity Research Unit, GlaxoSmithKline, Stevenage, United Kingdom
- Clinical Pharmacology and Experimental Medicine, GlaxoSmithKline, Stevenage, United Kingdom
- * E-mail:
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Interleukin-17A and Keratinocytes in Psoriasis. Int J Mol Sci 2020; 21:ijms21041275. [PMID: 32070069 PMCID: PMC7072868 DOI: 10.3390/ijms21041275] [Citation(s) in RCA: 167] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 02/11/2020] [Accepted: 02/11/2020] [Indexed: 02/06/2023] Open
Abstract
The excellent clinical efficacy of anti-interleukin 17A (IL-17A) biologics on psoriasis indicates a crucial pathogenic role of IL-17A in this autoinflammatory skin disease. IL-17A accelerates the proliferation of epidermal keratinocytes. Keratinocytes produce a myriad of antimicrobial peptides and chemokines, such as CXCL1, CXCL2, CXCL8, and CCL20. Antimicrobial peptides enhance skin inflammation. IL-17A is capable of upregulating the production of these chemokines and antimicrobial peptides in keratinocytes. CXCL1, CXCL2, and CXCL8 recruit neutrophils and CCL20 chemoattracts IL-17A-producing CCR6+ immune cells, which further contributes to forming an IL-17A-rich milieu. This feed-forward pathogenic process results in characteristic histopathological features, such as epidermal hyperproliferation, intraepidermal neutrophilic microabscess, and dermal CCR6+ cell infiltration. In this review, we focus on IL-17A and keratinocyte interaction regarding psoriasis pathogenesis.
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Win Maung HM, Chan-On W, Kunkeaw N, Khaenam P. Common transcriptional programs and the role of chemokine (C-C motif) ligand 20 ( CCL20) in cell migration of cholangiocarcinoma. EXCLI JOURNAL 2020; 19:154-166. [PMID: 32194362 PMCID: PMC7068202 DOI: 10.17179/excli2019-1893] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 01/14/2020] [Indexed: 12/15/2022]
Abstract
The incidence of cholangiocarcinoma (CCA) has risen in many countries, but there is still no appropriate screening and treatment available. The growing number of microarray data published todays can be a powerful resource for the discovery of biomarkers to tackle challenges in the management of CCA. This study analyzed multiple microarray datasets to identify the common transcriptional networks in CCA and select a possible biomarker for functional study in CCA cell lines. A systematic searching identified 4 microarray datasets from Gene Expression Omnibus (GEO) repository and PubMed articles. Differential expression analysis between tumor and normal tissues was performed in each dataset. In order to characterize the common expression pattern, differentially expressed genes (DEGs) from all datasets were combined and visualized by hierarchical clustering and heatmap. Gene enrichment analysis performed in each cluster revealed that over-expressed DEGs were enriched in cell cycle, cell migration and response to cytokines while under-expressed DEGs were enriched in metabolic processes such as oxidation-reduction, lipid, and drug. To explain tumor characteristics, genes enriched in cell migration and response to cytokines were further investigated. Among these genes, CCL20 was selected for functional study because its role has never been studied in CCA. Moreover, its signaling may be regulated by disrupting its only receptor, CCR6. Treatment with recombinant CCL20 induced higher cell migration and increased expression of N-cad. In contrast, knockdown of CCR6 by siRNA reduced cell migration ability and decreased N-cadherin level. Altogether, these results suggested the contribution of CCL20/CCR6 signaling in cell migration through epithelial-mesenchymal transition process. Thus, CCL20/CCR6 signaling might be a target for the management of CCA.
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Affiliation(s)
- Hay Mar Win Maung
- Center for Standardization and Product Validation, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, 73170, Thailand
| | - Waraporn Chan-On
- Center for Research and Innovation, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, 73170, Thailand
| | - Nawapol Kunkeaw
- Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, 73170, Thailand
| | - Prasong Khaenam
- Center for Standardization and Product Validation, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, 73170, Thailand
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29
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The EGFR-ERK/JNK-CCL20 Pathway in Scratched Keratinocytes May Underpin Koebnerization in Psoriasis Patients. Int J Mol Sci 2020; 21:ijms21020434. [PMID: 31936670 PMCID: PMC7013594 DOI: 10.3390/ijms21020434] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/06/2020] [Accepted: 01/08/2020] [Indexed: 12/20/2022] Open
Abstract
Epidermal keratinocytes represent a rich source of C-C motif chemokine 20 (CCL20) and recruit CCR6+ interleukin (IL)-17A–producing T cells that are known to be pathogenic for psoriasis. A previous study revealed that scratch injury on keratinocytes upregulates CCL20 production, which is implicated in the Koebner phenomenon characteristically seen in psoriasis patients. However, the molecular mechanisms leading to scratch-induced CCL20 production remain elusive. In this study, we demonstrate that scratch injury upregulates the phosphorylation of epidermal growth factor receptor (EGFR) and that the specific EGFR inhibitor PD153035 attenuates scratch-induced CCL20 upregulation in an extracellular signal-related kinase (ERK)-dependent, and to a lesser extent, a c-Jun N-terminal kinase (JNK)-dependent but p38 mitogen-activated protein kinase (MAPK)–independent manner. Immunoreactive CCL20 was visualized in the keratinocytes that lined the scratched wound. IL-17A also induced the phosphorylation of EGFR and further augmented scratch-induced CCL20 upregulation. The EGFR-ERK/JNK-CCL20 pathway in scratched keratinocytes may explain why Koebnerization is frequently seen in psoriasis patients.
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30
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Furue K, Ito T, Tsuji G, Nakahara T, Furue M. The CCL20 and CCR6 axis in psoriasis. Scand J Immunol 2019; 91:e12846. [PMID: 31692008 DOI: 10.1111/sji.12846] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 10/20/2019] [Accepted: 11/01/2019] [Indexed: 12/11/2022]
Abstract
Psoriasis is a TNF-α/IL-23/IL-17A-mediated inflammatory skin disease that causes a significant socioeconomic burden in afflicted patients. IL-17A-producing immune cells, including Th17 cells, are crucial effector cells in the development of psoriasis. IL-17A stimulates epidermal keratinocytes to produce CCL20, which eventually recruits CCR6 + Th17 cells into the lesional skin. Thus, the CCL20/CCR6 axis works as a driving force that prepares an IL-17A-rich cutaneous milieu. In this review, we summarize the current research topics on the CCL20/CCR6 axis and the therapeutic intervention of this axis for psoriasis.
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Affiliation(s)
- Kazuhisa Furue
- Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takamichi Ito
- Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Gaku Tsuji
- Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka, Japan
| | - Takeshi Nakahara
- Division of Skin Surface Sensing, Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masutaka Furue
- Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka, Japan.,Division of Skin Surface Sensing, Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
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31
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Furue K, Ito T, Tsuji G, Esaki H, Kido-Nakahara M, Nakahara T, Furue M. Does mechanical scratching cause the recruitment of T-helper 17 cells in atopic dermatitis? J Dermatol 2019; 46:e436-e437. [PMID: 31294475 DOI: 10.1111/1346-8138.15011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Kazuhisa Furue
- Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takamichi Ito
- Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Gaku Tsuji
- Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Skin Surface Sensing, Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hitokazu Esaki
- Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Makiko Kido-Nakahara
- Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Nakahara
- Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka, Japan
| | - Masutaka Furue
- Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Division of Skin Surface Sensing, Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.,Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka, Japan
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32
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Litman T. Personalized medicine-concepts, technologies, and applications in inflammatory skin diseases. APMIS 2019; 127:386-424. [PMID: 31124204 PMCID: PMC6851586 DOI: 10.1111/apm.12934] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 01/31/2019] [Indexed: 12/19/2022]
Abstract
The current state, tools, and applications of personalized medicine with special emphasis on inflammatory skin diseases like psoriasis and atopic dermatitis are discussed. Inflammatory pathways are outlined as well as potential targets for monoclonal antibodies and small-molecule inhibitors.
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Affiliation(s)
- Thomas Litman
- Department of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark
- Explorative Biology, Skin ResearchLEO Pharma A/SBallerupDenmark
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33
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Pérez-Jeldres T, Tyler CJ, Boyer JD, Karuppuchamy T, Bamias G, Dulai PS, Boland BS, Sandborn WJ, Patel DR, Rivera-Nieves J. Cell Trafficking Interference in Inflammatory Bowel Disease: Therapeutic Interventions Based on Basic Pathogenesis Concepts. Inflamm Bowel Dis 2019; 25:270-282. [PMID: 30165490 PMCID: PMC6327230 DOI: 10.1093/ibd/izy269] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Indexed: 12/27/2022]
Abstract
After 20 years of successful targeting of pro-inflammatory cytokines for the treatment of IBD, an alternative therapeutic strategy has emerged, based on several decades of advances in understanding the pathogenesis of IBD. The targeting of molecules involved in leukocyte traffic has recently become a safe and effective alternative. With 2 currently approved drugs (ie, natalizumab, vedolizumab) and several others in phase 3 trials (eg, etrolizumab, ozanimod, anti-MAdCAM-1), the blockade of trafficking molecules has firmly emerged as a new therapeutic era for IBD. We discuss the targets that have been explored in clinical trials: chemokines and its receptors (eg, IP10, CCR9), integrins (eg, natalizumab, AJM300, vedolizumab, and etrolizumab), and its endothelial ligands (MAdCAM-1, ICAM-1). We also discuss a distinct strategy that interferes with lymphocyte recirculation by blocking lymphocyte egress from lymph nodes (small molecule sphingosine-phosphate receptor [S1PR] agonists: fingolimod, ozanimod, etrasimod, amiselimod). Strategies on the horizon include additional small molecules, allosteric inhibitors that specifically bind to the active integrin form and nanovectors that allow for the use of RNA interference in the quest to modulate pro-inflammatory leukocyte trafficking in IBD.
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Affiliation(s)
- Tamara Pérez-Jeldres
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- Hospital San Borja Arriarán, Santiago, Chile
- Universidad Católica de Chile, Santiago, Chile
| | - Christopher J Tyler
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
| | - Joshua D Boyer
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
| | - Thangaraj Karuppuchamy
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
| | - Giorgos Bamias
- GI Unit, 3rd Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece
| | - Parambir S Dulai
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
| | - Brigid S Boland
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - William J Sandborn
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - Derek R Patel
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - Jesús Rivera-Nieves
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
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Ranasinghe R, Eri R. Modulation of the CCR6-CCL20 Axis: A Potential Therapeutic Target in Inflammation and Cancer. ACTA ACUST UNITED AC 2018; 54:medicina54050088. [PMID: 30453514 PMCID: PMC6262638 DOI: 10.3390/medicina54050088] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Revised: 11/01/2018] [Accepted: 11/13/2018] [Indexed: 12/23/2022]
Abstract
Prototypical functions of the chemokine receptor CCR6 include immune regulation by maneuvering cell chemotaxis and selective delimiting of the pro-inflammatory TH17 and regulatory Treg subsets during chronic or acute systemic inflammation. Inhibition of CCR6 is proposed to attenuate disease symptoms and promote recuperation of multiple inflammatory and autoimmune disorders. Prescription medicines with pharmacodynamics involving the inhibition of the chemokine axis CCR6–CCL20 are very limited. The development of such therapeutics is still at an early experimental stage and has mostly involved the utilization of pre-clinical models and neutralizing mono or polyclonal antibodies against either partner (CCR6 or CCL20). Other methods include the constitutive use of small molecules as peptide inhibitors or small interfering ribonucleic acid (siRNA) to interfere with transcription at the nuclear level. In our review, we aim to introduce the wide array of potential CCR6–CCL20 inhibitors with an emphasis on attendant immune-modulator capacity that have been tested in the research field to date and are immensely promising compounds as forerunners of future curatives. Sixteen different tractable inhibitors of the CCR6–CCL20 duo have been identified as possessing high medicinal potential by drug developers worldwide to treat autoimmune and inflammatory diseases as shown in Figure 1. A multitude of antibody preparations are already available in the current pharmaceutical market as patented treatments for diseases in which the CCR6–CCL20 axis is operative, yet they must be used only as supplements with existing routinely prescribed medication as they collectively produce adverse side effects. Novel inhibitors are needed to evaluate this invaluable therapeutic target which holds much promise in the research and development of complaisant remedies for inflammatory diseases.
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Affiliation(s)
- Ranmali Ranasinghe
- School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Tasmania 7248, Australia.
| | - Rajaraman Eri
- School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Tasmania 7248, Australia.
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35
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Improvement of pharmacokinetic properties of therapeutic antibodies by antibody engineering. Drug Metab Pharmacokinet 2018; 34:25-41. [PMID: 30472066 DOI: 10.1016/j.dmpk.2018.10.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 09/13/2018] [Accepted: 10/23/2018] [Indexed: 01/17/2023]
Abstract
Monoclonal antibodies (mAbs) have become an important therapeutic option for several diseases. Since several mAbs have shown promising efficacy in clinic, the competition to develop mAbs has become severe. In efforts to gain a competitive advantage over other mAbs and provide significant benefits to patients, innovations in antibody engineering have aimed at improving the pharmacokinetic properties of mAbs. Because engineering can provide therapeutics that are more convenient, safer, and more efficacious for patients in several disease areas, it is an attractive approach to provide significant benefits to patients. Further advances in engineering mAbs to modulate their pharmacokinetics were driven by the increase of total soluble target antigen concentration that is often observed after injecting a mAb, which then requires a high dosage to antagonize. To decrease the required dosage, several antibody engineering techniques have been invented that reduce the total concentration of soluble target antigen. Here, we review the various ways that antibody engineering can improve the pharmacokinetic properties of mAbs.
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36
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Reid J, Zamuner S, Edwards K, Rumley S, Nevin K, Feeney M, Zecchin C, Fernando D, Wisniacki N. In vivo affinity and target engagement in skin and blood in a first-time-in-human study of an anti-oncostatin M monoclonal antibody. Br J Clin Pharmacol 2018; 84:2280-2291. [PMID: 29900565 PMCID: PMC6138480 DOI: 10.1111/bcp.13669] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 05/04/2018] [Accepted: 05/28/2018] [Indexed: 01/30/2023] Open
Abstract
AIMS The oncostatin M (OSM) pathway drives fibrosis, inflammation and vasculopathy, and is a potential therapeutic target for inflammatory and fibrotic diseases. The aim of this first-time-in-human experimental medicine study was to assess the safety, tolerability, pharmacokinetics and target engagement of single subcutaneous doses of GSK2330811, an anti-OSM monoclonal antibody, in healthy subjects. METHODS This was a phase I, randomized, double-blind, placebo-controlled, single-dose escalation, first-time-in-human study of subcutaneously administered GSK2330811 in healthy adults (NCT02386436). Safety and tolerability, GSK2330811 pharmacokinetic profile, OSM levels in blood and skin, and the potential for antidrug antibody formation were assessed. The in vivo affinity of GSK2330811 for OSM and target engagement in serum and skin blister fluid (obtained via a skin suction blister model) were estimated using target-mediated drug disposition (TMDD) models in combination with compartmental and physiology-based pharmacokinetic (PBPK) models. RESULTS Thirty subjects were randomized to receive GSK2330811 and 10 to placebo in this completed study. GSK2330811 demonstrated a favourable safety profile in healthy subjects; no adverse events were serious or led to withdrawal. There were no clinically relevant trends in change from baseline in laboratory values, with the exception of a reversible dose-dependent reduction in platelet count. GSK2330811 exhibited linear pharmacokinetics over the dose range 0.1-6 mg kg-1 . The estimated in vivo affinity (nM) of GSK2330811 for OSM was 0.568 [95% confidence interval (CI) 0.455, 0.710] in the compartmental with TMDD model and 0.629 (95% CI 0.494, 0.802) using the minimal PBPK with TMDD model. CONCLUSIONS Single subcutaneous doses of GSK2330811 were well tolerated in healthy subjects. GSK2330811 demonstrated sufficient affinity to achieve target engagement in systemic circulation and target skin tissue, supporting the progression of GSK2330811 clinical development.
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Affiliation(s)
- Juliet Reid
- ImmunoInflammationGlaxoSmithKlineStevenageUK
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Holm LL, Vukmanovic-Stejic M, Blauenfeldt T, Benfield T, Andersen P, Akbar AN, Ruhwald M. A Suction Blister Protocol to Study Human T-cell Recall Responses In Vivo. J Vis Exp 2018. [PMID: 30148487 PMCID: PMC6126709 DOI: 10.3791/57554] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Cutaneous antigen-recall models allow for studies of human memory responses in vivo. When combined with skin suction blister (SB) induction, this model offers accessibility to rare populations of antigen-specific T-cells representative of the cellular memory response as well as the cytokine microenvironment in situ. This report describes the practical procedure of a cutaneous recall, an SB induction, and a harvest of antigen-specific T-cells. To exemplify the method, the tuberculin skin test is used for antigenic recall in individuals who, prior to this study, underwent a Bacillus Calmette-Guérin vaccination against an infection with Mycobacterium tuberculosis. Finally, examples of multiplex and flow cytometric analyses of SB specimens are provided, illustrating high fractions of antigen-specific polyfunctional CD4+ T-cells available by this sampling method compared with cells isolated from the blood. The method described here is safe and minimally invasive, provides a unique opportunity to study both innate and adaptive immune responses in vivo, and may be beneficial to a broad community of researchers working with cell-mediated immunity and human memory responses, in the context of vaccine development.
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Affiliation(s)
- Line L Holm
- Department of Infectious Disease Immunology, Center for Vaccine Research, Statens Serum Institut; Department of Infectious Diseases, Hvidovre Hospital; Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen;
| | | | - Thomas Blauenfeldt
- Department of Infectious Disease Immunology, Center for Vaccine Research, Statens Serum Institut
| | - Thomas Benfield
- Department of Infectious Diseases, Hvidovre Hospital; Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen
| | - Peter Andersen
- Department of Infectious Disease Immunology, Center for Vaccine Research, Statens Serum Institut
| | - Arne N Akbar
- Division of Infection and Immunity, University College London
| | - Morten Ruhwald
- Department of Infectious Disease Immunology, Center for Vaccine Research, Statens Serum Institut
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Bouma G, Zamuner S, Hicks K, Want A, Oliveira J, Choudhury A, Brett S, Robertson D, Felton L, Norris V, Fernando D, Herdman M, Tarzi R. CCL20 neutralization by a monoclonal antibody in healthy subjects selectively inhibits recruitment of CCR6 + cells in an experimental suction blister. Br J Clin Pharmacol 2017; 83:1976-1990. [PMID: 28295451 DOI: 10.1111/bcp.13286] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 02/21/2017] [Accepted: 03/06/2017] [Indexed: 01/10/2023] Open
Abstract
AIMS GSK3050002, a humanized IgG1κ antibody with high binding affinity to human CCL20, was administered in a first-in-human study to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD). An experimental skin suction blister model was employed to assess target engagement and the ability of the compound to inhibit recruitment of inflammatory CCR6 expressing cells. METHODS This study was a randomized, double-blind (sponsor open), placebo-controlled, single-centre, single ascending intravenous dose escalation trial in 48 healthy male volunteers. RESULTS GSK3050002 (0.1-20 mg kg-1 ) was well tolerated and no safety concerns were identified. The PK was linear over the dose range, with a half-life of approximately 2 weeks. Complex of GSK3050002/CCL20 increased in serum and blister fluid with increasing doses of GSK3050002. There were dose-dependent decreases in CCR6+ cell recruitment to skin blisters with maximal effects at doses of 5 mg kg-1 and higher, doses at which GSK3050002/CCL20 complex in serum and blister fluid also appeared to reach maximum levels. CONCLUSIONS These results indicate a relationship between PK, target engagement and PD, suggesting a selective inhibition of recruitment of CCR6+ cells by GSK3050002 and support further development of GSK3050002 in autoimmune and inflammatory diseases.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Virginia Norris
- GlaxoSmithKline, Hertfordshire, UK.,GN Clinical Consulting Ltd, London, UK
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