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1
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Lu Y, Man XY. Diversity and function of regulatory T cells in health and autoimmune diseases. J Autoimmun 2025; 151:103357. [PMID: 39805189 DOI: 10.1016/j.jaut.2025.103357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 12/31/2024] [Accepted: 01/04/2025] [Indexed: 01/16/2025]
Abstract
Regulatory T cell (Treg) play a pivotal role in immune regulation and maintaining host immune homeostasis. Treg heterogeneity, characterized by diverse gene expression profiles and functional states, is complex in both health and disease. Research reveals that Tregs are not a uniform population but exhibit diversity based on their origin, location, and functional status. This heterogeneity is crucial for understanding Treg roles in various pathological conditions. Dysfunctional Tregs are closely linked to the pathogenesis of autoimmune diseases, although the precise mechanisms remain unclear. The phenotypic and functional heterogeneity of Tregs is particularly significant in diseases such as systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, psoriasis and autoimmune liver diseases. This review explores Treg origins, classifications, and heterogeneity in these conditions, aiming to provide new perspectives and strategies for diagnosis and treatment. Understanding Treg heterogeneity and plasticity promises to reveal novel therapeutic targets and advance precision immunotherapy development.
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Affiliation(s)
- Yi Lu
- Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Xiao-Yong Man
- Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
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2
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Choe SI, Bourgeois J, Nidamanuri S, Rubenzik R. Pyoderma Gangrenosum in an Ulcerative Colitis Patient on Vedolizumab. Cureus 2024; 16:e69219. [PMID: 39398841 PMCID: PMC11469654 DOI: 10.7759/cureus.69219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2024] [Indexed: 10/15/2024] Open
Abstract
Pyoderma gangrenosum is a rare neutrophilic dermatosis that presents as a tender, rapidly progressive ulcer with violaceous, undermined borders. Pathophysiology is multifactorial and has been suggested to involve neutrophil dysfunction, increased T-cell activation, and inflammatory mediator release, often in settings that are known to have autoimmune or genetic diseases. Some medications that modify the immune response have been described to trigger pyoderma gangrenosum. Vedolizumab is a monoclonal antibody used in the management of inflammatory bowel disease that has been shown to be effective in the treatment of pyoderma gangrenosum but, in some cases, has been shown to paradoxically induce pyoderma gangrenosum. Vedolizumab causes gut-selective inhibition of lymphocyte migration, which may lead to the activation of lymphocytes in other organ systems, such as the skin. In this report, we present a case of pyoderma gangrenosum in a patient treated with vedolizumab for ulcerative colitis and explore the possible mechanism behind vedolizumab-induced pyoderma gangrenosum.
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Affiliation(s)
- Sharon I Choe
- Internal Medicine, Creighton University School of Medicine, Phoenix, USA
| | - Julien Bourgeois
- Internal Medicine, Creighton University School of Medicine, Phoenix, USA
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Patwardhan S, Hong J, Weiner J. Update on Maintenance Immunosuppression in Intestinal Transplantation. Gastroenterol Clin North Am 2024; 53:493-507. [PMID: 39068010 PMCID: PMC11284276 DOI: 10.1016/j.gtc.2023.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Outcomes in intestinal transplantation remain hampered by higher rates of rejection than any other solid organs. However, maintenance immunosuppression regimens have largely remained unchanged despite advances in therapies for induction and treatment of rejection and graft-versus-host disease. Recently, there have been a small number of new maintenance therapies attempted, and older agents have been used in new ways to achieve better outcomes. The authors herein review the traditional maintenance therapies and their mechanisms and then consider updates in new therapies and new ways of using old therapies for maintenance immunosuppression after intestinal transplantation.
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Affiliation(s)
- Satyajit Patwardhan
- Columbia Center for Translational Immunology, 650 West 168th Street, BB1705, New York, NY 10032, USA
| | - Julie Hong
- Columbia Center for Translational Immunology, 650 West 168th Street, BB1705, New York, NY 10032, USA
| | - Joshua Weiner
- Columbia Center for Translational Immunology, 650 West 168th Street, BB1705, New York, NY 10032, USA; Division of Abdominal Organ Transplantation, Columbia University Irving Medical Center, 622 West 168th Street, PH14-105, New York, NY 10032, USA.
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4
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Boden EK, Kongala R, Hindmarch DC, Shows DM, Juarez JG, Lord JD. Vedolizumab Efficacy Is Associated With Decreased Intracolonic Dendritic Cells, Not Memory T Cells. Inflamm Bowel Dis 2024; 30:704-717. [PMID: 37837660 PMCID: PMC11063563 DOI: 10.1093/ibd/izad224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Indexed: 10/16/2023]
Abstract
BACKGROUND Vedolizumab, an antibody blocking integrin α4β7, is a safe and effective therapy for Crohn's disease and ulcerative colitis. Blocking α4β7 from binding its cognate addressin MAdCAM-1 on intestinal blood vessel endothelial cells prevents T cells from migrating to the gut mucosa in animal models. However, data supporting this mechanism of action in humans is limited. METHODS We conducted a cross-sectional case-control study to evaluate the effect of vedolizumab on intestinal immune cell populations while avoiding the confounding effect of resolving inflammation on the cellularity of the colonic mucosa in treatment-responsive patients. Colon biopsies from 65 case subjects receiving vedolizumab were matched with biopsies from 65 control individuals, similar in disease type, medications, anatomic location, and inflammation. Biopsies were analyzed by flow cytometry and full messenger RNA transcriptome sequencing of sorted T cells. RESULTS No difference was seen between vedolizumab recipients and control individuals in the quantity of any antigen-experienced T lymphocyte subset or in the quality of the transcriptome in any experienced T cell subset. Fewer naïve colonic B and T cells were seen in vedolizumab recipients than control individuals, regardless of response. However, the most striking finding was a marked reduction in CD1c+ (BDCA1+) dendritic cells exclusively in vedolizumab-responsive patients. In blood, these dendritic cells ubiquitously express high levels of α4β7, which is rapidly downregulated upon vedolizumab exposure. CONCLUSIONS The clinical effects of vedolizumab reveal integrin α4β7-dependent dendritic cell migration to the intestinal mucosa to be central to inflammatory bowel disease pathogenesis.
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Affiliation(s)
- Elisa K Boden
- Center for Translational Research, Benaroya Research Institute, Seattle, WA, USA
- Division of Gastroenterology, Oregon Health and Science University, Portland, OR, USA
| | - Ramya Kongala
- Center for Translational Research, Benaroya Research Institute, Seattle, WA, USA
| | - Duncan C Hindmarch
- Center for Translational Research, Benaroya Research Institute, Seattle, WA, USA
| | - Donna M Shows
- Center for Translational Research, Benaroya Research Institute, Seattle, WA, USA
| | - Julius G Juarez
- GI Drug Discovery, Takeda Pharmaceuticals, Cambridge, MA, USA
| | - James D Lord
- Center for Translational Research, Benaroya Research Institute, Seattle, WA, USA
- Division of Gastroenterology, Virginia Mason Medical Center, Seattle, WA, USA
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5
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Mennillo E, Kim YJ, Lee G, Rusu I, Patel RK, Dorman LC, Flynn E, Li S, Bain JL, Andersen C, Rao A, Tamaki S, Tsui J, Shen A, Lotstein ML, Rahim M, Naser M, Bernard-Vazquez F, Eckalbar W, Cho SJ, Beck K, El-Nachef N, Lewin S, Selvig DR, Terdiman JP, Mahadevan U, Oh DY, Fragiadakis GK, Pisco A, Combes AJ, Kattah MG. Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis. Nat Commun 2024; 15:1493. [PMID: 38374043 PMCID: PMC10876948 DOI: 10.1038/s41467-024-45665-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 01/30/2024] [Indexed: 02/21/2024] Open
Abstract
Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we perform single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.
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Affiliation(s)
- Elvira Mennillo
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | | | - Gyehyun Lee
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Iulia Rusu
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Ravi K Patel
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | | | - Emily Flynn
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Stephanie Li
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Jared L Bain
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Christopher Andersen
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Arjun Rao
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Stanley Tamaki
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Jessica Tsui
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Alan Shen
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Madison L Lotstein
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Maha Rahim
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Mohammad Naser
- Biological Imaging Development CoLab, University of California San Francisco, San Francisco, CA, USA
| | | | - Walter Eckalbar
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Soo-Jin Cho
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Kendall Beck
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Najwa El-Nachef
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Sara Lewin
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Daniel R Selvig
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Jonathan P Terdiman
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Uma Mahadevan
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - David Y Oh
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Gabriela K Fragiadakis
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | | | - Alexis J Combes
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Michael G Kattah
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
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6
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Ozawa N, Yokobori T, Osone K, Bilguun EO, Okami H, Shimoda Y, Shiraishi T, Okada T, Sano A, Sakai M, Sohda M, Miyazaki T, Ide M, Ogawa H, Yao T, Oyama T, Shirabe K, Saeki H. MAdCAM-1 targeting strategy can prevent colitic cancer carcinogenesis and progression via suppression of immune cell infiltration and inflammatory signals. Int J Cancer 2024; 154:359-371. [PMID: 37676657 DOI: 10.1002/ijc.34722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 05/19/2023] [Accepted: 06/13/2023] [Indexed: 09/08/2023]
Abstract
Chronic inflammation caused by infiltrating immune cells can promote colitis-associated dysplasia/colitic cancer in ulcerative colitis (UC) by activating inflammatory cytokine signalling through the IL-6/p-STAT3 and TNFα/NF-κB pathways. Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on high endothelial venules promotes the migration of immune cells from the bloodstream to the gut via interaction with α4β7 integrin expressed on the immune cells. MAdCAM-1, has therefore drawn interest as a novel therapeutic target for treating active UC. However, the role of MAdCAM-1-positive endothelial cells in immune cell infiltration in dysplasia/colitic cancers remains unclear. We evaluated the expression of MAdCAM-1, CD31 and immune cell markers (CD8, CD68, CD163 and FOXP3) in samples surgically resected from 11 UC patients with dysplasia/colitic cancer and 17 patients with sporadic colorectal cancer (SCRC), using immunohistochemical staining. We used an azoxymethane/dextran sodium sulphate mouse model (AOM/DSS mouse) to evaluate whether dysplasia/colitic cancer could be suppressed with an anti-MAdCAM-1 blocking antibody by preventing immune cell infiltration. The number of MAdCAM-1-positive vessels and infiltrating CD8+ , CD68+ and CD163+ immune cells was significantly higher in dysplasia/colitic cancer than in normal, SCRC and UC mucosa. In AOM/DSS mice, the anti-MAdCAM-1 antibody reduced the number, mean diameter, depth of tumours, Ki67 positivity, number of CD8+ , CD68+ and CD163+ immune cells and the IL-6/p-STAT3 and TNF-α/NF-κB signalling. Our results indicate that targeting MAdCAM-1 is a promising strategy for controlling not only UC severity but also carcinogenesis and tumour progression by regulating inflammation/immune cell infiltration in patients with UC.
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Affiliation(s)
- Naoya Ozawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Takehiko Yokobori
- Division of Integrated Oncology Research, Gunma University, Initiative for Advanced Research (GIAR), Maebashi, Gunma, Japan
| | - Katsuya Osone
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Erkhem-Ochir Bilguun
- Division of Integrated Oncology Research, Gunma University, Initiative for Advanced Research (GIAR), Maebashi, Gunma, Japan
| | - Haruka Okami
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Yuki Shimoda
- Department of Diagnostic Pathology, Gunma University Graduate School of Medicine
| | - Takuya Shiraishi
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Takuhisa Okada
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Akihiko Sano
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Makoto Sakai
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Makoto Sohda
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Tatsuya Miyazaki
- Department of Gastroenterological Surgery, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan
| | - Munenori Ide
- Department of Pathology Diagnosis, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan
| | - Hiroomi Ogawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Bunkyouku, Tokyo, Japan
| | - Tetsunari Oyama
- Department of Diagnostic Pathology, Gunma University Graduate School of Medicine
| | - Ken Shirabe
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Hiroshi Saeki
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
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7
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Mennillo E, Kim YJ, Lee G, Rusu I, Patel RK, Dorman LC, Flynn E, Li S, Bain JL, Andersen C, Rao A, Tamaki S, Tsui J, Shen A, Lotstein ML, Rahim M, Naser M, Bernard-Vazquez F, Eckalbar W, Cho SJ, Beck K, El-Nachef N, Lewin S, Selvig DR, Terdiman JP, Mahadevan U, Oh DY, Fragiadakis GK, Pisco A, Combes AJ, Kattah MG. Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.01.21.525036. [PMID: 36711576 PMCID: PMC9882264 DOI: 10.1101/2023.01.21.525036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we performed single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.
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8
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Gordon H, Rodger B, Lindsay JO, Stagg AJ. Recruitment and Residence of Intestinal T Cells - Lessons for Therapy in Inflammatory Bowel Disease. J Crohns Colitis 2023; 17:1326-1341. [PMID: 36806613 DOI: 10.1093/ecco-jcc/jjad027] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Indexed: 02/23/2023]
Abstract
Targeting leukocyte trafficking in the management of inflammatory bowel disease [IBD] has been a significant therapeutic advance over the past 15 years. However, as with other advanced therapies, phase III clinical trials report response to trafficking inhibitors in only a proportion of patients, with fewer achieving clinical remission or mucosal healing. Additionally, there have been significant side effects, most notably progressive multifocal leukoencephalopathy in association with the α4 inhibitor natalizumab. This article reviews the mechanisms underpinning T cell recruitment and residence, to provide a background from which the strength and limitations of agents that disrupt leukocyte trafficking can be further explored. The therapeutic impact of trafficking inhibitors is underpinned by the complexity and plasticity of the intestinal immune response. Pathways essential for gut homing in health may be bypassed in the inflamed gut, thus providing alternative routes of entry when conventional homing molecules are targeted. Furthermore, there is conservation of trafficking architecture between proinflammatory and regulatory T cells. The persistence of resident memory cells within the gut gives rise to local established pro-inflammatory populations, uninfluenced by inhibition of trafficking. Finally, trafficking inhibitors may give rise to effects beyond the intended response, such as the impact of vedolizumab on innate immunity, as well as on target side effects. With significant research efforts into predictive biomarkers already underway, it is ultimately hoped that a better understanding of trafficking and residence will help us predict which patients are most likely to respond to inhibition of leukocyte trafficking, and how best to combine therapies.
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Affiliation(s)
- Hannah Gordon
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
- Department of Gastroenterology, Barts Health NHS Trust, London, UK
| | - Beverley Rodger
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
| | - James O Lindsay
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
- Department of Gastroenterology, Barts Health NHS Trust, London, UK
| | - Andrew J Stagg
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
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9
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Laukova M, Glatman Zaretsky A. Regulatory T cells as a therapeutic approach for inflammatory bowel disease. Eur J Immunol 2023; 53:e2250007. [PMID: 36562391 PMCID: PMC10107179 DOI: 10.1002/eji.202250007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/20/2022] [Accepted: 12/22/2022] [Indexed: 12/24/2022]
Abstract
Foxp3+ T regulatory (Treg) cells suppress inflammation and are essential for maintaining tissue homeostasis. A growing appreciation of tissue-specific Treg functions has built interest in leveraging the endogenous suppressive mechanisms of these cells into cellular therapeutics in organ-specific diseases. Notably, Treg cells play a critical role in maintaining the intestinal environment. As a barrier site, the gut requires Treg cells to mediate interactions with the microbiota, support barrier integrity, and regulate the immune system. Without fully functional Treg cells, intestinal inflammation and microbial dysbiosis ensue. Thus, there is a particular interest in developing Treg cellular therapies for intestinal inflammatory disease, such as inflammatory bowel disease (IBD). This article reviews some of the critical pathways that are dysregulated in IBD, Treg cell mechanisms of suppression, and the efforts and approaches in the field to develop these cells as a cellular therapy for IBD.
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10
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Gonzalez-Vivo M, Lund Tiirikainen MK, Andreu M, Fernandez-Clotet A, López-García A, Murciano Gonzalo F, Abril Rodriguez L, de Jesús-Gil C, Ruiz-Romeu E, Sans-de San Nicolàs L, Santamaria-Babí LF, Márquez-Mosquera L. Memory T Cell Subpopulations as Early Predictors of Remission to Vedolizumab in Ulcerative Colitis. Front Med (Lausanne) 2022; 9:837294. [PMID: 35783609 PMCID: PMC9240758 DOI: 10.3389/fmed.2022.837294] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
Background Vedolizumab is a humanized monoclonal antibody targeting the α4β7 integrin used for the treatment of ulcerative colitis. Few biomarkers related to vedolizumab response have been identified. The aim of this work was to assess whether baseline circulating CD4+ and CD8+ memory T-lymphocyte subpopulations could help to identify patients with response to vedolizumab treatment in ulcerative colitis. Methods Prospective pilot study in 15 patients with active ulcerative colitis and previous failure to anti-TNFα starting vedolizumab treatment. Peripheral blood samples were obtained before the first dose of vedolizumab and at week 6 and 14 of treatment. Clinical remission was defined as a Mayo Clinic partial score of ≤2 points without any concomitant dose of steroids. Biochemical remission or endoscopic improvement was defined as fecal calprotectin <250 mcg/g or Mayo endoscopic subscore ≤1. Results At week 14, nine patients achieved clinical remission and eight patients achieved biochemical remission or endoscopic improvement. Patients in clinical remission presented higher baseline CD8 α4β7+ memory T cells concentration when compared with patients with no remission. In addition, patients with biochemical remission or endoscopic improvement at week 14 presented higher baseline concentration of CD8 α4β7+ memory T cells. No differences were identified according to flare severity, extent of disease or type of anti-TNFα failure. There were no significant differences regarding changes in T cell subsets during vedolizumab induction. Conclusion CD8+ α4β7+ memory T cells before starting vedolizumab therapy could be an early predictor of remission in ulcerative colitis patients and therefore help to select a subset of responders.
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Affiliation(s)
- Maria Gonzalez-Vivo
- Department of Gastroenterology, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
- *Correspondence: Maria Gonzalez-Vivo,
| | - Minna K. Lund Tiirikainen
- Grup d’Immunologia Translacional, Departament de Biologia Cel⋅lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona (UB), Parc Científic de Barcelona (PCB), Barcelona, Spain
| | - Montserrat Andreu
- Department of Gastroenterology, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | | | - Alicia López-García
- Department of Gastroenterology, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | | | | | - Carmen de Jesús-Gil
- Grup d’Immunologia Translacional, Departament de Biologia Cel⋅lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona (UB), Parc Científic de Barcelona (PCB), Barcelona, Spain
| | - Ester Ruiz-Romeu
- Grup d’Immunologia Translacional, Departament de Biologia Cel⋅lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona (UB), Parc Científic de Barcelona (PCB), Barcelona, Spain
| | - Lídia Sans-de San Nicolàs
- Grup d’Immunologia Translacional, Departament de Biologia Cel⋅lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona (UB), Parc Científic de Barcelona (PCB), Barcelona, Spain
| | - Lluis F. Santamaria-Babí
- Grup d’Immunologia Translacional, Departament de Biologia Cel⋅lular, Fisiologia i Immunologia, Facultat de Biologia, Universitat de Barcelona (UB), Parc Científic de Barcelona (PCB), Barcelona, Spain
| | - Lucía Márquez-Mosquera
- Department of Gastroenterology, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
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11
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Mikacenic C, Bhatraju P, Robinson-Cohen C, Kosamo S, Fohner AE, Dmyterko V, Long SA, Cerosaletti K, Calfee CS, Matthay MA, Walley KR, Russell JA, Christie JD, Meyer NJ, Christiani DC, Wurfel MM. Single Nucleotide Variant in FAS Associates With Organ Failure and Soluble Fas Cell Surface Death Receptor in Critical Illness. Crit Care Med 2022; 50:e284-e293. [PMID: 34593707 PMCID: PMC8863632 DOI: 10.1097/ccm.0000000000005333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Multiple organ failure in critically ill patients is associated with poor prognosis, but biomarkers contributory to pathogenesis are unknown. Previous studies support a role for Fas cell surface death receptor (Fas)-mediated apoptosis in organ dysfunction. Our objectives were to test for associations between soluble Fas and multiple organ failure, identify protein quantitative trait loci, and determine associations between genetic variants and multiple organ failure. DESIGN Retrospective observational cohort study. SETTING Four academic ICUs at U.S. hospitals. PATIENTS Genetic analyses were completed in a discovery (n = 1,589) and validation set (n = 863). Fas gene expression and flow cytometry studies were completed in outpatient research participants (n = 250). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS In discovery and validation sets of critically ill patients, we tested for associations between enrollment plasma soluble Fas concentrations and Sequential Organ Failure Assessment score on day 3. We conducted a genome-wide association study of plasma soluble Fas (discovery n = 1,042) and carried forward a single nucleotide variant in the FAS gene, rs982764, for validation (n = 863). We further tested whether the single nucleotide variant in FAS (rs982764) was associated with Sequential Organ Failure Assessment score, FAS transcriptional isoforms, and Fas cell surface expression. Higher plasma soluble Fas was associated with higher day 3 Sequential Organ Failure Assessment scores in both the discovery (β = 4.07; p < 0.001) and validation (β = 6.96; p < 0.001) sets. A single nucleotide variant in FAS (rs982764G) was associated with lower plasma soluble Fas concentrations and lower day 3 Sequential Organ Failure Assessment score in meta-analysis (-0.21; p = 0.02). Single nucleotide variant rs982764G was also associated with a lower relative expression of the transcript for soluble as opposed to transmembrane Fas and higher cell surface expression of Fas on CD4+ T cells. CONCLUSIONS We found that single nucleotide variant rs982764G was associated with lower plasma soluble Fas concentrations in a discovery and validation population, and single nucleotide variant rs982764G was also associated with lower organ dysfunction on day 3. These findings support further study of the Fas pathway as a potential mediator of organ dysfunction in critically ill patients.
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Affiliation(s)
| | - Pavan Bhatraju
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA
| | | | - Susanna Kosamo
- Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
| | - Alison E. Fohner
- Department of Epidemiology, Institute of Public Health Genetics, University of Washington, Seattle, WA
| | - Victoria Dmyterko
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA
| | | | | | - Carolyn S. Calfee
- Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California San Francisco, CA
| | - Michael A. Matthay
- Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California San Francisco, CA
| | - Keith R. Walley
- St. Paul’s Hospital, University of British Columbia, Vancouver, BC
| | - James A. Russell
- St. Paul’s Hospital, University of British Columbia, Vancouver, BC
| | - Jason D. Christie
- Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Nuala J. Meyer
- Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - David C. Christiani
- Harvard University School of Public Health and Division of Pulmonary and Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, MA
| | - Mark M. Wurfel
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA
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12
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Porter RJ, Arends MJ, Churchhouse AMD, Din S. Inflammatory Bowel Disease-Associated Colorectal Cancer: Translational Risks from Mechanisms to Medicines. J Crohns Colitis 2021; 15:2131-2141. [PMID: 34111282 PMCID: PMC8684457 DOI: 10.1093/ecco-jcc/jjab102] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The cumulative impact of chronic inflammation in patients with inflammatory bowel diseases predisposes to the development of inflammatory bowel disease-associated colorectal cancer [IBD-CRC]. Inflammation can induce mutagenesis, and the relapsing-remitting nature of this inflammation, together with epithelial regeneration, may exert selective pressure accelerating carcinogenesis. The molecular pathogenesis of IBD-CRC, termed the 'inflammation-dysplasia-carcinoma' sequence, is well described. However, the immunopathogenesis of IBD-CRC is less well understood. The impact of novel immunosuppressive therapies, which aim to achieve deep remission, is mostly unknown. Therefore, this timely review summarizes the clinical context of IBD-CRC, outlines the molecular and immunological basis of disease pathogenesis, and considers the impact of novel biological therapies.
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Affiliation(s)
- Ross J Porter
- Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, UK
- NHS Lothian Edinburgh IBD Unit, Western General Hospital, UK
| | - Mark J Arends
- Division of Pathology, Cancer Research UK Edinburgh Centre, Institute of Cancer & Genetics, Western General Hospital, University of Edinburgh, UK
| | | | - Shahida Din
- NHS Lothian Edinburgh IBD Unit, Western General Hospital, UK
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13
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The influence of cytokines on the complex pathology of ulcerative colitis. Autoimmun Rev 2021; 21:103017. [PMID: 34902606 DOI: 10.1016/j.autrev.2021.103017] [Citation(s) in RCA: 205] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 12/08/2021] [Indexed: 12/18/2022]
Abstract
Ulcerative colitis (UC) specifically affects the colon and rectum through multifactorial mechanisms associated with genetic alterations, environmental factors, microbiota, and mucosal immune dysregulation. In patients with corticosteroid-refractory UC, current therapies primarily employ antibodies against tumor necrosis factor-α, α4β7 integrin, and interleukin (IL)-12/23 p40; and a small-molecule Janus kinase inhibitor. Despite these revolutionary molecular targeting therapies introduced during the last two decades, 30%-55% of patients fail to respond such molecular targeting agents in the induction phase, requiring changes in treatment. Here we review basic and clinical research aimed to address this problem, focusing on the pathogenic effects of cytokines produced by innate and adaptive immune cells. For example, IL-1β, IL-6, tumor necrosis factor-α, T helper (Th) 1-, Th2-, and Th17-associated cytokines are expressed at relatively higher levels in the intestinal tissues of patients with UC. However, their expression levels depend on disease stage and patient characteristics. The complex pathology of UC may induce differences in responses to therapy. The findings of such studies strongly support the argument that future targeted therapies must focus on differences in cytokine levels associated with the stages of UC as well as on the distinct cytokine expression profiles of individual patients.
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14
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Biological Treatments in Inflammatory Bowel Disease: A Complex Mix of Mechanisms and Actions. BIOLOGICS 2021. [DOI: 10.3390/biologics1020012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic disease that requires lifelong medication and whose incidence is increasing over the world. There is currently no cure for IBD, and the current therapeutic objective is to control the inflammatory process. Approximately one third of treated patients do not respond to treatment and refractoriness to treatment is common. Therefore, pharmacological treatments, such as monoclonal antibodies, are urgently needed, and new treatment guidelines are regularly published. Due to the extremely important current role of biologics in the therapy of IBD, herein we have briefly reviewed the main biological treatments currently available. In addition, we have focused on the mechanisms of action of the most relevant groups of biological agents in IBD therapy, which are not completely clear but are undoubtfully important for understanding both their therapeutic efficacy and the adverse side effects they may have. Further studies are necessary to better understand the action mechanism of these drugs, which will in turn help us to understand how to improve their efficacy and safety. These studies will hopefully pave the path for a personalized medicine.
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15
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Ziani W, Shao J, Fang A, Connolly PJ, Wang X, Veazey RS, Xu H. Mucosal integrin α4β7 blockade fails to reduce the seeding and size of viral reservoirs in SIV-infected rhesus macaques. FASEB J 2021; 35:e21282. [PMID: 33484474 PMCID: PMC7839271 DOI: 10.1096/fj.202002235r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/04/2020] [Accepted: 12/01/2020] [Indexed: 12/18/2022]
Abstract
Cellular viral reservoirs are rapidly established in tissues upon HIV‐1/SIV infection, which persist throughout viral infection, even under long‐term antiretroviral therapy (ART). Specific integrins are involved in the homing of cells to gut‐associated lymphoid tissues (GALT) and inflamed tissues, which may promote the seeding and dissemination of HIV‐1/SIV to these tissue sites. In this study, we investigated the efficacy of prophylactic integrin blockade (α4β7 antibody or α4β7/α4β1 dual antagonist TR‐14035) on viral infection, as well as dissemination and seeding of viral reservoirs in systemic and lymphoid compartments post‐SIV inoculation. The results showed that blockade of α4β7/α4β1 did not decrease viral infection, replication, or reduce viral reservoir size in tissues of rhesus macaques after SIV infection, as indicated by equivalent levels of plasma viremia and cell‐associated SIV RNA/DNA to controls. Surprisingly, TR‐14035 administration in acute SIV infection resulted in consistently higher viremia and more rapid disease progression. These findings suggest that integrin blockade alone fails to effectively control viral infection, replication, dissemination, and reservoir establishment in HIV‐1/SIV infection. The use of integrin blockade for prevention or/and therapeutic strategies requires further investigation.
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Affiliation(s)
- Widade Ziani
- Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, USA
| | - Jiasheng Shao
- Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, USA
| | - Angela Fang
- Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, USA
| | - Patrick J Connolly
- Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, USA
| | - Xiaolei Wang
- Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, USA
| | - Ronald S Veazey
- Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, USA
| | - Huanbin Xu
- Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, USA
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16
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Luzentales-Simpson M, Pang YCF, Zhang A, Sousa JA, Sly LM. Vedolizumab: Potential Mechanisms of Action for Reducing Pathological Inflammation in Inflammatory Bowel Diseases. Front Cell Dev Biol 2021; 9:612830. [PMID: 33614645 PMCID: PMC7887288 DOI: 10.3389/fcell.2021.612830] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/12/2021] [Indexed: 12/22/2022] Open
Abstract
Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC), and Crohn’s disease (CD), are a group of disorders characterized by chronic, relapsing, and remitting, or progressive inflammation along the gastrointestinal tract. IBD is accompanied by massive infiltration of circulating leukocytes into the intestinal mucosa. Leukocytes such as neutrophils, monocytes, and T-cells are recruited to the affected site, exacerbating inflammation and causing tissue damage. Current treatments used to block inflammation in IBD include aminosalicylates, corticosteroids, immunosuppressants, and biologics. The first successful biologic, which revolutionized IBD treatment, targeted the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα). Infliximab, adalimumab, and other anti-TNF antibodies neutralize TNFα, preventing interactions with its receptors and reducing the inflammatory response. However, up to 40% of people with IBD become unresponsive to anti-TNFα therapy. Thus, more recent biologics have been designed to block leukocyte trafficking to the inflamed intestine by targeting integrins and adhesins. For example, natalizumab targets the α4 chain of integrin heterodimers, α4β1 and α4β7, on leukocytes. However, binding of α4β1 is associated with increased risk for developing progressive multifocal leukoencephalopathy, an often-fatal disease, and thus, it is not used to treat IBD. To target leukocyte infiltration without this life-threatening complication, vedolizumab was developed. Vedolizumab specifically targets the α4β7 integrin and was approved to treat IBD based on the presumption that it would block T-cell recruitment to the intestine. Though vedolizumab is an effective treatment for IBD, some studies suggest that it may not block T-cell recruitment to the intestine and its mechanism(s) of action remain unclear. Vedolizumab may reduce inflammation by blocking recruitment of T-cells, or pro-inflammatory monocytes and dendritic cells to the intestine, and/or vedolizumab may lead to changes in the programming of innate and acquired immune cells dampening down inflammation.
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Affiliation(s)
- Matthew Luzentales-Simpson
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC, Canada
| | - Yvonne C F Pang
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC, Canada
| | - Ada Zhang
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC, Canada
| | - James A Sousa
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC, Canada
| | - Laura M Sly
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC, Canada
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17
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Cordes F, Foell D, Ding JN, Varga G, Bettenworth D. Differential regulation of JAK/STAT-signaling in patients with ulcerative colitis and Crohn's disease. World J Gastroenterol 2020; 26:4055-4075. [PMID: 32821070 PMCID: PMC7403801 DOI: 10.3748/wjg.v26.i28.4055] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 05/24/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023] Open
Abstract
In 2018, the pan-Janus kinase (JAK) inhibitor tofacitinib was launched for the treatment of ulcerative colitis (UC). Although tofacitinib has proven efficacious in patients with active UC, it failed in patients with Crohn's disease (CD). This finding strongly hints at a different contribution of JAK signaling in both entities. Here, we review the current knowledge on the interplay between the JAK/signal transducer and activator of transcription (STAT) pathway and inflammatory bowel diseases (IBD). In particular, we provide a detailed overview of the differences and similarities of JAK/STAT-signaling in UC and CD, highlight the impact of the JAK/STAT pathway in experimental colitis models and summarize the published evidence on JAK/STAT-signaling in immune cells of IBD as well as the genetic association between the JAK/STAT pathway and IBD. Finally, we describe novel treatment strategies targeting JAK/STAT inhibition in UC and CD and comment on the limitations and challenges of the new drug class.
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Affiliation(s)
- Friederike Cordes
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster D-48149, Germany
| | - Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster D-48149, Germany
| | - John Nik Ding
- Department of Gastroenterology, St. Vincent’s Hospital, Melbourne 3002, Australia
- Department of Medicine, University of Melbourne, East Melbourne 3002, Australia
| | - Georg Varga
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster D-48149, Germany
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster D-48149, Germany
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18
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Safe and Successful Treatment of Acute Cellular Rejection of an Intestine and Abdominal Wall Transplant With Vedolizumab. Transplant Direct 2020; 6:e527. [PMID: 32095513 PMCID: PMC7004630 DOI: 10.1097/txd.0000000000000973] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/15/2019] [Accepted: 11/20/2019] [Indexed: 01/02/2023] Open
Abstract
Graft survival rates after intestinal transplantation (ITx) are still the lowest in comparison to other solid organ transplants. One of the main reasons is the frequent occurrence of acute cellular rejection (ACR). Vedolizumab is an antibody against α4β7+ integrin involved in gut-homing of T cells which has been approved for inflammatory bowel diseases (IBD). We report its off-label use to treat ACR after ITx.
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19
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Guo Y, Bai AP. Plasticity of Th17 Cells Contributes to Crohn's Disease. Gastroenterology 2019; 157:1689. [PMID: 31542410 DOI: 10.1053/j.gastro.2019.06.046] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 06/21/2019] [Indexed: 12/02/2022]
Affiliation(s)
- Yuan Guo
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ai-Ping Bai
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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20
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Zundler S, Becker E, Schulze LL, Neurath MF. Immune cell trafficking and retention in inflammatory bowel disease: mechanistic insights and therapeutic advances. Gut 2019; 68:1688-1700. [PMID: 31127023 DOI: 10.1136/gutjnl-2018-317977] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/01/2019] [Accepted: 05/03/2019] [Indexed: 12/12/2022]
Abstract
Intestinal immune cell trafficking has been identified as a central event in the pathogenesis of inflammatory bowel diseases (IBD). Intensive research on different aspects of the immune mechanisms controlling and controlled by T cell trafficking and retention has led to the approval of the anti-α4β7 antibody vedolizumab, the ongoing development of a number of further anti-trafficking agents (ATAs) such as the anti-β7 antibody etrolizumab or the anti-MAdCAM-1 antibody ontamalimab and the identification of potential future targets like G-protein coupled receptor 15. However, several aspects of the biology of immune cell trafficking and regarding the mechanism of action of ATAs are still unclear, for example, which impact these compounds have on the trafficking of non-lymphocyte populations like monocytes and how precisely these therapies differ with regard to their effect on immune cell subpopulations. This review will summarise recent advances of basic science in the field of intestinal immune cell trafficking and discuss these findings with regard to different pharmacological approaches from a translational perspective.
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Affiliation(s)
- Sebastian Zundler
- Department of Medicine 1, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Emily Becker
- Department of Medicine 1, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Lisa Lou Schulze
- Department of Medicine 1, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Kussmaul Campus for Medical Research & Translational Research Center, Erlangen, Germany
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21
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Wittner M, Schlicker V, Libera J, Bockmann JH, Horvatits T, Seiz O, Kummer S, Manthey CF, Hüfner A, Kantowski M, Rösch T, Degen O, Huber S, Eberhard JM, Schulze zur Wiesch J. Comparison of the integrin α4β7 expression pattern of memory T cell subsets in HIV infection and ulcerative colitis. PLoS One 2019; 14:e0220008. [PMID: 31356607 PMCID: PMC6663001 DOI: 10.1371/journal.pone.0220008] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 07/05/2019] [Indexed: 02/07/2023] Open
Abstract
Anti-α4β7 therapy with vedolizumab (VDZ) has been suggested as possible immune intervention in HIV. Relatively little is known about the α4β7-integrin (α4β7) expression of different T-cell subsets in different anatomical compartments of healthy individuals, patients with HIV or inflammatory bowel disease (IBD). Surface expression of α4β7 as well as the frequency of activation, homing and exhaustion markers of T cells were assessed by multicolour flow cytometry in healthy volunteers (n = 15) compared to HIV infected patients (n = 52) or patients diagnosed with ulcerative colitis (UC) (n = 14), 6 of whom treated with vedolizumab. In addition, lymph nodal cells (n = 6), gut-derived cells of healthy volunteers (n = 5) and patients with UC (n = 6) were analysed. Additionally, we studied longitudinal PBMC samples of an HIV patient who was treated with vedolizumab for concomitant UC. Overall, only minor variations of the frequency of α4β7 on total CD4+ T cells were detectable regardless of the disease status or (VDZ) treatment status in peripheral blood and the studied tissues. Peripheral α4β7+ CD4+ T cells of healthy individuals and patients with UC showed a higher activation status and were more frequently CCR5+ than their α4β7- counterparts. Also, the frequency of α4β7+ cells was significantly lower in peripheral blood CD4+ effector memory T cells of HIV-infected compared to healthy individuals and this reduced frequency did not recover in HIV patients on ART. Conversely, the frequency of peripheral blood naïve α4β7+ CD4+ T cells was significantly reduced under VDZ treatment. The results of the current study will contribute to the understanding of the dynamics of α4β7 expression pattern on T cells in HIV and UC and will be useful for future studies investigating VDZ as possible HIV cure strategy.
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Affiliation(s)
- Melanie Wittner
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Infectious Disease Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), partner site Hamburg, Lübeck, Borstel, Riems, Germany
| | - Veronika Schlicker
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), partner site Hamburg, Lübeck, Borstel, Riems, Germany
| | - Jana Libera
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Infectious Disease Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jan-Hendrik Bockmann
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), partner site Hamburg, Lübeck, Borstel, Riems, Germany
| | - Thomas Horvatits
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Oliver Seiz
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Silke Kummer
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Infectious Disease Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), partner site Hamburg, Lübeck, Borstel, Riems, Germany
| | - Carolin F. Manthey
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anja Hüfner
- Infectious Disease Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marcus Kantowski
- Clinic and Polyclinic for Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas Rösch
- Clinic and Polyclinic for Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Olaf Degen
- Infectious Disease Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Samuel Huber
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johanna M. Eberhard
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Infectious Disease Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), partner site Hamburg, Lübeck, Borstel, Riems, Germany
| | - Julian Schulze zur Wiesch
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Infectious Disease Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), partner site Hamburg, Lübeck, Borstel, Riems, Germany
- * E-mail:
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