|
1
|
Minopoli A, Perini G, Cui L, Palmieri V, De Spirito M, Papi M. Biomaterial-driven 3D scaffolds for immune cell expansion toward personalized immunotherapy. Acta Biomater 2025:S1742-7061(25)00351-4. [PMID: 40348072 DOI: 10.1016/j.actbio.2025.05.027] [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: 11/15/2024] [Revised: 04/12/2025] [Accepted: 05/07/2025] [Indexed: 05/14/2025]
Abstract
Immunotherapy has emerged as a transformative medical approach in recent years, providing novel treatments for cancer eradication, autoimmune disorders, and infectious diseases. Fundamental to the success of therapy is the enrichment of the immune cell population, particularly T cells, natural killer cells, and dendritic cells. However, achieving a robust and long-term proliferation of immune cells is still challenging both in vivo and ex vivo. In vivo expansion leverages the patient's natural microenvironment and regulatory mechanisms through therapeutic interventions like immune checkpoint inhibitors, cytokine therapy, and targeted antibodies. This approach fosters long-term immune memory and sustained protection. In contrast, ex vivo expansion involves isolation, manipulation, and expansion of the immune cells under controlled conditions before reinfusion, allowing for precise control over the process and generating potent immune cell populations. Hydrogels, due to their tunable biomechanical properties, high biocompatibility, and ability to mimic the extracellular matrix, provide an ideal platform for both in vivo and ex vivo immune cell expansion. For instance, hydrogel-based scaffolds or beads can facilitate a controlled and efficient expansion of immune cells ex vivo, whereas injectable and implantable hydrogels can provide innovative solutions for enhancing immune cell activity within the patient supporting prolonged immune cell activity. This review aims to elucidate the importance of hydrogel-based strategies in immune cell expansion, advancing the development of effective, personalized immunotherapies to improve patient outcomes. STATEMENT OF SIGNIFICANCE: This review highlights the transformative potential of hydrogel-based 3D scaffolds in advancing personalized immunotherapy. By integrating in vivo and ex vivo strategies, hydrogels provide an innovative platform to enhance immune cell expansion, addressing critical challenges in immunotherapy. The discussion emphasizes the unique biomechanical and biochemical tunability of hydrogels, enabling precise mimicry of the extracellular matrix to support T cell proliferation, activation, and memory formation. These advances offer scalable, cost-effective solutions for producing high-quality immune cells, contributing to more effective cancer treatments, autoimmune disease management, and infectious disease control. By bridging materials science and immunology, this work underscores the pivotal role of hydrogels in shaping the future of immune-based therapies.
Collapse
Affiliation(s)
- Antonio Minopoli
- Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCSS, 00168 Rome, Italy
| | - Giordano Perini
- Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCSS, 00168 Rome, Italy
| | - Lishan Cui
- Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCSS, 00168 Rome, Italy
| | - Valentina Palmieri
- Fondazione Policlinico Universitario A. Gemelli IRCSS, 00168 Rome, Italy; Istituto dei Sistemi Complessi, Consiglio Nazionale delle Ricerche, CNR, via dei Taurini 19, 00185 Rome, Italy
| | - Marco De Spirito
- Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCSS, 00168 Rome, Italy.
| | - Massimiliano Papi
- Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Rome, Italy; Fondazione Policlinico Universitario A. Gemelli IRCSS, 00168 Rome, Italy.
| |
Collapse
|
|
2
|
Thorp EB, Ananthakrishnan A, Lantz CW. Decoding immune cell interactions during cardiac allograft vasculopathy: insights derived from bioinformatic strategies. Front Cardiovasc Med 2025; 12:1568528. [PMID: 40342971 PMCID: PMC12058854 DOI: 10.3389/fcvm.2025.1568528] [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] [Received: 01/30/2025] [Accepted: 04/04/2025] [Indexed: 05/11/2025] Open
Abstract
Chronic allograft vasculopathy (CAV) is a major cause of late graft failure in heart transplant recipients, characterized by progressive intimal thickening and diffuse narrowing of the coronary arteries. Unlike atherosclerosis, CAV exhibits a distinct cellular composition and lesion distribution, yet its pathogenesis remains incompletely understood. A major challenge in CAV research has been the limited application of advanced "-omics" technologies, which have revolutionized the study of other vascular diseases. Recent advancements in single-cell and spatial transcriptomics, proteomics, and metabolomics have begun to uncover the complex immune-endothelial-stromal interactions driving CAV progression. Notably, single-cell RNA sequencing has identified previously unrecognized immune cell populations and signaling pathways implicated in endothelial injury and vascular remodeling after heart transplantation. Despite these breakthroughs, studies applying these technologies to CAV remain sparse, limiting the translation of these insights into clinical practice. This review aims to bridge this gap by summarizing recent findings from single-cell and multi-omic approaches, highlighting key discoveries, and discussing their implications for understanding CAV pathogenesis.
Collapse
Affiliation(s)
- Edward B. Thorp
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Aparnaa Ananthakrishnan
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Connor W. Lantz
- Department of Surgery, Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| |
Collapse
|
|
3
|
Khosravi-Maharlooei M, Li HW, Sykes M. T Cell Development and Responses in Human Immune System Mice. Annu Rev Immunol 2025; 43:83-112. [PMID: 39705163 PMCID: PMC12031645 DOI: 10.1146/annurev-immunol-082223-041615] [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: 12/22/2024]
Abstract
Human Immune System (HIS) mice constructed with mature human immune cells or with human hematopoietic stem cells and thymic tissue have provided an important tool for human immunological research. In this article, we first review the different types of HIS mice based on human tissues transplanted and sources of the tissues. We then focus on knowledge of human T cell development and responses obtained using HIS mouse models. These areas include the development of human T cell subsets, with a focus on αβ conventional T cells and regulatory T cells, and human T cell responses in the settings of infection, transplantation rejection and tolerance, autoimmune disease, cancer immunotherapy, and regulatory T cell therapy. We also discuss the limitations and potential future applications of HIS mouse models.
Collapse
Affiliation(s)
- Mohsen Khosravi-Maharlooei
- Department of Immunology and Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Hao Wei Li
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY, USA;
| | - Megan Sykes
- Department of Microbiology and Immunology and Department of Surgery, Columbia University Medical Center, Columbia University, New York, NY, USA
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, Columbia University, New York, NY, USA;
| |
Collapse
|
|
4
|
Rodger B, Clough J, Vasconcelos J, Canavan JB, Macallan D, Prevost AT, Lord GM, Irving P. Protocol for a first-in-human feasibility study of T regulatory cells (TR004) for inflammatory bowel disease using (ex vivo) Treg expansion (TRIBUTE). BMJ Open 2025; 15:e092733. [PMID: 39855667 PMCID: PMC11759877 DOI: 10.1136/bmjopen-2024-092733] [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: 08/21/2024] [Accepted: 12/20/2024] [Indexed: 01/27/2025] Open
Abstract
INTRODUCTION Crohn's disease (CD) is a chronic, immune-mediated inflammatory bowel disease (IBD), presenting with symptoms of abdominal pain and bleeding from the gastrointestinal tract. There is no known cure. In vitro-expanded 'thymus-derived' regulatory T cells (tTreg) have shown promise in preclinical models of IBD, leading to interest in their use as a potential therapy in CD. We present a study protocol for a first-in-human study of Tregs for IBD using ex vivo Treg expansion. This study will explore the preliminary safety and tolerability of a single dose of Treg immunotherapy and will inform the design of a subsequent larger trial. METHODS AND ANALYSIS Four patients will be recruited from gastroenterology clinics at Guy's and St Thomas' NHS Foundation Trust. Eligible participants are those who are at least 18 years old, have a diagnosis of active moderate to severe CD and have failed to respond to or tolerate at least two prior lines of standard medication. Participants receive a single dose of autologous ex vivo-expanded Tregs and will be followed up to week 21 to collect safety and exploratory efficacy data. Additional safety monitoring will occur at 1 and 2 years post-dose. The primary endpoint is defined as the occurrence of dose-limiting toxicity occurring within 5 weeks post-infusion. ETHICS AND DISSEMINATION The study protocol and related documents have been approved by a NHS Research Ethics Committee, the Health Research Authority and the Medicines and Healthcare products Regulatory Agency for Clinical Trial Authorisation. It is intended that the results of the trial will be presented at international conferences and will be submitted for publication in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER NCT03185000.
Collapse
Affiliation(s)
- Beverley Rodger
- King's College London Faculty of Life Sciences and Medicine, London, UK
| | - Jennifer Clough
- King's College London Faculty of Life Sciences and Medicine, London, UK
| | - Joana Vasconcelos
- Dept of Primary Care and Public Health Sciences, King's College London, London, UK
| | - James B Canavan
- King's College London Faculty of Life Sciences and Medicine, London, UK
| | - D Macallan
- Department of Genitourinary Medicine, St. George's Healthcare NHS Trust, London, UK
| | - A Toby Prevost
- Cicely Saunders Institute, King's College London, London, UK
| | - Graham M Lord
- MRC Centre for Transplantation, King's College London, London, UK
| | - Peter Irving
- King's College London Faculty of Life Sciences and Medicine, London, UK
| |
Collapse
|
|
5
|
Aiyengar A, Romano M, Burch M, Lombardi G, Fanelli G. The potential of autologous regulatory T cell (Treg) therapy to prevent Cardiac Allograft Vasculopathy (CAV) in paediatric heart transplant recipients. Front Immunol 2024; 15:1444924. [PMID: 39315099 PMCID: PMC11416935 DOI: 10.3389/fimmu.2024.1444924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 08/19/2024] [Indexed: 09/25/2024] Open
Abstract
Paediatric heart transplant is an established treatment for end stage heart failure in children, however patients have to commit to lifelong medical surveillance and adhere to daily immunosuppressants to minimise the risk of rejection. Compliance with immunosuppressants can be burdensome with their toxic side effects and need for frequent blood monitoring especially in children. Though the incidence of early rejection episodes has significantly improved overtime, the long-term allograft health and survival is determined by Cardiac Allograft Vasculopathy (CAV) which affects a vast number of post-transplant patients. Once CAV has set in, there is no medical or surgical treatment to reverse it and graft survival is significantly compromised across all age groups. Current treatment strategies include novel immunosuppressant agents and drugs to lower blood lipid levels to address the underlying immunological pathophysiology and to manage traditional cardiac risk factors. Translational researchers are seeking novel immunological approaches that can lead to permanent acceptance of the allograft such as using regulatory T cell (Tregs) immunotherapy. Clinical trials in the setting of graft versus host disease, autoimmunity and kidney and liver transplantation using Tregs have shown the feasibility and safety of this strategy. This review will summarise current knowledge of the latest clinical therapies for CAV and pre-clinical evidence in support of Treg therapy for CAV. We will also discuss the different Treg sources and the considerations of translating this into a feasible immunotherapy in clinical practice in the paediatric population.
Collapse
Affiliation(s)
- Apoorva Aiyengar
- Department of Cardiology, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom
- Research Department of Children’s Cardiovascular Disease, Institute of Cardiovascular Science, University College London, London, United Kingdom
| | - Marco Romano
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College, London, United Kingdom
| | - Michael Burch
- Department of Cardiology, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom
| | - Giovanna Lombardi
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College, London, United Kingdom
| | - Giorgia Fanelli
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College, London, United Kingdom
| |
Collapse
|
|
6
|
Ekwe AP, Au R, Zhang P, McEnroe BA, Tan ML, Saldan A, Henden AS, Hutchins CJ, Henderson A, Mudie K, Kerr K, Fuery M, Kennedy GA, Hill GR, Tey SK. Clinical grade multiparametric cell sorting and gene-marking of regulatory T cells. Cytotherapy 2024; 26:719-728. [PMID: 38530690 DOI: 10.1016/j.jcyt.2024.02.023] [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: 07/28/2023] [Revised: 02/25/2024] [Accepted: 02/26/2024] [Indexed: 03/28/2024]
Abstract
BACKGROUND AIMS Regulatory T cells (Tregs) are the main mediators of peripheral tolerance. Treg-directed therapy has shown promising results in preclinical studies of diverse immunopathologies. At present, the clinical applicability of adoptive Treg transfer is limited by difficulties in generating Tregs at sufficient cell dose and purity. METHODS We developed a Good Manufacturing Practice (GMP) compliant method based on closed-system multiparametric Fluorescence-Activated Cell Sorting (FACS) to purify Tregs, which are then expanded in vitro and gene-marked with a clinical grade retroviral vector to enable in vivo fate tracking. Following small-scale optimization, we conducted four clinical-scale processing runs. RESULTS We showed that Tregs could be enriched to 87- 92% purity following FACS-sorting, and expanded and transduced to yield clinically relevant cell dose of 136-732×106 gene-marked cells, sufficient for a cell dose of at least 2 × 106 cells/kg. The expanded Tregs were highly demethylated in the FOXP3 Treg-specific demethylated region (TSDR), consistent with bona fide natural Tregs. They were suppressive in vitro, but a small percentage could secrete proinflammatory cytokines, including interferon-γ and interleukin-17A. CONCLUSIONS This study demonstrated the feasibility of isolating, expanding and gene-marking Tregs in clinical scale, thus paving the way for future phase I trials that will advance knowledge about the in vivo fate of transferred Tregs and its relationship with concomitant Treg-directed pharmacotherapy and clinical response.
Collapse
Affiliation(s)
- Adaeze Precious Ekwe
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology (QUT), Kelvin Grove, Queensland, Australia
| | - Raymond Au
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Ping Zhang
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Benjamin A McEnroe
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Mei Ling Tan
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Alda Saldan
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Andrea S Henden
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia; Faculty of Medicine, University of Queensland, St Lucia, Queensland, Australia
| | - Cheryl J Hutchins
- Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
| | - Ashleigh Henderson
- Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
| | - Kari Mudie
- Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
| | - Keri Kerr
- Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
| | - Madonna Fuery
- Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
| | - Glen A Kennedy
- Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia; Faculty of Medicine, University of Queensland, St Lucia, Queensland, Australia
| | - Geoffrey R Hill
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Siok-Keen Tey
- Translational Cancer Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology (QUT), Kelvin Grove, Queensland, Australia; Department of Haematology and Bone Marrow Transplantation, Cancer Care Services, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia; Faculty of Medicine, University of Queensland, St Lucia, Queensland, Australia.
| |
Collapse
|
|
7
|
Han JL, Zimmerer JM, Zeng Q, Chaudhari S, Satoskar A, Abdel-Rasoul M, Uwase H, Breuer CK, Bumgardner GL. Antibody-Suppressor CXCR5+CD8+ T Cells Are More Potent Regulators of Humoral Alloimmunity after Kidney Transplant in Mice Compared to CD4+ Regulatory T Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1504-1518. [PMID: 38517294 PMCID: PMC11047759 DOI: 10.4049/jimmunol.2300289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 02/27/2024] [Indexed: 03/23/2024]
Abstract
Adoptive cell therapy (ACT), especially with CD4+ regulatory T cells (CD4+ Tregs), is an emerging therapeutic strategy to minimize immunosuppression and promote long-term allograft acceptance, although much research remains to realize its potential. In this study, we investigated the potency of novel Ab-suppressor CXCR5+CD8+ T cells (CD8+ TAb-supp) in comparison with conventional CD25highFoxp3+CD4+ Tregs for suppression of humoral alloimmunity in a murine kidney transplant (KTx) model of Ab-mediated rejection (AMR). We examined quantity of peripheral blood, splenic and graft-infiltrating CD8+ TAb-supp, and CD4+ Tregs in KTx recipients and found that high alloantibody-producing CCR5 knockout KTx recipients have significantly fewer post-transplant peripheral blood and splenic CD8+ TAb-supp, as well as fewer splenic and graft-infiltrating CD4+ Tregs compared with wild-type KTx recipients. ACT with alloprimed CXCR5+CD8+ T cells reduced alloantibody titer, splenic alloprimed germinal center (GC) B cell quantity, and improved AMR histology in CCR5 knockout KTx recipients. ACT with alloprimed CD4+ Treg cells improved AMR histology without significantly inhibiting alloantibody production or the quantity of splenic alloprimed GC B cells. Studies with TCR transgenic mice confirmed Ag specificity of CD8+ TAb-supp-mediated effector function. In wild-type recipients, CD8 depletion significantly increased alloantibody titer, GC B cells, and severity of AMR pathology compared with isotype-treated controls. Anti-CD25 mAb treatment also resulted in increased but less pronounced effect on alloantibody titer, quantity of GC B cells, and AMR pathology than CD8 depletion. To our knowledge, this is the first report that CD8+ TAb-supp cells are more potent regulators of humoral alloimmunity than CD4+ Treg cells.
Collapse
Affiliation(s)
- Jing L. Han
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
- Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH
| | - Jason M. Zimmerer
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - Qiang Zeng
- Center for Regenerative Medicine, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | - Sachi Chaudhari
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - Anjali Satoskar
- Department of Pathology, The Ohio State University, Columbus, OH
| | | | - Hope Uwase
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - Christopher K. Breuer
- Center for Regenerative Medicine, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | - Ginny L. Bumgardner
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| |
Collapse
|
|
8
|
Otunla AA, Shanmugarajah K, Davies AH, Lucia Madariaga M, Shalhoub J. The Biological Parallels Between Atherosclerosis and Cardiac Allograft Vasculopathy: Implications for Solid Organ Chronic Rejection. Cardiol Rev 2024; 32:2-11. [PMID: 38051983 DOI: 10.1097/crd.0000000000000437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Atherosclerosis and solid organ chronic rejection are pervasive chronic disease states that account for significant morbidity and mortality in developed countries. Recently, a series of shared molecular pathways have emerged, revealing biological parallels from early stages of development up to the advanced forms of pathology. These shared mechanistic processes are inflammatory in nature, reflecting the importance of inflammation in both disorders. Vascular inflammation triggers endothelial dysfunction and disease initiation through aberrant vasomotor control and shared patterns of endothelial activation. Endothelial dysfunction leads to the recruitment of immune cells and the perpetuation of the inflammatory response. This drives lesion formation through the release of key cytokines such as IFN-y, TNF-alpha, and IL-2. Continued interplay between the adaptive and innate immune response (represented by T lymphocytes and macrophages, respectively) promotes lesion instability and thrombotic complications; hallmarks of advanced disease in both atherosclerosis and solid organ chronic rejection. The aim of this study is to identify areas of overlap between atherosclerosis and chronic rejection. We then discuss new approaches to improve current understanding of the pathophysiology of both disorders, and eventually design novel therapeutics.
Collapse
Affiliation(s)
- Afolarin A Otunla
- From the Medical Sciences Division, University of Oxford, Oxford, United Kingdom
| | | | - Alun H Davies
- Section of Vascular Surgery, Department of Surgery & Cancer, Imperial College London, London, United Kingdom
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London, United Kingdom
| | | | - Joseph Shalhoub
- Section of Vascular Surgery, Department of Surgery & Cancer, Imperial College London, London, United Kingdom
- Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London, United Kingdom
| |
Collapse
|
|
9
|
Baron KJ, Turnquist HR. Clinical Manufacturing of Regulatory T Cell Products For Adoptive Cell Therapy and Strategies to Improve Therapeutic Efficacy. Organogenesis 2023; 19:2164159. [PMID: 36681905 PMCID: PMC9870008 DOI: 10.1080/15476278.2022.2164159] [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] [Indexed: 01/23/2023] Open
Abstract
Based on successes in preclinical animal transplant models, adoptive cell therapy (ACT) with regulatory T cells (Tregs) is a promising modality to induce allograft tolerance or reduce the use of immunosuppressive drugs to prevent rejection. Extensive work has been done in optimizing the best approach to manufacture Treg cell products for testing in transplant recipients. Collectively, clinical evaluations have demonstrated that large numbers of Tregs can be expanded ex vivo and infused safely. However, these trials have failed to induce robust drug-free tolerance and/or significantly reduce the level of immunosuppression needed to prevent solid organ transplant (SOTx) rejection. Improving Treg therapy effectiveness may require increasing Treg persistence or orchestrating Treg migration to secondary lymphatic tissues or places of inflammation. In this review, we describe current clinical Treg manufacturing methods used for clinical trials. We also highlight current strategies being implemented to improve delivered Treg ACT persistence and migration in preclinical studies.
Collapse
Affiliation(s)
- Kassandra J. Baron
- Departments of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Department of Infectious Disease and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, USA
| | - Hēth R. Turnquist
- Departments of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA,CONTACT Hēth R. Turnquist Departments of Surgery, University of Pittsburgh School of Medicine, Thomas E. Starzl Transplantation Institute 200 Lothrop Street, BST W1542, PittsburghPA 15213, USA
| |
Collapse
|
|
10
|
Annamalai C, Kute V, Sheridan C, Halawa A. Hematopoietic cell-based and non-hematopoietic cell-based strategies for immune tolerance induction in living-donor renal transplantation: A systematic review. Transplant Rev (Orlando) 2023; 37:100792. [PMID: 37709652 DOI: 10.1016/j.trre.2023.100792] [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: 12/30/2022] [Revised: 04/24/2023] [Accepted: 08/17/2023] [Indexed: 09/16/2023]
Abstract
INTRODUCTION Despite its use to prevent acute rejection, lifelong immunosuppression can adversely impact long-term patient and graft outcomes. In theory, immunosuppression withdrawal is the ultimate goal of kidney transplantation, and is made possible by the induction of immunological tolerance. The purpose of this paper is to review the safety and efficacy of immune tolerance induction strategies in living-donor kidney transplantation, both chimerism-based and non-chimerism-based. The impact of these strategies on transplant outcomes, including acute rejection, allograft function and survival, cost, and immune monitoring, will also be discussed. MATERIALS AND METHODS Databases such as PubMed, Scopus, and Web of Science, as well as additional online resources such as EBSCO, were exhaustively searched. Adult living-donor kidney transplant recipients who developed chimerism-based tolerance after concurrent bone marrow or hematopoietic stem cell transplantation or those who received non-chimerism-based, non-hematopoietic cell therapy using mesenchymal stromal cells, dendritic cells, or regulatory T cells were studied between 2000 and 2021. Individual sources of evidence were evaluated critically, and the strength of evidence and risk of bias for each outcome of the transplant tolerance study were assessed. RESULTS From 28,173 citations, 245 studies were retrieved after suitable exclusion and duplicate removal. Of these, 22 studies (2 RCTs, 11 cohort studies, 6 case-control studies, and 3 case reports) explicitly related to both interventions (chimerism- and non-chimerism-based immune tolerance) were used in the final review process and were critically appraised. According to the findings, chimerism-based strategies fostered immunotolerance, allowing for the safe withdrawal of immunosuppressive medications. Cell-based therapy, on the other hand, frequently did not induce tolerance except for minimising immunosuppression. As a result, the rejection rates, renal allograft function, and survival rates could not be directly compared between these two groups. While chimerism-based tolerance protocols posed safety concerns due to myelosuppression, including infections and graft-versus-host disease, cell-based strategies lacked these adverse effects and were largely safe. There was a lack of direct comparisons between HLA-identical and HLA-disparate recipients, and the cost implications were not examined in several of the retrieved studies. Most studies reported successful immunosuppressive weaning lasting at least 3 years (ranging up to 11.4 years in some studies), particularly with chimerism-based therapy, while only a few investigators used immune surveillance techniques. The studies reviewed were often limited by selection, classification, ascertainment, performance, and attrition bias. CONCLUSIONS This review demonstrates that chimerism-based hematopoietic strategies induce immune tolerance, and a substantial number of patients are successfully weaned off immunosuppression. Despite the risk of complications associated with myelosuppression. Non-chimerism-based, non-hematopoietic cell protocols, on the other hand, have been proven to facilitate immunosuppression minimization but seldom elicit immunological tolerance. However, the results of this review must be interpreted with caution because of the non-randomised study design, potential confounding, and small sample size of the included studies. Further validation and refinement of tolerogenic protocols in accordance with local practice preferences is also warranted, with an emphasis on patient selection, cost ramifications, and immunological surveillance based on reliable tolerance assays.
Collapse
Affiliation(s)
- Chandrashekar Annamalai
- Postgraduate School of Medicine, Institute of Teaching and Learning, Faculty of Health and Life Sciences, University of Liverpool, UK.
| | - Vivek Kute
- Nephrology and Transplantation, Institute of Kidney Diseases and Research Center and Dr. H L Trivedi Institute of Transplantation Sciences (IKDRC-ITS), Ahmedabad, India
| | - Carl Sheridan
- Department of Eye and Vision Science, Ocular Cell Transplantation, Faculty of Health and Life Sciences, University of Liverpool, UK
| | - Ahmed Halawa
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| |
Collapse
|
|
11
|
Tseng HT, Lin YW, Huang CY, Shih CM, Tsai YT, Liu CW, Tsai CS, Lin FY. Animal Models for Heart Transplantation Focusing on the Pathological Conditions. Biomedicines 2023; 11:biomedicines11051414. [PMID: 37239085 DOI: 10.3390/biomedicines11051414] [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: 03/30/2023] [Revised: 04/29/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
Cardiac transplant recipients face many complications due to transplant rejection. Scientists must conduct animal experiments to study disease onset mechanisms and develop countermeasures. Therefore, many animal models have been developed for research topics including immunopathology of graft rejection, immunosuppressive therapies, anastomotic techniques, and graft preservation techniques. Small experimental animals include rodents, rabbits, and guinea pigs. They have a high metabolic rate, high reproductive rate, small size for easy handling, and low cost. Additionally, they have genetically modified strains for pathological mechanisms research; however, there is a lacuna, as these research results rarely translate directly to clinical applications. Large animals, including canines, pigs, and non-human primates, have anatomical structures and physiological states that are similar to those of humans; therefore, they are often used to validate the results obtained from small animal studies and directly speculate on the feasibility of applying these results in clinical practice. Before 2023, PubMed Central® at the United States National Institute of Health's National Library of Medicine was used for literature searches on the animal models for heart transplantation focusing on the pathological conditions. Unpublished reports and abstracts from conferences were excluded from this review article. We discussed the applications of small- and large-animal models in heart transplantation-related studies. This review article aimed to provide researchers with a complete understanding of animal models for heart transplantation by focusing on the pathological conditions created by each model.
Collapse
Affiliation(s)
- Horng-Ta Tseng
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Departments of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yi-Wen Lin
- Institute of Oral Biology, National Yang Ming Chiao Tung University (Yangming Campus), Taipei 112304, Taiwan
| | - Chun-Yao Huang
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Departments of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Chun-Ming Shih
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Departments of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yi-Ting Tsai
- Division of Cardiovascular Surgery, Tri-Service General Hospital, Defense Medical Center, Taipei 11490, Taiwan
| | - Chen-Wei Liu
- Department of Basic Medical Science, College of Medicine, University of Arizona, Phoenix, AZ 85721, USA
| | - Chien-Sung Tsai
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiovascular Surgery, Tri-Service General Hospital, Defense Medical Center, Taipei 11490, Taiwan
- Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei 11490, Taiwan
| | - Feng-Yen Lin
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Departments of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| |
Collapse
|
|
12
|
McCallion O, Bilici M, Hester J, Issa F. Regulatory T-cell therapy approaches. Clin Exp Immunol 2023; 211:96-107. [PMID: 35960852 PMCID: PMC10019137 DOI: 10.1093/cei/uxac078] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 07/26/2022] [Accepted: 08/10/2022] [Indexed: 11/13/2022] Open
Abstract
Regulatory T cells (Tregs) have enormous therapeutic potential to treat a variety of immunopathologies characterized by aberrant immune activation. Adoptive transfer of ex vivo expanded autologous Tregs continues to progress through mid- to late-phase clinical trials in several disease spaces and has generated promising preliminary safety and efficacy signals to date. However, the practicalities of this strategy outside of the clinical trial setting remain challenging. Here, we review the current landscape of regulatory T-cell therapy, considering emergent approaches and technologies presenting novel ways to engage Tregs, and reflect on the progress necessary to deliver their therapeutic potential to patients.
Collapse
Affiliation(s)
- Oliver McCallion
- Translational Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Merve Bilici
- Translational Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Joanna Hester
- Translational Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Fadi Issa
- Correspondence. Fadi Issa, Translational Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
| |
Collapse
|
|
13
|
Kaljanac M, Abken H. Do Treg Speed Up with CARs? Chimeric Antigen Receptor Treg Engineered to Induce Transplant Tolerance. Transplantation 2023; 107:74-85. [PMID: 36226849 PMCID: PMC9746345 DOI: 10.1097/tp.0000000000004316] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 06/13/2022] [Accepted: 06/21/2022] [Indexed: 02/07/2023]
Abstract
Adoptive transfer of regulatory T cells (Treg) can induce transplant tolerance in preclinical models by suppressing alloantigen-directed inflammatory responses; clinical translation was so far hampered by the low abundance of Treg with allo-specificity in the peripheral blood. In this situation, ex vivo engineering of Treg with a T-cell receptor (TCR) or chimeric antigen receptor (CAR) provides a cell population with predefined specificity that can be amplified and administered to the patient. In contrast to TCR-engineered Treg, CAR Treg can be redirected toward a broad panel of targets in an HLA-unrestricted fashion' making these cells attractive to provide antigen-specific tolerance toward the transplanted organ. In preclinical models, CAR Treg accumulate and amplify at the targeted transplant, maintain their differentiated phenotype, and execute immune repression more vigorously than polyclonal Treg. With that, CAR Treg are providing hope in establishing allospecific, localized immune tolerance in the long term' and the first clinical trials administering CAR Treg for the treatment of transplant rejection are initiated. Here, we review the current platforms for developing and manufacturing alloantigen-specific CAR Treg and discuss the therapeutic potential and current hurdles in translating CAR Treg into clinical exploration.
Collapse
Affiliation(s)
- Marcell Kaljanac
- Division Genetic Immunotherapy, and Chair Genetic Immunotherapy, Leibniz Institute for Immunotherapy, University Regensburg, Regensburg, Germany
| | - Hinrich Abken
- Division Genetic Immunotherapy, and Chair Genetic Immunotherapy, Leibniz Institute for Immunotherapy, University Regensburg, Regensburg, Germany
| |
Collapse
|
|
14
|
O'Neil A, Brook M, Abdul-Wahab S, Hester J, Lombardi G, Issa F. A GMP Protocol for the Manufacture of Tregs for Clinical Application. Methods Mol Biol 2023; 2559:205-227. [PMID: 36180635 DOI: 10.1007/978-1-0716-2647-4_14] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Infusion of regulatory T cells is a promising therapeutic strategy in organ transplantation to modulate the immune system, prevent rejection, minimize the need for pharmaceutical immunosuppression, and improve long-term transplant outcomes. Here we describe a GMP-compliant method we have used for the manufacture of ex vivo expanded autologous regulatory T cells for use in clinical trials.
Collapse
Affiliation(s)
- Alice O'Neil
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Matthew Brook
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Seetha Abdul-Wahab
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Joanna Hester
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Giovanna Lombardi
- MRC Centre for Transplantation, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, UK
| | - Fadi Issa
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
| |
Collapse
|
|
15
|
Sanders JM, Jeyamogan S, Mathew JM, Leventhal JR. Foxp3+ regulatory T cell therapy for tolerance in autoimmunity and solid organ transplantation. Front Immunol 2022; 13:1055466. [PMID: 36466912 PMCID: PMC9714335 DOI: 10.3389/fimmu.2022.1055466] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 11/02/2022] [Indexed: 08/03/2023] Open
Abstract
Regulatory T cells (Tregs) are critical for tolerance in humans. The exact mechanisms by which the loss of peripheral tolerance leads to the development of autoimmunity and the specific role Tregs play in allograft tolerance are not fully understood; however, this population of T cells presents a unique opportunity in the development of targeted therapeutics. In this review, we discuss the potential roles of Foxp3+ Tregs in the development of tolerance in transplantation and autoimmunity, and the available data regarding their use as a treatment modality.
Collapse
Affiliation(s)
- Jes M. Sanders
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Shareni Jeyamogan
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - James M. Mathew
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Simpson Querrey Institute for BioNanotechnology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Joseph R. Leventhal
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Simpson Querrey Institute for BioNanotechnology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| |
Collapse
|
|
16
|
Janakiraman H, Becker SA, Bradshaw A, Rubinstein MP, Camp ER. Critical evaluation of an autologous peripheral blood mononuclear cell-based humanized cancer model. PLoS One 2022; 17:e0273076. [PMID: 36095023 PMCID: PMC9467357 DOI: 10.1371/journal.pone.0273076] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 07/26/2022] [Indexed: 11/29/2022] Open
Abstract
The use of humanized mouse models for oncology is rapidly expanding. Autologous patient-derived systems are particularly attractive as they can model the human cancer's heterogeneity and immune microenvironment. In this study, we developed an autologous humanized mouse cancer model by engrafting NSG mice with patient-derived xenografts and infused matched peripheral blood mononuclear cells (PBMCs). We first defined the time course of xenogeneic graft-versus-host-disease (xGVHD) and determined that only minimal xGVHD was observed for up to 8 weeks. Next, colorectal and pancreatic cancer patient-derived xenograft bearing NSG mice were infused with 5x106 human PBMCS for development of the humanized cancer models (iPDX). Early after infusion of human PBMCs, iPDX mice demonstrated engraftment of human CD4+ and CD8+ T cells in the blood of both colorectal and pancreatic cancer patient-derived models that persisted for up to 8 weeks. At the end of the experiment, iPDX xenografts maintained the features of the primary human tumor including tumor grade and cell type. The iPDX tumors demonstrated infiltration of human CD3+ cells with high PD-1 expression although we observed significant intra and inter- model variability. In summary, the iPDX models reproduced key features of the corresponding human tumor. The observed variability and high PD-1 expression are important considerations that need to be addressed in order to develop a reproducible model system.
Collapse
Affiliation(s)
- Harinarayanan Janakiraman
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of America
| | - Scott A. Becker
- Molecular and Systems Pharmacology, Emory University, Atlanta, GA, United States of America
| | - Alexandra Bradshaw
- Department of Surgery, Medical University Of South Carolina, Charleston, SC, United States of America
| | - Mark P. Rubinstein
- The Pelotonia Institute for Immuno-Oncology, Ohio State University Comprehensive Cancer Center–James, Columbus, OH, United States of America
| | - Ernest Ramsay Camp
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of America
- Dan L. Duncan Comprehensive Cancer Center, Houston, Texas, United States of America
- Michael E. DeBakey VA Medical Center, Houston, Texas, United States of America
| |
Collapse
|
|
17
|
Gille I, Claas FHJ, Haasnoot GW, Heemskerk MHM, Heidt S. Chimeric Antigen Receptor (CAR) Regulatory T-Cells in Solid Organ Transplantation. Front Immunol 2022; 13:874157. [PMID: 35720402 PMCID: PMC9204347 DOI: 10.3389/fimmu.2022.874157] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 04/01/2022] [Indexed: 11/13/2022] Open
Abstract
Solid organ transplantation is the treatment of choice for various end-stage diseases, but requires the continuous need for immunosuppression to prevent allograft rejection. This comes with serious side effects including increased infection rates and development of malignancies. Thus, there is a clinical need to promote transplantation tolerance to prevent organ rejection with minimal or no immunosuppressive treatment. Polyclonal regulatory T-cells (Tregs) are a potential tool to induce transplantation tolerance, but lack specificity and therefore require administration of high doses. Redirecting Tregs towards mismatched donor HLA molecules by modifying these cells with chimeric antigen receptors (CAR) would render Tregs far more effective at preventing allograft rejection. Several studies on HLA-A2 specific CAR Tregs have demonstrated that these cells are highly antigen-specific and show a superior homing capacity to HLA-A2+ allografts compared to polyclonal Tregs. HLA-A2 CAR Tregs have been shown to prolong survival of HLA-A2+ allografts in several pre-clinical humanized mouse models. Although promising, concerns about safety and stability need to be addressed. In this review the current research, obstacles of CAR Treg therapy, and its potential future in solid organ transplantation will be discussed.
Collapse
Affiliation(s)
- Ilse Gille
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands.,Department of Hematology, Leiden University Medical Center, Leiden, Netherlands
| | - Frans H J Claas
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands.,Eurotransplant Reference Laboratory, Leiden University Medical Center, Leiden, Netherlands
| | - Geert W Haasnoot
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands.,Eurotransplant Reference Laboratory, Leiden University Medical Center, Leiden, Netherlands
| | | | - Sebastiaan Heidt
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands.,Eurotransplant Reference Laboratory, Leiden University Medical Center, Leiden, Netherlands
| |
Collapse
|
|
18
|
Ex vivo-expanded human CD19 +TIM-1 + regulatory B cells suppress immune responses in vivo and are dependent upon the TIM-1/STAT3 axis. Nat Commun 2022; 13:3121. [PMID: 35660734 PMCID: PMC9166804 DOI: 10.1038/s41467-022-30613-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 05/05/2022] [Indexed: 02/07/2023] Open
Abstract
Regulatory B cells (Breg) are a heterogenous population with immune-modulating functions. The rarity of human IL-10+ Breg makes translational studies difficult. Here we report ex vivo expansion of human B cells with in vivo regulatory function (expBreg). CD154-stimulation of human CD19+ B cells drives >900-fold expansion of IL-10+ B cells that is maintained in culture for 14 days. Whilst expBreg-mediated suppressive function is partially dependent on IL-10 expression, CRISPR-mediated gene deletions demonstrate predominant roles for TIM-1 and CD154. TIM-1 regulates STAT3 signalling and modulates downstream suppressive function. In a clinically relevant humanised mouse model of skin transplantation, expBreg prolongs human allograft survival. Meanwhile, CD19+CD73-CD25+CD71+TIM-1+CD154+ Breg cells are enriched in the peripheral blood of human donors with cutaneous squamous cell carcinoma (SCC). TIM-1+ and pSTAT3+ B cells are also identified in B cell clusters within histological sections of human cutaneous SCC tumours. Our findings thus provide insights on Breg homoeostasis and present possible targets for Breg-related therapies.
Collapse
|
|
19
|
Brook MO, Hester J, Petchey W, Rombach I, Dutton S, Bottomley MJ, Black J, Abdul-Wahab S, Bushell A, Lombardi G, Wood K, Friend P, Harden P, Issa F. Transplantation Without Overimmunosuppression (TWO) study protocol: a phase 2b randomised controlled single-centre trial of regulatory T cell therapy to facilitate immunosuppression reduction in living donor kidney transplant recipients. BMJ Open 2022; 12:e061864. [PMID: 35428650 PMCID: PMC9014059 DOI: 10.1136/bmjopen-2022-061864] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Regulatory T cell (Treg) therapy has been demonstrated to facilitate long-term allograft survival in preclinical models of transplantation and may permit reduction of immunosuppression and its associated complications in the clinical setting. Phase 1 clinical trials have shown Treg therapy to be safe and feasible in clinical practice. Here we describe a protocol for the TWO study, a phase 2b randomised control trial of Treg therapy in living donor kidney transplant recipients that will confirm safety and explore efficacy of this novel treatment strategy. METHODS AND ANALYSIS 60 patients will be randomised on a 1:1 basis to Treg therapy (TR001) or standard clinical care (control). Patients in the TR001 arm will receive an infusion of autologous polyclonal ex vivo expanded Tregs 5 days after transplantation instead of standard monoclonal antibody induction. Maintenance immunosuppression will be reduced over the course of the post-transplant period to low-dose tacrolimus monotherapy. Control participants will receive a standard basiliximab-based immunosuppression regimen with long-term tacrolimus and mycophenolate mofetil immunosuppression. The primary endpoint is biopsy proven acute rejection over 18 months; secondary endpoints include immunosuppression burden, chronic graft dysfunction and drug-related complications. ETHICS AND DISSEMINATION Ethical approval has been provided by the National Health Service Health Research Authority South Central-Oxford A Research Ethics Committee (reference 18/SC/0054). The study also received authorisation from the UK Medicines and Healthcare products Regulatory Agency and is being run in accordance with the principles of Good Clinical Practice, in collaboration with the registered trials unit Oxford Clinical Trials Research Unit. Results from the TWO study will be published in peer-reviewed scientific/medical journals and presented at scientific/clinical symposia and congresses. TRIAL REGISTRATION NUMBER ISRCTN: 11038572; Pre-results.
Collapse
Affiliation(s)
- Matthew Oliver Brook
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Joanna Hester
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - William Petchey
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Ines Rombach
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Susan Dutton
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Matthew James Bottomley
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Joanna Black
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Seetha Abdul-Wahab
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
- NIHR Biomedical Research Centre GMP unit, Guy's Hospital, London, UK
| | - Andrew Bushell
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Giovanna Lombardi
- NIHR Biomedical Research Centre GMP unit, Guy's Hospital, London, UK
- Peter Gorer Department of Immunobiology, King's College London Faculty of Life Sciences and Medicine, London, UK
| | - Kathryn Wood
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Peter Friend
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Paul Harden
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Fadi Issa
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| |
Collapse
|
|
20
|
Zorzetti N, Lauro A, Khouzam S, Marino IR. Immunosuppression, Compliance, and Tolerance After Orthotopic Liver Transplantation: State of the Art. EXP CLIN TRANSPLANT 2022; 20:3-9. [PMID: 35384800 DOI: 10.6002/ect.mesot2021.l13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Orthotopic liver transplantation is the treatment of choice for several otherwise irreversible forms of acute and chronic liver diseases. Early implemented immunosuppressant regimens have had disappointing results with high rejection rates. However, new drugs have reduced the daily immunosuppression requirements, thereby improving graft and patient survival as well as kidney function. Liver rejection is a T-cell-driven immune response and is the active target of immunosuppressive agents. Immunosuppressants can be divided into pharmacological or biological drugs: the gold standard is the calcineurin inhibitors, steroids, mycophenolate mofetil, and mechanistic target of rapamycin inhibitors. Compliance with these agents is essential, although they can increase the risk of infections and neoplastic diseases. In some patients, graft tolerance can be achieved. Graft tolerance is defined as the absence of acute and chronic rejection in a graft, with normal function and histology in an immunosuppression-free, fully immunocompetent host, usually as the final result of a successful attempt at immunosuppression withdrawal. The occurrence of immunosuppressive-related complications has led to new protocols aimed at protecting renal function and preventing de novo cancer and dysmetabolic syndrome. The backbone of immunosuppression remains calcineurin inhibitors in association with other drugs, mainly over the short-term period. To avoid rejection and the side effects on renal dysfunction, de novo cancer, and cardiovascular syndrome, optimal long-term immunosuppressive therapy should be tailored in liver transplant recipients.
Collapse
Affiliation(s)
- Noemi Zorzetti
- From the Department of General Surgery, Ospedale A. Costa, Porretta Terme-Bologna, Italy
| | | | | | | |
Collapse
|
|
21
|
Bernaldo-de-Quirós E, Pion M, Martínez-Bonet M, Correa-Rocha R. A New Generation of Cell Therapies Employing Regulatory T Cells (Treg) to Induce Immune Tolerance in Pediatric Transplantation. Front Pediatr 2022; 10:862807. [PMID: 35633970 PMCID: PMC9130702 DOI: 10.3389/fped.2022.862807] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
Kidney transplantation is the most common solid organ transplant and the preferred treatment for pediatric patients with end-stage renal disease, but it is still not a definitive solution due to immune graft rejection. Regulatory T cells (Treg) and their control over effector T cells is a crucial and intrinsic tolerance mechanism in limiting excessive immune responses. In the case of transplants, Treg are important for the survival of the transplanted organ, and their dysregulation could increase the risk of rejection in transplanted children. Chronic immunosuppression to prevent rejection, for which Treg are especially sensitive, have a detrimental effect on Treg counts, decreasing the Treg/T-effector balance. Cell therapy with Treg cells is a promising approach to restore this imbalance, promoting tolerance and thus increasing graft survival. However, the strategies used to date that employ peripheral blood as a Treg source have shown limited efficacy. Moreover, it is not possible to use this approach in pediatric patients due to the limited volume of blood that can be extracted from children. Here, we outline our innovative strategy that employs the thymus removed during pediatric cardiac surgeries as a source of therapeutic Treg that could make this therapy accessible to transplanted children. The advantageous properties and the massive amount of Treg cells obtained from pediatric thymic tissue (thyTreg) opens a new possibility for Treg therapies to prevent rejection in pediatric kidney transplants. We are recruiting patients in a clinical trial to prevent rejection in heart-transplanted children through the infusion of autologous thyTreg cells (NCT04924491). If its efficacy is confirmed, thyTreg therapy may establish a new paradigm in preventing organ rejection in pediatric transplants, and their allogeneic use would extend its application to other solid organ transplantation.
Collapse
Affiliation(s)
- Esther Bernaldo-de-Quirós
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Marjorie Pion
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Marta Martínez-Bonet
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Rafael Correa-Rocha
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| |
Collapse
|
|
22
|
Current Status, Barriers, and Future Directions for Humanized Mouse Models to Evaluate Stem Cell–Based Islet Cell Transplant. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1387:89-106. [DOI: 10.1007/5584_2022_711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
23
|
Kaiser D, Otto NM, McCallion O, Hoffmann H, Zarrinrad G, Stein M, Beier C, Matz I, Herschel M, Hester J, Moll G, Issa F, Reinke P, Roemhild A. Freezing Medium Containing 5% DMSO Enhances the Cell Viability and Recovery Rate After Cryopreservation of Regulatory T Cell Products ex vivo and in vivo. Front Cell Dev Biol 2021; 9:750286. [PMID: 34926446 PMCID: PMC8677839 DOI: 10.3389/fcell.2021.750286] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 10/05/2021] [Indexed: 12/29/2022] Open
Abstract
Cell therapies have significant therapeutic potential in diverse fields including regenerative medicine, transplantation tolerance, and autoimmunity. Within these fields, regulatory T cells (Treg) have been deployed to ameliorate aberrant immune responses with great success. However, translation of the cryopreservation strategies employed for other cell therapy products, such as effector T cell therapies, to Treg therapies has been challenging. The lack of an optimized cryopreservation strategy for Treg products presents a substantial obstacle to their broader application, particularly as administration of fresh cells limits the window available for sterility and functional assessment. In this study, we aimed to develop an optimized cryopreservation strategy for our CD4+CD25+Foxp3+ Treg clinical product. We investigate the effect of synthetic or organic cryoprotectants including different concentrations of DMSO on Treg recovery, viability, phenotype, cytokine production, suppressive capacity, and in vivo survival following GMP-compliant manufacture. We additionally assess the effect of adding the extracellular cryoprotectant polyethylene glycol (PEG), or priming cellular expression of heat shock proteins as strategies to improve viability. We find that cryopreservation in serum-free freezing medium supplemented with 10% human serum albumin and 5% DMSO facilitates improved Treg recovery and functionality and supports a reduced DMSO concentration in Treg cryopreservation protocols. This strategy may be easily incorporated into clinical manufacture protocols for future studies.
Collapse
Affiliation(s)
- Daniel Kaiser
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Natalie Maureen Otto
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Department of Nephrology and Internal Intensive Care Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Oliver McCallion
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Henrike Hoffmann
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Ghazaleh Zarrinrad
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Maik Stein
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Carola Beier
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Isabell Matz
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Marleen Herschel
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Joanna Hester
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Guido Moll
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Fadi Issa
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Petra Reinke
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Department of Nephrology and Internal Intensive Care Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Andy Roemhild
- Berlin Center for Advanced Therapies (BeCAT), Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany
| |
Collapse
|
|
24
|
Jarvis LB, Rainbow DB, Coppard V, Howlett SK, Georgieva Z, Davies JL, Mullay HK, Hester J, Ashmore T, Van Den Bosch A, Grist JT, Coles AJ, Mousa HS, Pluchino S, Mahbubani KT, Griffin JL, Saeb-Parsy K, Issa F, Peruzzotti-Jametti L, Wicker LS, Jones JL. Therapeutically expanded human regulatory T-cells are super-suppressive due to HIF1A induced expression of CD73. Commun Biol 2021; 4:1186. [PMID: 34650224 PMCID: PMC8516976 DOI: 10.1038/s42003-021-02721-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 09/27/2021] [Indexed: 12/14/2022] Open
Abstract
The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression.
Collapse
Affiliation(s)
- Lorna B Jarvis
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Daniel B Rainbow
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
| | - Valerie Coppard
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Sarah K Howlett
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Zoya Georgieva
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Jessica L Davies
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | | | - Joanna Hester
- Department of Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Tom Ashmore
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
| | | | - James T Grist
- Department of Radiology, University of Cambridge, Cambridge, UK
| | - Alasdair J Coles
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Hani S Mousa
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Stefano Pluchino
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | | | - Julian L Griffin
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
- Imperial College London Dementia Research Institute & Section of Biomolecular Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | | | - Fadi Issa
- Department of Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | | | - Linda S Wicker
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
| | - Joanne L Jones
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
| |
Collapse
|
|
25
|
Safinia N, Vaikunthanathan T, Lechler RI, Sanchez‐Fueyo A, Lombardi G. Advances in Liver Transplantation: where are we in the pursuit of transplantation tolerance? Eur J Immunol 2021; 51:2373-2386. [PMID: 34375446 PMCID: PMC10015994 DOI: 10.1002/eji.202048875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 06/07/2021] [Accepted: 07/23/2021] [Indexed: 12/22/2022]
Abstract
Liver transplantation is the ultimate treatment option for end-stage liver disease. Breakthroughs in surgical practice and immunosuppression have seen considerable advancements in survival after transplantation. However, the intricate management of immunosuppressive regimens, balancing desired immunological quiescence while minimizing toxicity has proven challenging. Diminishing improvements in long-term morbidity and mortality have been inextricably linked with the protracted use of these medications. As such, there is now enormous interest to devise protocols that will allow us to minimize or completely withdraw immunosuppressants after transplantation. Immunosuppression withdrawal trials have proved the reality of tolerance following liver transplantation, however, without intervention will only occur after several years at the risk of potential cumulative immunosuppression-related morbidity. Focus has now been directed at accelerating this phenomenon through tolerance-inducing strategies. In this regard, efforts have seen the use of regulatory cell immunotherapy. Here we focus particularly on regulatory T cells, discussing preclinical data that propagated several clinical trials of adoptive cell therapy in liver transplantation. Furthermore, we describe efforts to further optimize the specificity and survival of regulatory cell therapy guided by concurrent immunomonitoring studies and the development of novel technologies including chimeric antigen receptors and co-administration of low-dose IL-2.
Collapse
Affiliation(s)
- Niloufar Safinia
- Division of Transplantation Immunology & Mucosal BiologyKing's College LondonLondonUK
| | | | - Robert Ian Lechler
- Division of Transplantation Immunology & Mucosal BiologyKing's College LondonLondonUK
| | | | - Giovanna Lombardi
- Division of Transplantation Immunology & Mucosal BiologyKing's College LondonLondonUK
| |
Collapse
|
|
26
|
Miyamoto E, Takahagi A, Ohsumi A, Martinu T, Hwang D, Boonstra KM, Joe B, Umana JM, Bei KF, Vosoughi D, Liu M, Cypel M, Keshavjee S, Juvet SC. Ex vivo delivery of regulatory T cells for control of alloimmune priming in the donor lung. Eur Respir J 2021; 59:13993003.00798-2021. [PMID: 34475226 DOI: 10.1183/13993003.00798-2021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 08/17/2021] [Indexed: 11/05/2022]
Abstract
Survival after lung transplantation (LTx) is hampered by uncontrolled inflammation and alloimmunity. Regulatory T cells (Tregs) are being studied as a cellular therapy in solid organ transplantation. Whether these systemically administered Tregs can function at the appropriate location and time is an important concern. We hypothesized that in vitro expanded, recipient-derived Tregs can be delivered to donor lungs prior to LTx via ex vivo lung perfusion (EVLP), maintaining their immunomodulatory ability.In a rat model, Wistar Kyoto (WKy) CD4+CD25high Tregs were expanded in vitro prior to EVLP. Expanded Tregs were administered to Fisher 344 (F344) donor lungs during EVLP; left lungs were transplanted into WKy recipients. Treg localisation and function post-transplant were assessed. In a proof-of-concept experiment, cryopreserved expanded human CD4+CD25+CD127low Tregs were thawed and injected into discarded human lungs during EVLP.Rat Tregs entered the lung parenchyma and retained suppressive function. Expanded Tregs had no adverse effect on donor lung physiology during EVLP; lung water as measured by wet-to-dry weight ratio was reduced by Treg therapy. The administered cells remained in the graft at 3 days post-transplant where they reduced activation of intragraft effector CD4+ T cells; these effects were diminished by day 7. Human Tregs entered the lung parenchyma during EVLP where they expressed key immunoregulatory molecules (CTLA4+, 4-1BB+, CD39+, and CD15s+).Pre-transplant Treg administration can inhibit alloimmunity within the lung allograft at early time points post- transplant. Our organ-directed approach has potential for clinical translation.
Collapse
Affiliation(s)
- Ei Miyamoto
- Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Akihiro Takahagi
- Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Akihiro Ohsumi
- Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Tereza Martinu
- Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - David Hwang
- Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Kristen M Boonstra
- Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Betty Joe
- Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Juan Mauricio Umana
- Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Ke F Bei
- Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Daniel Vosoughi
- Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Mingyao Liu
- Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Marcelo Cypel
- Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Shaf Keshavjee
- Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Stephen C Juvet
- Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
27
|
Pilat N, Lefsihane K, Brouard S, Kotsch K, Falk C, Steiner R, Thaunat O, Fusil F, Montserrat N, Amarelli C, Casiraghi F. T- and B-cell therapy in solid organ transplantation: current evidence and future expectations. Transpl Int 2021; 34:1594-1606. [PMID: 34448274 DOI: 10.1111/tri.13972] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 07/08/2021] [Indexed: 01/13/2023]
Abstract
Cell therapy has emerged as an attractive therapeutic option in organ transplantation. During the last decade, the therapeutic potency of Treg immunotherapy has been shown in various preclinical animal models and safety was demonstrated in first clinical trials. However, there are still critical open questions regarding specificity, survival, and migration to the target tissue so the best Treg population for infusion into patients is still under debate. Recent advances in CAR technology hold the promise for Treg-functional superiority. Another exciting strategy is the generation of B-cell antibody receptor (BAR) Treg/cytotoxic T cells to specifically regulate or deplete alloreactive memory B cells. Finally, B cells are also capable of immune regulation, making them promising candidates for immunomodulatory therapeutic strategies. This article summarizes available literature on cell-based innovative therapeutic approaches aiming at modulating alloimmune response for transplantation. Crucial areas of investigation that need a joined effort of the transplant community for moving the field toward successful achievement of tolerance are highlighted.
Collapse
Affiliation(s)
- Nina Pilat
- Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Katia Lefsihane
- International Center of Infectiology Research (CIRI), French Institute of Health and Medical Research (INSERM) Unit 1111, Claude Bernard University Lyon I, National Center for Scientific Research (CNRS) Mixed University Unit (UMR) 5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France
| | - Sophie Brouard
- CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Université de Nantes, Nantes, France
| | - Katja Kotsch
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Department for General and Visceral Surgery, Berlin Institute of Health, Berlin, Germany
| | - Christine Falk
- Institute of Transplant Immunology, Hannover Medical School, MHH, Hannover, Germany
| | - Romy Steiner
- Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Olivier Thaunat
- International Center of Infectiology Research (CIRI), French Institute of Health and Medical Research (INSERM) Unit 1111, Claude Bernard University Lyon I, National Center for Scientific Research (CNRS) Mixed University Unit (UMR) 5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France.,Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France.,Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
| | - Floriane Fusil
- International Center of Infectiology Research (CIRI), French Institute of Health and Medical Research (INSERM) Unit 1111, Claude Bernard University Lyon I, National Center for Scientific Research (CNRS) Mixed University Unit (UMR) 5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France
| | - Nuria Montserrat
- Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Cristiano Amarelli
- Department of Cardiac Surgery and Transplants Monaldi, A.O. dei Colli, Naples, Italy
| | | |
Collapse
|
|
28
|
Mengrelis K, Kucera F, Shahid N, Watt E, Ross S, Lau CI, Adams S, Gilmour K, Pils D, Crompton T, Burch M, Davies EG. T cell phenotype in paediatric heart transplant recipients. Pediatr Transplant 2021; 25:e13930. [PMID: 33326675 DOI: 10.1111/petr.13930] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 11/01/2020] [Accepted: 11/03/2020] [Indexed: 01/31/2023]
Abstract
Paediatric heart transplantation recipients suffer an increased incidence of infectious, autoimmune and allergic problems. The relative roles of thymus excision and immunosuppressive treatments in contributing to these sequelae are not clear. We compared the immunological phenotypes of 25 heart transplant recipients (Tx), 10 children who underwent thymus excision during non-transplantation cardiac surgery (TE) and 25 age range-matched controls, in two age bands: 1-9 and 10-16 years. Significant differences from controls were seen mainly in the younger age band with Tx showing lower CD3 and CD4 cell counts whilst TE showed lower CD8 cell counts. Naïve T cell and recent thymic emigrant proportions and counts were significantly lower than controls in both groups in the lower age band. T cell recombination excision circle (TREC) levels were lower than controls in both groups in both age bands. There were no differences in regulatory T cells, but in those undergoing thymus excision in infancy, their proportions were higher in TE than Tx, a possible direct effect of immunosuppression. T cell receptor V beta spectratyping showed fewer peaks in both groups than in controls (predominantly in the older age band). Thymus excision in infancy was associated with lower CD8 cell counts and higher proportions of Tregs in TE compared to Tx. These data are consistent with thymus excision, particularly in infancy, being the most important influence on immunological phenotype after heart transplantation.
Collapse
Affiliation(s)
- Konstantinos Mengrelis
- UCL Great Ormond Street Institute of Child Health, London, UK.,Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Filip Kucera
- Department of Cardiology, Great Ormond Street Hospital, London, UK
| | - Nadia Shahid
- Department of Immunology, Great Ormond Street Hospital, London, UK
| | - Eleanor Watt
- Department of Haematology, Great Ormond Street Hospital, London, UK
| | - Susan Ross
- UCL Great Ormond Street Institute of Child Health, London, UK
| | - Ching-In Lau
- UCL Great Ormond Street Institute of Child Health, London, UK
| | - Stuart Adams
- Department of Haematology, Great Ormond Street Hospital, London, UK
| | - Kimberly Gilmour
- Department of Immunology, Great Ormond Street Hospital, London, UK
| | - Dietmar Pils
- Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Tessa Crompton
- UCL Great Ormond Street Institute of Child Health, London, UK
| | - Michael Burch
- Department of Cardiology, Great Ormond Street Hospital, London, UK
| | - E Graham Davies
- UCL Great Ormond Street Institute of Child Health, London, UK.,Department of Immunology, Great Ormond Street Hospital, London, UK
| |
Collapse
|
|
29
|
Petrus-Reurer S, Romano M, Howlett S, Jones JL, Lombardi G, Saeb-Parsy K. Immunological considerations and challenges for regenerative cellular therapies. Commun Biol 2021; 4:798. [PMID: 34172826 PMCID: PMC8233383 DOI: 10.1038/s42003-021-02237-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 05/17/2021] [Indexed: 02/06/2023] Open
Abstract
The central goal of regenerative medicine is to replace damaged or diseased tissue with cells that integrate and function optimally. The capacity of pluripotent stem cells to produce unlimited numbers of differentiated cells is of considerable therapeutic interest, with several clinical trials underway. However, the host immune response represents an important barrier to clinical translation. Here we describe the role of the host innate and adaptive immune responses as triggers of allogeneic graft rejection. We discuss how the immune response is determined by the cellular therapy. Additionally, we describe the range of available in vitro and in vivo experimental approaches to examine the immunogenicity of cellular therapies, and finally we review potential strategies to ameliorate immune rejection. In conclusion, we advocate establishment of platforms that bring together the multidisciplinary expertise and infrastructure necessary to comprehensively investigate the immunogenicity of cellular therapies to ensure their clinical safety and efficacy.
Collapse
Affiliation(s)
- Sandra Petrus-Reurer
- Department of Surgery, University of Cambridge, and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
| | - Marco Romano
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom
| | - Sarah Howlett
- Department of Clinical Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Joanne Louise Jones
- Department of Clinical Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Giovanna Lombardi
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom
| | - Kourosh Saeb-Parsy
- Department of Surgery, University of Cambridge, and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
| |
Collapse
|
|
30
|
Tacias-Pascacio VG, Castañeda-Valbuena D, Morellon-Sterling R, Tavano O, Berenguer-Murcia Á, Vela-Gutiérrez G, Rather IA, Fernandez-Lafuente R. Bioactive peptides from fisheries residues: A review of use of papain in proteolysis reactions. Int J Biol Macromol 2021; 184:415-428. [PMID: 34157329 DOI: 10.1016/j.ijbiomac.2021.06.076] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/10/2021] [Accepted: 06/10/2021] [Indexed: 12/19/2022]
Abstract
Papain is a cysteine endopeptidase of vegetal origin (papaya (Carica papaya L.) with diverse applications in food technology. In this review we have focused our attention on its application in the production of bio-peptides by hydrolysis of proteins from fish residues. This way, a residual material, that can become a contaminant if dumped without control, is converted into highly interesting products. The main bioactivity of the produced peptides is their antioxidant activity, followed by their nutritional and functional activities, but peptides with many other bioactivities have been produced. Thera are also examples of production of hydrolysates with several bioactivities. The enzyme may be used alone, or in combination with other enzymes to increase the degree of hydrolysis.
Collapse
Affiliation(s)
- Veymar G Tacias-Pascacio
- Facultad de Ciencias de la Nutrición y Alimentos, Universidad de Ciencias y Artes de Chiapas, Lib. Norte Pte. 1150, 29039 Tuxtla Gutiérrez, Chiapas, Mexico; Tecnológico Nacional de México/Instituto Tecnológico de Tuxtla Gutiérrez, Carretera Panamericana Km. 1080, 29050 Tuxtla Gutiérrez, Chiapas, Mexico.
| | - Daniel Castañeda-Valbuena
- Tecnológico Nacional de México/Instituto Tecnológico de Tuxtla Gutiérrez, Carretera Panamericana Km. 1080, 29050 Tuxtla Gutiérrez, Chiapas, Mexico
| | | | - Olga Tavano
- Faculty of Nutrition, Alfenas Federal Univ., 700 Gabriel Monteiro da Silva St, Alfenas, MG 37130-000, Brazil
| | - Ángel Berenguer-Murcia
- Departamento de Química Inorgánica e Instituto Universitario de Materiales, Universidad de Alicante, Alicante, Spain
| | - Gilber Vela-Gutiérrez
- Facultad de Ciencias de la Nutrición y Alimentos, Universidad de Ciencias y Artes de Chiapas, Lib. Norte Pte. 1150, 29039 Tuxtla Gutiérrez, Chiapas, Mexico
| | - Irfan A Rather
- Center of Excellence in Bionanoscience Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Roberto Fernandez-Lafuente
- Departamento de Biocatálisis, ICP-CSIC, Campus UAM-CSIC, Madrid, Spain; Center of Excellence in Bionanoscience Research, External Scientific Advisory Academics, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
| |
Collapse
|
|
31
|
Cui X, Pan G, Chen Y, Guo X, Liu T, Zhang J, Yang X, Cheng M, Gao H, Jiang F. The p53 pathway in vasculature revisited: A therapeutic target for pathological vascular remodeling? Pharmacol Res 2021; 169:105683. [PMID: 34019981 DOI: 10.1016/j.phrs.2021.105683] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/26/2021] [Accepted: 05/14/2021] [Indexed: 02/08/2023]
Abstract
Pathological vascular remodeling contributes to the development of restenosis following intraluminal interventions, transplant vasculopathy, and pulmonary arterial hypertension. Activation of the tumor suppressor p53 may counteract vascular remodeling by inhibiting aberrant proliferation of vascular smooth muscle cells and repressing vascular inflammation. In particular, the development of different lines of small-molecule p53 activators ignites the hope of treating remodeling-associated vascular diseases by targeting p53 pharmacologically. In this review, we discuss the relationships between p53 and pathological vascular remodeling, and summarize current experimental data suggesting that drugging the p53 pathway may represent a novel strategy to prevent the development of vascular remodeling.
Collapse
Affiliation(s)
- Xiaopei Cui
- Shandong Key Laboratory of Cardiovascular Proteomics and Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Guopin Pan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China; Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Medical University, Xinxiang, Henan Province, China
| | - Ye Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Xiaosun Guo
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Tengfei Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Jing Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Xiaofan Yang
- Department of Pediatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Mei Cheng
- Shandong Key Laboratory of Cardiovascular Proteomics and Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Haiqing Gao
- Shandong Key Laboratory of Cardiovascular Proteomics and Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Fan Jiang
- Shandong Key Laboratory of Cardiovascular Proteomics and Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.
| |
Collapse
|
|
32
|
Mansourabadi AH, Mohamed Khosroshahi L, Noorbakhsh F, Amirzargar A. Cell therapy in transplantation: A comprehensive review of the current applications of cell therapy in transplant patients with the focus on Tregs, CAR Tregs, and Mesenchymal stem cells. Int Immunopharmacol 2021; 97:107669. [PMID: 33965760 DOI: 10.1016/j.intimp.2021.107669] [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: 12/24/2020] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 02/07/2023]
Abstract
Organ transplantation is a practical treatment for patients with end-stage organ failure. Despite the advances in short-term graft survival, long-term graft survival remains the main challenge considering the increased mortality and morbidity associated with chronic rejection and the toxicity of immunosuppressive drugs. Since a novel therapeutic strategy to induce allograft tolerance seems urgent, focusing on developing novel and safe approaches to prolong graft survival is one of the main goals of transplant investigators. Researchers in the field of organ transplantation are interested in suppressing or optimizing the immune responses by focusing on immune cells including mesenchymal stem cells (MSCs), polyclonal regulatory Tcells (Tregs), and antigen-specific Tregs engineered with chimeric antigen receptors (CAR Tregs). We review the mechanistic pathways, phenotypic and functional characteristics of these cells, and their promising application in organ transplantation.
Collapse
Affiliation(s)
- Amir Hossein Mansourabadi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran; Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), 009821 Tehran, Iran; Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), 009821 Tehran, Iran
| | - Leila Mohamed Khosroshahi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran
| | - Farshid Noorbakhsh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran.
| | - Aliakbar Amirzargar
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran.
| |
Collapse
|
|
33
|
Zou Y, Liu H, Cheng Zhou, Wu J. Sleeve Technique is Superior to End-to-End Anastomosis and Cuff Technology in Mouse Model of Graft Vascular Disease. Ann Vasc Surg 2021; 73:438-445. [PMID: 33539949 DOI: 10.1016/j.avsg.2021.01.055] [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: 07/28/2020] [Revised: 01/07/2021] [Accepted: 01/08/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Graft vascular disease (GVD) is the main reason of late transplanted organ failure, which limits the long-term survival of patients. Murine aortic transplant is widely used in the field to understand the mechanisms leading to GVD. Currently, 3 major techniques, end-to-end anastomosis, sleeve suture and cuff technology, have been used to study the mechanism of GVD. However, which method is more suitable in mouse model of GVD? Herein, we compared these 3 surgical techniques in a mouse allograft arteriosclerosis model to determine the technique with the most appreciable outcomes. METHODS Male C57Bl/6 (H-2b) and BALB/c (H-2d) mice were used for aorta transplantation with these 3 techniques. These 3 techniques were compared with regard to donor artery acquisition time, artery anastomosis time, overall surgical time, the amount of bleeding of each technique and the success rate of surgery. Hematoxylin and eosin (H&E) and Masson staining were used to examine the pathological changes of grafted vessels. The protein expression of phospho-NF-κb P65 and PCNA were determined to validate laminar flow and proliferative capacity of neointima obtained from different surgical and control groups. RESULTS Sleeve suture had a shorter vascular anastomosis time and total operation time than end-to-end anastomosis and cuff technique. Sleeve suture and cuff technique had significantly fewer amount of bleeding from the site of vascular anastomosis than end-to-end anastomosis. Moreover, sleeve suture had the highest success rate among these 3 techniques. There was no difference in the degree of graft stenosis and collagen deposition between these 3 techniques. In addition, there was no significant difference in the expression of phospho-NF-κb P65and PCNA between the experimental group. CONCLUSIONS Sleeve suture is superior to end-to-end anastomosis and cuff technique with regard to vascular grafting in the murine model.
Collapse
Affiliation(s)
- Yanqiang Zou
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Liu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cheng Zhou
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Jie Wu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| |
Collapse
|
|
34
|
Harden PN, Game DS, Sawitzki B, Van der Net JB, Hester J, Bushell A, Issa F, Brook MO, Alzhrani A, Schlickeiser S, Scotta C, Petchey W, Streitz M, Blancho G, Tang Q, Markmann J, Lechler RI, Roberts ISD, Friend PJ, Hilton R, Geissler EK, Wood KJ, Lombardi G. Feasibility, long-term safety, and immune monitoring of regulatory T cell therapy in living donor kidney transplant recipients. Am J Transplant 2021; 21:1603-1611. [PMID: 33171020 PMCID: PMC7613119 DOI: 10.1111/ajt.16395] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/14/2020] [Accepted: 10/31/2020] [Indexed: 01/25/2023]
Abstract
Short-term outcomes in kidney transplantation are marred by progressive transplant failure and mortality secondary to immunosuppression toxicity. Immune modulation with autologous polyclonal regulatory T cell (Treg) therapy may facilitate immunosuppression reduction promoting better long-term clinical outcomes. In a Phase I clinical trial, 12 kidney transplant recipients received 1-10 × 106 Treg per kg at Day +5 posttransplantation in lieu of induction immunosuppression (Treg Therapy cohort). Nineteen patients received standard immunosuppression (Reference cohort). Primary outcomes were rejection-free and patient survival. Patient and transplant survival was 100%; acute rejection-free survival was 100% in the Treg Therapy versus 78.9% in the reference cohort at 48 months posttransplant. Treg therapy revealed no excess safety concerns. Four patients in the Treg Therapy cohort had mycophenolate mofetil withdrawn successfully and remain on tacrolimus monotherapy. Treg infusion resulted in a long-lasting dose-dependent increase in peripheral blood Tregs together with an increase in marginal zone B cell numbers. We identified a pretransplantation immune phenotype suggesting a high risk of unsuccessful ex-vivo Treg expansion. Autologous Treg therapy is feasible, safe, and is potentially associated with a lower rejection rate than standard immunosuppression. Treg therapy may provide an exciting opportunity to minimize immunosuppression therapy and improve long-term outcomes.
Collapse
Affiliation(s)
- Paul N Harden
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - David S Game
- Department of Transplantation, Guys and St Thomas's Hospital NHS Trust, London, UK
| | - Birgit Sawitzki
- Institute of Medical Immunology, Charite University of Medicine, Berlin, Germany
| | - Jeroen B Van der Net
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Joanna Hester
- Transplantation Research Immunology Group, University of Oxford, Oxford, UK
| | - Andrew Bushell
- Transplantation Research Immunology Group, University of Oxford, Oxford, UK
| | - Fadi Issa
- Transplantation Research Immunology Group, University of Oxford, Oxford, UK
| | - Matthew O Brook
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.,Transplantation Research Immunology Group, University of Oxford, Oxford, UK
| | - Alaa Alzhrani
- Transplantation Research Immunology Group, University of Oxford, Oxford, UK
| | - Stephan Schlickeiser
- Institute of Medical Immunology, Charite University of Medicine, Berlin, Germany
| | - Cristiano Scotta
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Science, Kings College London, London, UK
| | - William Petchey
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Mathias Streitz
- Institute of Medical Immunology, Charite University of Medicine, Berlin, Germany
| | - Gilles Blancho
- Centre of Research in Transplantation and Immunology, Nantes University, Nantes, France
| | - Quizhi Tang
- UCSF Transplantation Research Lab, Department of Surgery, University of California, San Francisco, California
| | - James Markmann
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts
| | - Robert I Lechler
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Science, Kings College London, London, UK
| | - Ian S D Roberts
- Department of Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Peter J Friend
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Rachel Hilton
- Department of Transplantation, Guys and St Thomas's Hospital NHS Trust, London, UK
| | - Edward K Geissler
- Department of Surgery, Division of Experimental Surgery, University of Regensburg, Regensburg, Germany
| | - Kathryn J Wood
- Transplantation Research Immunology Group, University of Oxford, Oxford, UK
| | - Giovanna Lombardi
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Science, Kings College London, London, UK
| |
Collapse
|
|
35
|
Adigbli G, Hua P, Uchiyama M, Roberts I, Hester J, Watt SM, Issa F. Development of LT-HSC-Reconstituted Non-Irradiated NBSGW Mice for the Study of Human Hematopoiesis In Vivo. Front Immunol 2021; 12:642198. [PMID: 33868276 PMCID: PMC8044770 DOI: 10.3389/fimmu.2021.642198] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 03/03/2021] [Indexed: 11/26/2022] Open
Abstract
Humanized immune system (HIS) mouse models are useful tools for the in vivo investigation of human hematopoiesis. However, the majority of HIS models currently in use are biased towards lymphocyte development and fail to support long-term multilineage leucocytes and erythrocytes. Those that achieve successful multilineage reconstitution often require preconditioning steps which are expensive, cause animal morbidity, are technically demanding, and poorly reproducible. In this study, we address this challenge by using HSPC-NBSGW mice, in which NOD,B6.SCID IL-2rγ-/-KitW41/W41 (NBSGW) mice are engrafted with human CD133+ hematopoietic stem and progenitor cells (HSPCs) without the need for preconditioning by sublethal irradiation. These HSPCs are enriched in long-term hematopoietic stem cells (LT-HSCs), while NBSGW mice are permissive to human hematopoietic stem cell (HSC) engraftment, thus reducing the cell number required for successful HIS development. B cells reconstitute with the greatest efficiency, including mature B cells capable of class-switching following allogeneic stimulation and, within lymphoid organs and peripheral blood, T cells at a spectrum of stages of maturation. In the thymus, human thymocytes are identified at all major stages of development. Phenotypically distinct subsets of myeloid cells, including dendritic cells and mature monocytes, engraft to a variable degree in the bone marrow and spleen, and circulate in peripheral blood. Finally, we observe human erythrocytes which persist in the periphery at high levels following macrophage clearance. The HSPC-NBSGW model therefore provides a useful platform for the study of human hematological and immunological processes and pathologies.
Collapse
Affiliation(s)
- George Adigbli
- Transplantation Research and Immunology Group, John Radcliffe Hospital, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Peng Hua
- MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, United Kingdom
- Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Masateru Uchiyama
- Transplantation Research and Immunology Group, John Radcliffe Hospital, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Irene Roberts
- MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, United Kingdom
- Department of Paediatrics, Children’s Hospital, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Joanna Hester
- Transplantation Research and Immunology Group, John Radcliffe Hospital, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Suzanne M. Watt
- Nuffield Division of Clinical Laboratory Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
- Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, and Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
| | - Fadi Issa
- Transplantation Research and Immunology Group, John Radcliffe Hospital, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| |
Collapse
|
|
36
|
Oberholtzer N, Atkinson C, Nadig SN. Adoptive Transfer of Regulatory Immune Cells in Organ Transplantation. Front Immunol 2021; 12:631365. [PMID: 33737934 PMCID: PMC7960772 DOI: 10.3389/fimmu.2021.631365] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 01/18/2021] [Indexed: 12/13/2022] Open
Abstract
Chronic graft rejection remains a significant barrier to solid organ transplantation as a treatment for end-organ failure. Patients receiving organ transplants typically require systemic immunosuppression in the form of pharmacological immunosuppressants for the duration of their lives, leaving these patients vulnerable to opportunistic infections, malignancies, and other use-restricting side-effects. In recent years, a substantial amount of research has focused on the use of cell-based therapies for the induction of graft tolerance. Inducing or adoptively transferring regulatory cell types, including regulatory T cells, myeloid-derived suppressor cells, and IL-10 secreting B cells, has the potential to produce graft-specific tolerance in transplant recipients. Significant progress has been made in the optimization of these cell-based therapeutic strategies as our understanding of their underlying mechanisms increases and new immunoengineering technologies become more widely available. Still, many questions remain to be answered regarding optimal cell types to use, appropriate dosage and timing, and adjuvant therapies. In this review, we summarize what is known about the cellular mechanisms that underly the current cell-based therapies being developed for the prevention of allograft rejection, the different strategies being explored to optimize these therapies, and all of the completed and ongoing clinical trials involving these therapies.
Collapse
Affiliation(s)
- Nathaniel Oberholtzer
- Department of Surgery, Medical University of South Carolina, Charleston, SC, United States
| | - Carl Atkinson
- Department of Surgery, Medical University of South Carolina, Charleston, SC, United States
| | - Satish N Nadig
- Department of Surgery, Medical University of South Carolina, Charleston, SC, United States
| |
Collapse
|
|
37
|
Regulatory T Cells for the Induction of Transplantation Tolerance. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021. [PMID: 33523454 DOI: 10.1007/978-981-15-6407-9_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/10/2023]
Abstract
Organ transplantation is the optimal treatment for terminal and irreversible organ failure. Achieving transplantation tolerance has long been the ultimate goal in the field of transplantation. Regulatory T cell (Treg)-based therapy is a promising novel approach for inducing donor organ-specific tolerance. Tregs play critical roles in the maintenance of immune homeostasis and self-tolerance, by promoting transplantation tolerance through a variety of mechanisms on different target cells, including anti-inflammatory cytokine production, induction of apoptosis, disruption of metabolic pathways, and mutual interaction with dendritic cells. The continued success of Treg-based therapy in the clinical setting is critically dependent on preclinical studies that support its translational potential. However, although some initial clinical trials of adoptive Treg therapy have successively demonstrated safety and efficacy for immunosuppressant minimization and transplantation tolerance induction, most Treg-based hematopoietic stem cell and solid organ clinical trials are still in their infancy. These clinical trials have not only focused on safety and efficacy but also included optimization and standardization protocols of good manufacturing practice regarding cell isolation, expansion, dosing, timing, specificity, quality control, concomitant immunosuppressants, and post-administration monitoring. We herein report a brief introduction of Tregs, including their phenotypic and functional characterization, and focus on the clinical translation of Treg-based therapeutic applications in the setting of transplantation.
Collapse
|
|
38
|
Humanization of Immunodeficient Animals for the Modeling of Transplantation, Graft Versus Host Disease, and Regenerative Medicine. Transplantation 2021; 104:2290-2306. [PMID: 32068660 PMCID: PMC7590965 DOI: 10.1097/tp.0000000000003177] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The humanization of animals is a powerful tool for the exploration of human disease pathogenesis in biomedical research, as well as for the development of therapeutic interventions with enhanced translational potential. Humanized models enable us to overcome biologic differences that exist between humans and other species, while giving us a platform to study human processes in vivo. To become humanized, an immune-deficient recipient is engrafted with cells, tissues, or organoids. The mouse is the most well studied of these hosts, with a variety of immunodeficient strains available for various specific uses. More recently, efforts have turned to the humanization of other animal species such as the rat, which offers some technical and immunologic advantages over mice. These advances, together with ongoing developments in the incorporation of human transgenes and additional mutations in humanized mouse models, have expanded our opportunities to replicate aspects of human allotransplantation and to assist in the development of immunotherapies. In this review, the immune and tissue humanization of various species is presented with an emphasis on their potential for use as models for allotransplantation, graft versus host disease, and regenerative medicine.
Collapse
|
|
39
|
Identification, selection, and expansion of non-gene modified alloantigen-reactive Tregs for clinical therapeutic use. Cell Immunol 2020; 357:104214. [PMID: 32977154 PMCID: PMC8482792 DOI: 10.1016/j.cellimm.2020.104214] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 09/02/2020] [Accepted: 09/05/2020] [Indexed: 12/29/2022]
Abstract
Transplantation is limited by the need for life-long pharmacological immunosuppression, which carries significant morbidity and mortality. Regulatory T cell (Treg) therapy holds significant promise as a strategy to facilitate immunosuppression minimization. Polyclonal Treg therapy has been assessed in a number of Phase I/II clinical trials in both solid organ and hematopoietic transplantation. Attention is now shifting towards the production of alloantigen-reactive Tregs (arTregs) through co-culture with donor antigen. These allospecific cells harbour potent suppressive function and yet their specificity implies a theoretical reduction in off-target effects. This review will cover the progress in the development of arTregs including their potential application for clinical use in transplantation, the knowledge gained so far from clinical trials of Tregs in transplant patients, and future directions for Treg therapy.
Collapse
|
|
40
|
Masoud AG, Lin J, Azad AK, Farhan MA, Fischer C, Zhu LF, Zhang H, Sis B, Kassiri Z, Moore RB, Kim D, Anderson CC, Vederas JC, Adam BA, Oudit GY, Murray AG. Apelin directs endothelial cell differentiation and vascular repair following immune-mediated injury. J Clin Invest 2020; 130:94-107. [PMID: 31738185 DOI: 10.1172/jci128469] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 09/18/2019] [Indexed: 01/06/2023] Open
Abstract
Sustained, indolent immune injury of the vasculature of a heart transplant limits long-term graft and recipient survival. This injury is mitigated by a poorly characterized, maladaptive repair response. Vascular endothelial cells respond to proangiogenic cues in the embryo by differentiation to specialized phenotypes, associated with expression of apelin. In the adult, the role of developmental proangiogenic cues in repair of the established vasculature is largely unknown. We found that human and minor histocompatibility-mismatched donor mouse heart allografts with alloimmune-mediated vasculopathy upregulated expression of apelin in arteries and myocardial microvessels. In vivo, loss of donor heart expression of apelin facilitated graft immune cell infiltration, blunted vascular repair, and worsened occlusive vasculopathy in mice. In vitro, an apelin receptor agonist analog elicited endothelial nitric oxide synthase activation to promote endothelial monolayer wound repair and reduce immune cell adhesion. Thus, apelin acted as an autocrine growth cue to sustain vascular repair and mitigate the effects of immune injury. Treatment with an apelin receptor agonist after vasculopathy was established markedly reduced progression of arterial occlusion in mice. Together, these initial data identify proangiogenic apelin as a key mediator of coronary vascular repair and a pharmacotherapeutic target for immune-mediated injury of the coronary vasculature.
Collapse
Affiliation(s)
| | - Jiaxin Lin
- Department of Surgery.,Department of Medical Microbiology and Immunology, and
| | | | | | - Conrad Fischer
- Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada
| | | | - Hao Zhang
- Department of Medicine.,Mazankowski Heart Institute, Edmonton, Alberta, Canada
| | - Banu Sis
- Department of Laboratory Medicine and Pathology and
| | - Zamaneh Kassiri
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
| | | | | | - Colin C Anderson
- Department of Surgery.,Department of Medical Microbiology and Immunology, and
| | - John C Vederas
- Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada
| | | | - Gavin Y Oudit
- Department of Medicine.,Mazankowski Heart Institute, Edmonton, Alberta, Canada
| | | |
Collapse
|
|
41
|
Arroyo Hornero R, Georgiadis C, Hua P, Trzupek D, He LZ, Qasim W, Todd JA, Ferreira RC, Wood KJ, Issa F, Hester J. CD70 expression determines the therapeutic efficacy of expanded human regulatory T cells. Commun Biol 2020; 3:375. [PMID: 32665635 PMCID: PMC7360768 DOI: 10.1038/s42003-020-1097-8] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 06/17/2020] [Indexed: 12/27/2022] Open
Abstract
Regulatory T cells (Tregs) are critical mediators of immune homeostasis. The co-stimulatory molecule CD27 is a marker of highly suppressive Tregs, although the role of the CD27-CD70 receptor-ligand interaction in Tregs is not clear. Here we show that after prolonged in vitro stimulation, a significant proportion of human Tregs gain stable CD70 expression while losing CD27. The expression of CD70 in expanded Tregs is associated with a profound loss of regulatory function and an unusual ability to provide CD70-directed co-stimulation to TCR-activated conventional T cells. Genetic deletion of CD70 or its blockade prevents Tregs from delivering this co-stimulatory signal, thus maintaining their regulatory activity. High resolution targeted single-cell RNA sequencing of human peripheral blood confirms the presence of CD27-CD70+ Treg cells. These findings have important implications for Treg-based clinical studies where cells are expanded over extended periods in order to achieve sufficient treatment doses.
Collapse
Affiliation(s)
- Rebeca Arroyo Hornero
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK
| | - Christos Georgiadis
- Molecular and Cellular Immunology Unit, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK
| | - Peng Hua
- MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, UK
| | - Dominik Trzupek
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, OX3 7BN, UK
| | - Li-Zhen He
- Celldex Therapeutics, Inc., Hampton, NJ, 08827, USA
| | - Waseem Qasim
- Molecular and Cellular Immunology Unit, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK
| | - John A Todd
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, OX3 7BN, UK
| | - Ricardo C Ferreira
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, OX3 7BN, UK
| | - Kathryn J Wood
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK
| | - Fadi Issa
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK
| | - Joanna Hester
- Transplantation Research and Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.
| |
Collapse
|
|
42
|
The Effects of an IL-21 Receptor Antagonist on the Alloimmune Response in a Humanized Mouse Skin Transplant Model. Transplantation 2020; 103:2065-2074. [PMID: 31343579 DOI: 10.1097/tp.0000000000002773] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Interleukin 21 (IL-21) is involved in regulating the expansion and effector function of a broad range of leukocytes, including T cells and B cells. In transplantation, the exact role of IL-21 in the process of allograft rejection is unknown. To further explore this, the aim of this study is to test the effect of an IL-21 receptor (IL-21R) blocking antibody on the early phase of allograft rejection in a humanized skin transplantation model in mice reconstituted with human T and B cells. METHODS Immunodeficient Balb/c IL2rγRag2 mice were transplanted with human skin followed by adoptive transfer of human allogeneic splenocytes. Control animals were treated with a phosphate buffered saline vehicle while the other group was treated with a humanized anti-IL-21R antibody (αIL-21R). RESULTS In the phosphate buffered saline-treated animals, human skin allografts were infiltrated with lymphocytes and developed a thickened epidermis with increased expression of the inflammatory markers Keratin 17 (Ker17) and Ki67. In mice treated with αIL-21R, these signs of allograft reactivity were significantly reduced. Concordantly, STAT3 phosphorylation was inhibited in this group. Of note, treatment with αIL-21R attenuated the process of T and B cell reconstitution after adoptive cellular transfer. CONCLUSIONS These findings demonstrate that blockade of IL-21 signaling can delay allograft rejection in a humanized skin transplantation model.
Collapse
|
|
43
|
Successful Regulatory T Cell-Based Therapy Relies on Inhibition of T Cell Effector Function and Enrichment of FOXP3+ Cells in a Humanized Mouse Model of Skin Inflammation. J Immunol Res 2020; 2020:7680131. [PMID: 32509883 PMCID: PMC7244960 DOI: 10.1155/2020/7680131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 01/19/2020] [Accepted: 01/30/2020] [Indexed: 11/17/2022] Open
Abstract
Background Recent clinical trials using regulatory T cells (Treg) support the therapeutic potential of Treg-based therapy in transplantation and autoinflammatory diseases. Despite these clinical successes, the effect of Treg on inflamed tissues, as well as their impact on immune effector function in vivo, is poorly understood. Therefore, we here evaluated the effect of human Treg injection on cutaneous inflammatory processes in vivo using a humanized mouse model of human skin inflammation (huPBL-SCID-huSkin). Methods SCID beige mice were transplanted with human skin followed by intraperitoneal (IP) injection of 20‐40 × 106 allogeneic human PBMCs. This typically results in human skin inflammation as indicated by epidermal thickening (hyperkeratosis) and changes in dermal inflammatory markers such as the antimicrobial peptide hBD2 and epidermal barrier cytokeratins K10 and K16, as well as T cell infiltration in the dermis. Ex vivo-expanded human Treg were infused intraperitoneally. Human cutaneous inflammation and systemic immune responses were analysed by immunohistochemistry and flow cytometry. Results We confirmed that human Treg injection inhibits skin inflammation and the influx of effector T cells. As a novel finding, we demonstrate that human Treg injection led to a reduction of IL-17-secreting cells while promoting a relative increase in immunosuppressive FOXP3+ Treg in the human skin, indicating active immune regulation in controlling the local proinflammatory response. Consistent with the local control (skin), systemically (splenocytes), we observed that Treg injection led to lower frequencies of IFNγ and IL-17A-expressing human T cells, while a trend towards enrichment of FOXP3+ Treg was observed. Conclusion Taken together, we demonstrate that inhibition of skin inflammation by Treg infusion, next to a reduction of infiltrating effector T cells, is mediated by restoring both the local and systemic balance between cytokine-producing effector T cells and immunoregulatory T cells. This work furthers our understanding of Treg-based immunotherapy.
Collapse
|
|
44
|
Fukasaku Y, Goto R, Ganchiku Y, Emoto S, Zaitsu M, Watanabe M, Kawamura N, Fukai M, Shimamura T, Taketomi A. Novel immunological approach to asses donor reactivity of transplant recipients using a humanized mouse model. Hum Immunol 2020; 81:342-353. [PMID: 32345498 DOI: 10.1016/j.humimm.2020.04.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 04/04/2020] [Accepted: 04/22/2020] [Indexed: 12/17/2022]
Abstract
In organ transplantation, a reproducible and robust immune-monitoring assay has not been established to determine individually tailored immunosuppressants (IS). We applied humanized mice reconstituted with human (hu-) peripheral blood mononuclear cells (PBMCs) obtained from living donor liver transplant recipients to evaluate their immune status. Engraftment of 2.5 × 106 hu-PBMCs from healthy volunteers and recipients in the NSG mice was achieved successfully. The reconstituted lymphocytes consisted mainly of hu-CD3+ lymphocytes with predominant CD45RA-CD62Llo TEM and CCR6-CXCR3+CD4+ Th1 cells in hu-PBMC-NSG mice. Interestingly, T cell allo-reactivity of hu-PBMC-NSG mice was amplified significantly compared with that of freshly isolated PBMCs (p < 0.05). Furthermore, magnified hu-T cell responses to donor antigens (Ag) were observed in 2/10 immunosuppressed recipients with multiple acute rejection (AR) experiences, suggesting that the immunological assay in hu-PBMC-NSG mice revealed hidden risks of allograft rejection by IS. Furthermore, donor Ag-specific hyporesponsiveness was maintained in recipients who had been completely weaned off IS (n = 4), despite homeostatic proliferation of hu-T cells in the hu-PBMC-NSG mice. The immunological assay in humanized mice provides a new tool to assess recipient immunity in the absence of IS and explore the underlying mechanisms to maintaining operational tolerance.
Collapse
Affiliation(s)
- Yasutomo Fukasaku
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo 060-8648, Japan
| | - Ryoichi Goto
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo 060-8648, Japan.
| | - Yoshikazu Ganchiku
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo 060-8648, Japan
| | - Shin Emoto
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo 060-8648, Japan
| | - Masaaki Zaitsu
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo 060-8648, Japan
| | - Masaaki Watanabe
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo 060-8648, Japan; Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8648, Japan
| | - Norio Kawamura
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo 060-8648, Japan; Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8648, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo 060-8648, Japan
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo 060-8648, Japan.
| |
Collapse
|
|
45
|
Dandel M, Hetzer R. Impact of rejection-related immune responses on the initiation and progression of cardiac allograft vasculopathy. Am Heart J 2020; 222:46-63. [PMID: 32018202 DOI: 10.1016/j.ahj.2019.12.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 12/22/2019] [Indexed: 12/17/2022]
|
|
46
|
Zhao TX, Newland SA, Mallat Z. 2019 ATVB Plenary Lecture: Interleukin-2 Therapy in Cardiovascular Disease: The Potential to Regulate Innate and Adaptive Immunity. Arterioscler Thromb Vasc Biol 2020; 40:853-864. [PMID: 32078364 DOI: 10.1161/atvbaha.119.312287] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Regulatory T cells and type-2 innate lymphoid cells represent 2 subsets of immune cells, which have been shown in preclinical models to be important in atherosclerosis and myocardial repair. Regulatory T cells play a crucial role in immune homeostasis and tolerance via their interactions with effector T cells, dendritic cells, and monocytes/macrophages. They also utilize and secrete inhibitory cytokines, including interleukin 10 and transforming growth factor β, to regulate or suppress pathogenic immune responses. Type-2 innate lymphoid cells have an important role in type-2 immune responses and tissue repair through secreting interleukins 5 and 13, as well as a variety of biological mediators and growth factors. Intriguingly, interleukin-2 has emerged as a common cytokine, which can be harnessed to upregulate both cell types, and also has important translational consequences as clinical trials are ongoing for its use in cardiovascular disease. Here, we briefly review the biology of these regulatory immune cell types, discuss the preclinical and clinical evidence for their functions in cardiovascular disease, examine the prospects for clinical translation and current ongoing trials, and finally, postulate how overlap in the mechanisms of upregulation may be leveraged in future treatments for patients.
Collapse
Affiliation(s)
- Tian X Zhao
- From the Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, United Kingdom (T.X.Z., S.A.N., Z.M.)
| | - Stephen A Newland
- From the Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, United Kingdom (T.X.Z., S.A.N., Z.M.)
| | - Ziad Mallat
- From the Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, United Kingdom (T.X.Z., S.A.N., Z.M.)
- Paris-Descartes Université, Inserm U970, France (Z.M.)
| |
Collapse
|
|
47
|
Wang M, Deng J, Lai H, Lai Y, Meng G, Wang Z, Zhou Z, Chen H, Yu Z, Li S, Jiang H. Vagus Nerve Stimulation Ameliorates Renal Ischemia-Reperfusion Injury through Inhibiting NF- κB Activation and iNOS Protein Expression. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:7106525. [PMID: 32148655 PMCID: PMC7053466 DOI: 10.1155/2020/7106525] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 12/17/2019] [Indexed: 12/19/2022]
Abstract
OBJECTIVE In renal ischemia/reperfusion injury (RIRI), nuclear factor κB (NF-κB (NF-κB (NF. METHODS Eighteen male Sprague-Dawley rats were randomly allocated into the sham group, the I/R group, and the VNS+I/R group, 6 rats per group. An RIRI model was induced by a right nephrectomy and blockade of the left renal pedicle vessels for 45 min. After 6 h of reperfusion, the blood samples and renal samples were collected. The VNS treatment was performed throughout the I/R process in the VNS+I/R group using specific parameters (20 Hz, 0.1 ms in duration, square waves) known to produce a small but reliable bradycardia. Blood was used for evaluation of renal function and inflammatory state. Renal injury was evaluated via TUNEL staining. Renal samples were harvested to evaluate renal oxidative stress, NF-κB (NF. RESULTS The VNS treatment reduces serum creatinine (Cr) and blood urea nitrogen (BUN) levels. Simultaneously, the levels of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1-beta (IL-1β) were significantly increased in the I/R group, but VNS treatment markedly ameliorated this inflammatory response. Furthermore, the VNS ameliorated oxidant stress and renal injury, indicated by a decrease in 3-nitrotyrosine (3-NT) formation and MDA and MPO levels and an increase in the SOD level compared to that in the I/R group. Finally, the VNS also significantly decreases NF-κB (NF. CONCLUSION Our findings indicate that NF-κB activation increased iNOS expression and promoted RIRI and that VNS treatment attenuated RIRI by inhibiting iNOS expression, oxidative stress, and inflammation via NF-κB inactivation.κB (NF-κB (NF.
Collapse
Affiliation(s)
- Meng Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060 Hubei, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 Hubei, China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 Hubei, China
| | - Jielin Deng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060 Hubei, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 Hubei, China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 Hubei, China
| | - Huanzhu Lai
- Department of Cardiology, First Hospital of Jilin University, Changchun, 130021 Jilin, China
| | - Yanqiu Lai
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060 Hubei, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 Hubei, China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 Hubei, China
| | - Guannan Meng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060 Hubei, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 Hubei, China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 Hubei, China
| | - Zhenya Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060 Hubei, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 Hubei, China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 Hubei, China
| | - Zhen Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060 Hubei, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 Hubei, China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 Hubei, China
| | - Hu Chen
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060 Hubei, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 Hubei, China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 Hubei, China
| | - Zhiyao Yu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060 Hubei, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 Hubei, China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 Hubei, China
| | - Shuyan Li
- Department of Cardiology, First Hospital of Jilin University, Changchun, 130021 Jilin, China
| | - Hong Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060 Hubei, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060 Hubei, China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060 Hubei, China
| |
Collapse
|
|
48
|
Ius F, Salman J, Knoefel AK, Sommer W, Nakagiri T, Verboom M, Siemeni T, Poyanmehr R, Bobylev D, Kuehn C, Avsar M, Erdfelder C, Hallensleben M, Boethig D, Hecker H, Schwerk N, Mueller C, Welte T, Falk C, Preissler G, Haverich A, Tudorache I, Warnecke G. Increased frequency of CD4 + CD25 high CD127 low T cells early after lung transplant is associated with improved graft survival - a retrospective study. Transpl Int 2020; 33:503-516. [PMID: 31903646 DOI: 10.1111/tri.13568] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 05/04/2019] [Accepted: 12/20/2019] [Indexed: 12/30/2022]
Abstract
In this retrospective study, we analyzed the presence of any association of three CD4+ CD25high regulatory T-cell subpopulations at 3 weeks after lung transplantation with the later incidence of chronic lung allograft dysfunction and graft survival. Among lung-transplanted patients between January 2009 and April 2018, only patients with sufficient T-cell measurements at 3 weeks after transplantation were included into the study. Putative regulatory T cells were defined as CD4+ CD25high T cells, detected in peripheral blood and further analyzed for CD127low , FoxP3+ , and CD152+ using fluorescence-activated cell sorting (FACS) analysis. Associations of regulatory T cells with chronic lung allograft dysfunction (CLAD) and graft survival were evaluated using Cox analysis. During the study period, 724 (71%) patients were included into the study. Freedom from chronic lung allograft dysfunction (CLAD) and graft survival amounted to 66% and 68% at 5 years. At the multivariable analysis, increasing frequencies of CD127low were associated with better freedom from CLAD (hazard ratio for each 1% increase of %CD127low , HR = 0.989, 95% CI = 0.981-0.996, P = 0.003) and better graft survival (HR = 0.991, 95% CI = 0.984-0.999, P = 0.026). A higher frequency of CD127low regulatory T cells in peripheral blood early after lung transplantation estimated a protective effect against chronic lung allograft dysfunction, mortality, and re-transplantation.
Collapse
Affiliation(s)
- Fabio Ius
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Jawad Salman
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Ann-Kathrin Knoefel
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Wiebke Sommer
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany.,German Center for Lung Research (DZL), Hannover, Germany
| | - Tomoyuki Nakagiri
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Murielle Verboom
- Department of Transfusion Medicine, Hannover Medical School, Hannover, Germany
| | - Thierry Siemeni
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Reza Poyanmehr
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Dmitry Bobylev
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Christian Kuehn
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Murat Avsar
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Caroline Erdfelder
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | | | - Dietmar Boethig
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Hartmut Hecker
- Institute for Biometry, Hannover Medical School, Hannover, Germany
| | - Nicolaus Schwerk
- Department of pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
| | - Carsten Mueller
- Department of pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
| | - Tobias Welte
- German Center for Lung Research (DZL), Hannover, Germany.,Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
| | - Christine Falk
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Gerhard Preissler
- German Center for Lung Research (DZL), Hannover, Germany.,Department of Surgery, Munich Lung Transplant Group, Ludwig-Maximilian's University, Munich, Germany
| | - Axel Haverich
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany.,German Center for Lung Research (DZL), Hannover, Germany
| | - Igor Tudorache
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Gregor Warnecke
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany.,German Center for Lung Research (DZL), Hannover, Germany
| |
Collapse
|
|
49
|
O’Connell AK, Douam F. Humanized Mice for Live-Attenuated Vaccine Research: From Unmet Potential to New Promises. Vaccines (Basel) 2020; 8:E36. [PMID: 31973073 PMCID: PMC7157703 DOI: 10.3390/vaccines8010036] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 01/11/2020] [Accepted: 01/13/2020] [Indexed: 01/24/2023] Open
Abstract
Live-attenuated vaccines (LAV) represent one of the most important medical innovations in human history. In the past three centuries, LAV have saved hundreds of millions of lives, and will continue to do so for many decades to come. Interestingly, the most successful LAVs, such as the smallpox vaccine, the measles vaccine, and the yellow fever vaccine, have been isolated and/or developed in a purely empirical manner without any understanding of the immunological mechanisms they trigger. Today, the mechanisms governing potent LAV immunogenicity and long-term induced protective immunity continue to be elusive, and therefore hamper the rational design of innovative vaccine strategies. A serious roadblock to understanding LAV-induced immunity has been the lack of suitable and cost-effective animal models that can accurately mimic human immune responses. In the last two decades, human-immune system mice (HIS mice), i.e., mice engrafted with components of the human immune system, have been instrumental in investigating the life-cycle and immune responses to multiple human-tropic pathogens. However, their use in LAV research has remained limited. Here, we discuss the strong potential of LAVs as tools to enhance our understanding of human immunity and review the past, current and future contributions of HIS mice to this endeavor.
Collapse
Affiliation(s)
| | - Florian Douam
- Department of Microbiology, National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, MA 02118, USA;
| |
Collapse
|
|
50
|
Marin E, Bouchet-Delbos L, Renoult O, Louvet C, Nerriere-Daguin V, Managh AJ, Even A, Giraud M, Vu Manh TP, Aguesse A, Bériou G, Chiffoleau E, Alliot-Licht B, Prieur X, Croyal M, Hutchinson JA, Obermajer N, Geissler EK, Vanhove B, Blancho G, Dalod M, Josien R, Pecqueur C, Cuturi MC, Moreau A. Human Tolerogenic Dendritic Cells Regulate Immune Responses through Lactate Synthesis. Cell Metab 2019; 30:1075-1090.e8. [PMID: 31801055 DOI: 10.1016/j.cmet.2019.11.011] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 07/17/2019] [Accepted: 11/12/2019] [Indexed: 12/22/2022]
Abstract
Cell therapy is a promising strategy for treating patients suffering from autoimmune or inflammatory diseases or receiving a transplant. Based on our preclinical studies, we have generated human autologous tolerogenic dendritic cells (ATDCs), which are being tested in a first-in-man clinical trial in kidney transplant recipients. Here, we report that ATDCs represent a unique subset of monocyte-derived cells based on phenotypic, transcriptomic, and metabolic analyses. ATDCs are characterized by their suppression of T cell proliferation and their expansion of Tregs through secreted factors. ATDCs produce high levels of lactate that shape T cell responses toward tolerance. Indeed, T cells take up ATDC-secreted lactate, leading to a decrease of their glycolysis. In vivo, ATDCs promote elevated levels of circulating lactate and delay graft-versus-host disease by reducing T cell proliferative capacity. The suppression of T cell immunity through lactate production by ATDCs is a novel mechanism that distinguishes ATDCs from other cell-based immunotherapies.
Collapse
Affiliation(s)
- Eros Marin
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, CHU Nantes, ITUN, Nantes, France
| | - Laurence Bouchet-Delbos
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, CHU Nantes, ITUN, Nantes, France
| | - Ophélie Renoult
- Centre de Recherche en Cancérologie et Immunologie Nantes-Angers UMR1232, INSERM, Université de Nantes, Nantes, France
| | - Cédric Louvet
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, CHU Nantes, ITUN, Nantes, France
| | - Véronique Nerriere-Daguin
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, CHU Nantes, ITUN, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| | - Amy J Managh
- Centre for Analytical Science, Department of Chemistry, Loughborough University, Loughborough, UK
| | - Amandine Even
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, CHU Nantes, ITUN, Nantes, France
| | - Matthieu Giraud
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, CHU Nantes, ITUN, Nantes, France
| | - Thien Phong Vu Manh
- Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, CNRS, INSERM, CIML, Marseille, France
| | - Audrey Aguesse
- UMR 1280 PhAN, Mass Spectrometry Core Facility, INRA, CRNHO, West Human Nutrition Research Center, Nantes, France
| | - Gaelle Bériou
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, CHU Nantes, ITUN, Nantes, France
| | - Elise Chiffoleau
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, CHU Nantes, ITUN, Nantes, France
| | - Brigitte Alliot-Licht
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, CHU Nantes, ITUN, Nantes, France; Faculté d'Odontologie, Université de Nantes, Nantes, France
| | - Xavier Prieur
- Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France
| | - Mikael Croyal
- UMR 1280 PhAN, Mass Spectrometry Core Facility, INRA, CRNHO, West Human Nutrition Research Center, Nantes, France
| | - James A Hutchinson
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Natasa Obermajer
- Division of Surgical Oncology, University of Pittsburgh, Hillman Cancer Center, Pittsburgh, PA, USA
| | - Edward K Geissler
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Bernard Vanhove
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, CHU Nantes, ITUN, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| | - Gilles Blancho
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, CHU Nantes, ITUN, Nantes, France
| | - Marc Dalod
- Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, CNRS, INSERM, CIML, Marseille, France
| | - Régis Josien
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, CHU Nantes, ITUN, Nantes, France; Laboratoire d'Immunologie, CHU Nantes, Nantes Université, Nantes, France
| | - Claire Pecqueur
- Centre de Recherche en Cancérologie et Immunologie Nantes-Angers UMR1232, INSERM, Université de Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| | - Maria-Cristina Cuturi
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, CHU Nantes, ITUN, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France
| | - Aurélie Moreau
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, CHU Nantes, ITUN, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France.
| |
Collapse
|