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Gupta A, Ricart E, Cohen L. Hematopoietic stem cell transplantation in Crohn's disease: a comprehensive review. Curr Opin Gastroenterol 2025:00001574-990000000-00189. [PMID: 40232992 DOI: 10.1097/mog.0000000000001096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
PURPOSE OF REVIEW Despite advances in medical therapies for the treatment of Crohn's disease (CD), 20-30% of patients fail to respond to these therapies (i.e. refractory CD). Medically refractory CD leads to significant disability increasing morbidity and mortality. To prevent the disability of refractory CD, hematopoietic stem cell transplantation (SCT) has emerged as a therapeutic strategy. RECENT FINDINGS Autologous (auto-SCT) and allogeneic SCT (allo-SCT) have been explored in clinical trials for refractory CD patients. We will review the stem cell transplant process, how each part of stem cell transplantation affects clinical efficacy and safety, and how specific clinical trials advanced our understanding of the role of stem cell transplant in the treatment of refractory CD. SUMMARY As multiple clinical trials using the same auto-SCT protocol demonstrated auto-SCT as clinically efficacious for refractory CD it supports that this treatment may be adopted as standard of care for select patients with refractory CD. To establish auto-SCT as a standard therapy will require the creation of international registries to track long-term SCT outcomes and translational studies to refine SCT protocols for CD patients as a cellular therapy that truly restores healthy intestinal immune cell populations from hematopoietic stem cells.
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Chen S, Qin Z, Zhou S, Xu Y, Zhu Y. The emerging role of intestinal stem cells in ulcerative colitis. Front Med (Lausanne) 2025; 12:1569328. [PMID: 40201327 PMCID: PMC11975877 DOI: 10.3389/fmed.2025.1569328] [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] [Received: 01/31/2025] [Accepted: 03/14/2025] [Indexed: 04/10/2025] Open
Abstract
Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease affecting the colon and rectum. Characterized by recurrent attacks, UC is often resistant to traditional anti-inflammatory therapies, imposing significant physiological, psychological, and economic burdens on patients. In light of these challenges, innovative targeted therapies have become a new expectation for patients with UC. A crucial pathological feature of UC is the impairment of the intestinal mucosal barrier, which underlies aberrant immune responses and inflammation. Intestinal stem cells (ISCs), which differentiate into intestinal epithelial cells, play a central role in maintaining this barrier. Growing studies have proved that regulating the regeneration and differentiation of ISC is a promising approach to treating UC. Despite this progress, there is a dearth of comprehensive articles describing the role of ISCs in UC. This review focuses on the importance of ISCs in maintaining the intestinal mucosal barrier in UC and discusses the latest findings on ISC functions, markers, and their regulatory mechanisms. Key pathways involved in ISC regulation, including the Wnt, Notch, Hedgehog (HH), Hippo/Yap, and autophagy pathways, are explored in detail. Additionally, this review examines recent advances in ISC-targeted therapies for UC, such as natural or synthetic compounds, microbial preparations, traditional Chinese medicine (TCM) extracts and compounds, and transplantation therapy. This review aims to offer novel therapeutic insights and strategies for patients who have long struggled with UC.
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Affiliation(s)
- Siqing Chen
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Zhang Qin
- The Fourth Hospital of Changsha (Changsha Hospital Affiliated with Hunan Normal University), Changsha, Hunan, China
| | - Sainan Zhou
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Yin Xu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Ying Zhu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
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Giordano A, Rovira M, Veny M, Barastegui R, Marín P, Martínez C, Fernández-Avilés F, Suárez-Lledó M, Domènech A, Serrahima A, Lozano M, Cid J, Ordás I, Fernández-Clotet A, Caballol B, Gallego M, Vara A, Masamunt MC, Giner À, Teubel I, Esteller M, Corraliza AM, Panés J, Salas A, Ricart E. Cyclophosphamide-free Mobilisation Increases Safety While Preserving the Efficacy of Autologous Haematopoietic Stem Cell Transplantation in Refractory Crohn's Disease Patients. J Crohns Colitis 2024; 18:1701-1712. [PMID: 38757210 DOI: 10.1093/ecco-jcc/jjae076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 05/07/2024] [Accepted: 05/16/2024] [Indexed: 05/18/2024]
Abstract
BACKGROUND AND AIM Autologous haematopoietic stem cell transplantation [AHSCT] is a therapeutic option for refractory Crohn's disease [CD]. However, high adverse event rates related to chemotherapy toxicity and immunosuppression limit its applicability. This study aims to evaluate AHSCT's safety and efficacy using a cyclophosphamide [Cy]-free mobilisation regimen. METHODS A prospective, observational study included 14 refractory CD patients undergoing AHSCT between June 2017 and October 2022. The protocol involved outpatient mobilisation with G-CSF 12-16 μg/kg/daily for 5 days, and optional Plerixafor 240 μg/d [1-2 doses] if the CD34 + cell count target was unmet. Standard conditioning with Cy and anti-thymocyte globulin was administered. Clinical, endoscopic, and radiological assessments were conducted at baseline and during follow-up. RESULTS All patients achieved successful outpatient mobilisation [seven patients needed Plerixafor] and underwent transplantation. Median follow-up was 106 weeks (interquartile range [IQR] 52-348). No mobilisation-related serious adverse events [SAEs] or CD worsening occurred. Clinical and endoscopic remission rates were 71% and 41.7% at 26 weeks, 64% and 25% at 52 weeks, and 71% and 16.7% at the last follow-up, respectively. The percentage of patients who restarted CD therapy for clinical relapse and/or endoscopic/radiological activity was 14% at 26 weeks, 57% at 52 weeks, and 86% at the last follow-up, respectively. Peripheral blood cell populations and antibody levels post-AHSCT were comparable to Cy-based mobilisation. CONCLUSIONS Cy-free mobilisation is safe and feasible in refractory CD patients undergoing AHSCT. Although relapse occurs in a significant proportion of patients, clinical and endoscopic responses are achieved upon CD-specific therapy reintroduction.
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Affiliation(s)
- Antonio Giordano
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Montserrat Rovira
- Bone Marrow Transplantation Unit, Haematology Department, Institute of Haematology and Oncology Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], University of Barcelona, Josep Carreras Leukaemia Research Foundation, Barcelona, Catalonia, Spain
| | - Marisol Veny
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Rebeca Barastegui
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Pedro Marín
- Bone Marrow Transplantation Unit, Haematology Department, Institute of Haematology and Oncology Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], University of Barcelona, Josep Carreras Leukaemia Research Foundation, Barcelona, Catalonia, Spain
| | - Carmen Martínez
- Bone Marrow Transplantation Unit, Haematology Department, Institute of Haematology and Oncology Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], University of Barcelona, Josep Carreras Leukaemia Research Foundation, Barcelona, Catalonia, Spain
| | - Francesc Fernández-Avilés
- Bone Marrow Transplantation Unit, Haematology Department, Institute of Haematology and Oncology Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], University of Barcelona, Josep Carreras Leukaemia Research Foundation, Barcelona, Catalonia, Spain
| | - María Suárez-Lledó
- Bone Marrow Transplantation Unit, Haematology Department, Institute of Haematology and Oncology Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], University of Barcelona, Josep Carreras Leukaemia Research Foundation, Barcelona, Catalonia, Spain
| | - Ariadna Domènech
- Bone Marrow Transplantation Unit, Haematology Department, Institute of Haematology and Oncology Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], University of Barcelona, Josep Carreras Leukaemia Research Foundation, Barcelona, Catalonia, Spain
| | - Anna Serrahima
- Bone Marrow Transplantation Unit, Haematology Department, Institute of Haematology and Oncology Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], University of Barcelona, Josep Carreras Leukaemia Research Foundation, Barcelona, Catalonia, Spain
| | - Miquel Lozano
- Apheresis Unit, Department of Hemotherapy and Hemostasis, ICAMS, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Catalonia, Spain
| | - Joan Cid
- Apheresis Unit, Department of Hemotherapy and Hemostasis, ICAMS, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Catalonia, Spain
| | - Ingrid Ordás
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Agnés Fernández-Clotet
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Berta Caballol
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Marta Gallego
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Alejandro Vara
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Maria Carme Masamunt
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Àngel Giner
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Iris Teubel
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Miriam Esteller
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Anna María Corraliza
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Julian Panés
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Azucena Salas
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Elena Ricart
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
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Smith B, Smith H, Machini M. Novel Pharmaceuticals and Therapeutics for Tumor Necrosis Factor-Alpha-Resistant Crohn's Disease: A Narrative Review. Cureus 2024; 16:e65357. [PMID: 39184689 PMCID: PMC11344558 DOI: 10.7759/cureus.65357] [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] [Received: 05/20/2024] [Accepted: 07/24/2024] [Indexed: 08/27/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a medical condition that causes persistent, relapsing inflammation of the gastrointestinal tract. It is an umbrella term encompassing two different conditions: ulcerative colitis (UC) and Crohn's disease (CD). The standard treatment for patients with moderate to severe CD is tumor necrosis factor-α (TNF-α) inhibitors; however, a subset of CD patients face challenges in regard to this disease's treatment. Certain populations of patients with CD may exhibit resistance or develop tolerance to TNF-α inhibitor therapy over time. The recurrent gastrointestinal inflammation associated with CD can severely impact the quality of life and lead to complications for those suffering from this condition. The symptomatic flare-ups these subpopulations continue to experience underscores why such a need for alternative therapies is desperately needed. These alternative therapies not only offer potential benefits for those with TNF-α resistance, but CD may also serve as a superior therapy option for those trying to avoid the adverse effects of CD treatments available today. This review aims to explore and investigate the novel drugs and therapies that are being investigated for the treatment of TNF-α resistant CD, such as upadacitinib, risankizumab, vedolizumab, synbiotics, fecal microbiota transplantation (FMT), and stem cell therapy. Upadacitinib is a Janus kinase inhibitor, Risankizumab is a monoclonal antibody targeting interleukin-23, and Vedolizumab is an integrin receptor antagonist. The latest advancements in CD management have shown encouraging results. Some of these novel drugs and therapies not only offer a potential solution for CD patients exhibiting resistance to TNF-α inhibitors but may also provide a superior alternative for individuals prone to opportunistic infections.
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Affiliation(s)
- Blake Smith
- Medical School, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA
| | - Haylie Smith
- Medical School, Edward Via College of Osteopathic Medicine, Spartanburg, USA
| | - Matthew Machini
- Foundational Sciences, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Clearwater, USA
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Guisado D, Talware S, Wang X, Davis A, Fozilov E, Etra A, Colombel JF, Schaniel C, Tastad C, Levine JE, Ferrara JLM, Chuang LS, Sabic K, Singh S, Marcellino BK, Hoffman R, Cho J, Cohen LJ. The reparative immunologic consequences of stem cell transplantation as a cellular therapy for refractory Crohn's disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.30.596699. [PMID: 38895305 PMCID: PMC11185544 DOI: 10.1101/2024.05.30.596699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Background Treatment strategies for Crohn's disease (CD) suppress diverse inflammatory pathways but many patients remain refractory to treatment. Autologous hematopoietic stem cell transplantation (SCT) has emerged as a therapy for medically refractory CD. SCT was developed to rescue cancer patients from myelosuppressive chemotherapy but its use for CD and other immune diseases necessitates reimagining SCT as a cellular therapy that restores appropriately responsive immune cell populations from hematopoietic progenitors in the stem cell autograft (i.e. immune "reset"). Here we present a paradigm to understand SCT as a cellular therapy for immune diseases and reveal how SCT re-establishes cellular immunity utilizing high-dimensional cellular phenotyping and functional studies of the stem cell grafts. Methods Immunophenotyping using CyTOF, single cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) sequencing was performed on peripheral blood and intestinal tissue samples from refractory CD patients who underwent SCT. The stem cell graft from these patients was analyzed using flow cytometry and functionally interrogated using a murine model for engraftment. Results Our study revealed a remodeling of intestinal macrophages capable of supporting mucosal healing that was independently validated using multimodal studies of immune reconstitution events including CyTOF and scRNA-seq. Functional interrogation of hematopoietic stem cells (HSCs) using a xenograft model demonstrated that HSCs shape the timing of immune reconstitution, the selected reconstitution of specific cell lineages and potentially the clinical efficacy of SCT. Conclusions These studies indicate that SCT serves as a myeloid-directed cellular therapy re-establishing homeostatic intestinal macrophages that support intestinal healing and suggest refractory CD evolves from impairment of restorative functions in myeloid cells. Furthermore, we report heterogeneity among HSCs from CD patients which may drive SCT outcomes and suggests an unrecognized impact of CD pathophysiology on HSC in the marrow niche.
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Gupta A, Guisado D, Ricart E, Colombel JF, Cohen L. Haematopoietic stem-cell transplantation in Crohn's disease. Lancet Gastroenterol Hepatol 2024; 9:499-500. [PMID: 38734002 DOI: 10.1016/s2468-1253(24)00055-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 02/26/2024] [Indexed: 05/13/2024]
Affiliation(s)
- Akshita Gupta
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA
| | - Daniela Guisado
- Division of Pediatric Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA
| | - Elena Ricart
- Hospital Clinic de Barcelona, Gastroenterology Department, Barcelona, Spain
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA
| | - Louis Cohen
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA.
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Lindsay JO, Hind D, Swaby L, Berntsson H, Bradburn M, Bannur C U, Byrne J, Clarke C, Desoysa L, Dickins B, Din S, Emsley R, Foulds GA, Gribben J, Hawkey C, Irving PM, Kazmi M, Lee E, Loban A, Lobo A, Mahida Y, Moran GW, Papaioannou D, Parkes M, Peniket A, Pockley AG, Satsangi J, Subramanian S, Travis S, Turton E, Uttenthal B, Rutella S, Snowden JA. Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol 2024; 9:333-345. [PMID: 38340759 DOI: 10.1016/s2468-1253(23)00460-0] [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] [Received: 11/18/2023] [Revised: 12/20/2023] [Accepted: 12/20/2023] [Indexed: 02/12/2024]
Abstract
BACKGROUND A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population. METHODS This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m2 with granulocyte colony-stimulating factor (G-CSF) 5 μg/kg) and stem-cell harvest (minimum 2·0 × 106 CD34+ cells per kg), before conditioning (fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. FINDINGS Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure. INTERPRETATION Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease. FUNDING Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.
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Affiliation(s)
- James O Lindsay
- Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
| | - Daniel Hind
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - Lizzie Swaby
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - Hannah Berntsson
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - Mike Bradburn
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - Uday Bannur C
- Department of Radiology, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Jennifer Byrne
- Department of Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Christopher Clarke
- Department of Radiology, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Lauren Desoysa
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - Ben Dickins
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Shahida Din
- Department of Gastroenterology, Western General Hospital, Edinburgh, UK
| | - Richard Emsley
- Department of Biostatistics & Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Gemma A Foulds
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - John Gribben
- Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Christopher Hawkey
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK; Translational Medical Sciences, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
| | - Peter M Irving
- Department of Gastroenterology, Guy's and Saint Thomas' Hospitals NHS Trust, London, UK
| | - Majid Kazmi
- King's College Hospital NHS Foundation Trust, London, UK
| | - Ellen Lee
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - Amanda Loban
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - Alan Lobo
- Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Yashwant Mahida
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK; Translational Medical Sciences, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
| | - Gordon W Moran
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK; Translational Medical Sciences, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
| | - Diana Papaioannou
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - Miles Parkes
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Andrew Peniket
- Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - A Graham Pockley
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Jack Satsangi
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
| | | | - Simon Travis
- NIHR Biomedical Research Centre, Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, University of Oxford, Oxford, UK
| | - Emily Turton
- Sheffield Clinical Trials Research Unit, University of Sheffield, Sheffield, UK
| | - Ben Uttenthal
- Department of Clinical Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Sergio Rutella
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - John A Snowden
- Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK; Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Rhudy CN, Perry CL, Hawk GS, Flomenhoft DR, Talbert JC, Barrett TA. Inflammatory Bowel Disease in Appalachian Kentucky: An Investigation of Outcomes and Health Care Utilization. Inflamm Bowel Dis 2024; 30:410-422. [PMID: 37280118 PMCID: PMC10906357 DOI: 10.1093/ibd/izad096] [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: 09/29/2022] [Indexed: 06/08/2023]
Abstract
BACKGROUND Rural residence has been associated with a lower incidence of inflammatory bowel disease (IBD) but higher health care utilization and worse outcomes. Socioeconomic status is intrinsically tied to both IBD incidence and outcomes. Inflammatory bowel disease outcomes have not been investigated in Appalachia: a rural, economically distressed region rife with risk factors for both increased incidence and unfavorable outcomes. METHODS Hospital inpatient discharge and outpatient services databases were utilized to assess outcomes in patients diagnosed with either Crohn's disease (CD) or ulcerative colitis (UC) in Kentucky. Encounters were classified by patient residence in Appalachian or non-Appalachian counties. Data were reported as crude and age-adjusted rates of visits per 100,000 population per year collected in 2016 to 2019. National inpatient discharge data from 2019, stratified by rural and urban classification codes, were utilized to compare Kentucky to national trends. RESULTS Crude and age-adjusted rates of inpatient, emergency department and outpatient encounters were higher in the Appalachian cohort for all 4 years observed. Appalachian inpatient encounters are more frequently associated with a surgical procedure (Appalachian, 676, 24.7% vs non-Appalachian, 1408, 22.2%; P = .0091). In 2019, the Kentucky Appalachian cohort had significantly higher crude and age-adjusted rates of inpatient discharges for all IBD diagnoses compared with national rural and nonrural populations (crude 55.2; 95% CI, 50.9-59.5; age-adjusted 56.7; 95% CI, 52.1-61.3). CONCLUSIONS There is disproportionately higher IBD health care utilization in Appalachian Kentucky compared with all cohorts, including the national rural population. There is a need for aggressive investigation into root causes of these disparate outcomes and identification of barriers to appropriate IBD care.
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Affiliation(s)
- Christian N Rhudy
- University of Kentucky Healthcare, Specialty Pharmacy and Infusion Services, Lexington, Kentucky, USA
| | - Courtney L Perry
- University of Kentucky College of Medicine, Department of Medicine, Division of Digestive Diseases and Nutrition, Lexington, Kentucky, USA
- University of Kentucky Healthcare, Specialty Pharmacy and Infusion Services, Lexington, Kentucky, USA
| | - Gregory S Hawk
- University of Kentucky, Dr. Bing Zhang Department of Statistics, Lexington, Kentucky, USA
| | - Deborah R Flomenhoft
- University of Kentucky College of Medicine, Department of Medicine, Division of Digestive Diseases and Nutrition, Lexington, Kentucky, USA
| | - Jeffery C Talbert
- University of Kentucky College of Medicine, Division of Biomedical Informatics, Lexington, Kentucky, USA
| | - Terrence A Barrett
- University of Kentucky College of Medicine, Department of Medicine, Division of Digestive Diseases and Nutrition, Lexington, Kentucky, USA
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9
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McDonald GB, Landsverk OJ, McGovern DP, Aasebø A, Paulsen V, Haritunians T, Reims HM, McLaughlin BM, Zisman T, Li D, Elholm ET, Jahnsen FL, Georges GE, Gedde-Dahl T. Allogeneic bone marrow transplantation for patients with treatment-refractory Crohn's Disease. Heliyon 2024; 10:e24026. [PMID: 38283244 PMCID: PMC10818189 DOI: 10.1016/j.heliyon.2024.e24026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/16/2023] [Accepted: 01/02/2024] [Indexed: 01/30/2024] Open
Abstract
Background & aims Durable remissions of Crohn's Disease (CD) have followed myeloablative conditioning therapy and allogeneic marrow transplantation. For patients with treatment-refractory disease, we used reduced-intensity conditioning to minimize toxicity, marrow from donors with low Polygenic Risk Scores for CD as cell sources, and protracted immune suppression to lower the risk of graft-versus-host disease (GVHD). Our aim was to achieve durable CD remissions while minimizing transplant-related complications. Methods DNA from patients and their HLA-matched unrelated donors was genotyped and Polygenic Risk Scores calculated. Donor marrow was infused following non-myeloablative conditioning. Patient symptoms and endoscopic findings were documented at intervals after transplant. Results We screened 807 patients, 143 of whom met eligibility criteria; 2 patients received allografts. Patient 1 had multiple complications and died at day 332 from respiratory failure. Patient 2 had resolution of CD symptoms until day 178 when CD recurred, associated with persistent host chimerism in both peripheral blood and intestinal mucosa. Withdrawal of immune suppression was followed by dominant donor immune chimerism in peripheral blood and resolution of CD findings. Over time, mucosal T-cells became donor-dominant. At 5 years after allografting, Patient 2 remained off all medications but had mild symptoms related to a jejunal stricture that required stricturoplasty at 6 years. At 8 years, she remains stable off medications. Conclusions The kinetics of immunologic chimerism after allogeneic marrow transplantation for CD patients depends on the intensity of the conditioning regimen and the magnitude of immune suppression. One patient achieved durable improvement of her previously refractory CD only after establishing donor immunologic chimerism in intestinal mucosa. Her course provides proof-of-principal for allografting as a potential treatment for refractory CD, but an immunoablative conditioning regimen should be considered for future studies.(ClinicalTrials.gov, NCT01570348).
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Affiliation(s)
- George B. McDonald
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
- Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | | | - Dermot P.B. McGovern
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Anders Aasebø
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Vemund Paulsen
- Department of Transplantation Medicine, Section of Gastroenterology, Oslo University Hospital Rikshospitalet, Norway
| | - Talin Haritunians
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Henrik M. Reims
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | | | - Timothy Zisman
- Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Dalin Li
- F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Elisabeth T.M.M. Elholm
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
- Department of Hematology, Oslo University Hospital, Norway and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Frode L. Jahnsen
- Department of Pathology, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Norway
| | - George E. Georges
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
- Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Tobias Gedde-Dahl
- Department of Hematology, Oslo University Hospital, Norway and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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10
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Kumar A, Smith PJ. Horizon scanning: new and future therapies in the management of inflammatory bowel disease. EGASTROENTEROLOGY 2023; 1:e100012. [PMID: 39944001 PMCID: PMC11731077 DOI: 10.1136/egastro-2023-100012] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 09/15/2023] [Indexed: 01/02/2025]
Abstract
The current mainstay treatment modalities for inflammatory bowel disease (IBD) include immunomodulators (methotrexate and thiopurines), biologics (antitumour necrosis factor alpha (TNF-α) being the most commonly used) and other monoclonal antibodies such as the anti-integrins and anti-interleukins (IL-12/23). While ideally treatment should be initiated early in the disease process to avoid relapses and complications, the major recurring issue continues to be primary and secondary loss of response, with often 'diminishing returns' in terms of efficacy for the next line of therapies prescribed for patients with IBD. Additional concerns include the long-term risk factors such as malignancy and susceptibility to infections. Recently, there has been an influx of new and emerging medications entering the market that are showing promising efficacy results in patients with moderate-to-severe disease who have previously failed to respond to multiple drugs. This review will focus on these novel and emerging therapies-in essence, 'horizon scanning'-which includes the antiadhesion agents, cytokine inhibitors, Janus kinase inhibitors, phosphodiesterase inhibitors, sphingosine-1 phosphate receptor modulators and MicroRNA-124 (miR-124) upregulators.
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Affiliation(s)
- Aditi Kumar
- Department of Gastroenterology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Philip J Smith
- Department of Gastroenterology, Royal Liverpool Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
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11
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Li S, Xu K, Cheng Y, Chen L, Yi A, Xiao Z, Zhao X, Chen M, Tian Y, Meng W, Tang Z, Zhou S, Ruan G, Wei Y. The role of complex interactions between the intestinal flora and host in regulating intestinal homeostasis and inflammatory bowel disease. Front Microbiol 2023; 14:1188455. [PMID: 37389342 PMCID: PMC10303177 DOI: 10.3389/fmicb.2023.1188455] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/10/2023] [Indexed: 07/01/2023] Open
Abstract
Pharmacological treatment of inflammatory bowel disease (IBD) is inefficient and difficult to discontinue appropriately, and enterobacterial interactions are expected to provide a new target for the treatment of IBD. We collected recent studies on the enterobacterial interactions among the host, enterobacteria, and their metabolite products and discuss potential therapeutic options. Intestinal flora interactions in IBD are affected in the reduced bacterial diversity, impact the immune system and are influenced by multiple factors such as host genetics and diet. Enterobacterial metabolites such as SCFAs, bile acids, and tryptophan also play important roles in enterobacterial interactions, especially in the progression of IBD. Therapeutically, a wide range of sources of probiotics and prebiotics exhibit potential therapeutic benefit in IBD through enterobacterial interactions, and some have gained wide recognition as adjuvant drugs. Different dietary patterns and foods, especially functional foods, are novel therapeutic modalities that distinguish pro-and prebiotics from traditional medications. Combined studies with food science may significantly improve the therapeutic experience of patients with IBD. In this review, we provide a brief overview of the role of enterobacteria and their metabolites in enterobacterial interactions, discuss the advantages and disadvantages of the potential therapeutic options derived from such metabolites, and postulate directions for further research.
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Affiliation(s)
- Siyu Li
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
- Basic Medicine College of Army Medical University, Army Medical University, Chongqing, China
| | - Kan Xu
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
- Basic Medicine College of Army Medical University, Army Medical University, Chongqing, China
| | - Yi Cheng
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Lu Chen
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ailin Yi
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Zhifeng Xiao
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xuefei Zhao
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Minjia Chen
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yuting Tian
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Wei Meng
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Zongyuan Tang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Shuhong Zhou
- Department of Laboratory Animal Center, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Guangcong Ruan
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yanling Wei
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
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12
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Tian CM, Zhang Y, Yang MF, Xu HM, Zhu MZ, Yao J, Wang LS, Liang YJ, Li DF. Stem Cell Therapy in Inflammatory Bowel Disease: A Review of Achievements and Challenges. J Inflamm Res 2023; 16:2089-2119. [PMID: 37215379 PMCID: PMC10199681 DOI: 10.2147/jir.s400447] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 05/03/2023] [Indexed: 05/24/2023] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory diseases of the gastrointestinal tract. Repeated inflammation can lead to complications, such as intestinal fistula, obstruction, perforation, and bleeding. Unfortunately, achieving durable remission and mucosal healing (MH) with current treatments is difficult. Stem cells (SCs) have the potential to modulate immunity, suppress inflammation, and have anti-apoptotic and pro-angiogenic effects, making them an ideal therapeutic strategy to target chronic inflammation and intestinal damage in IBD. In recent years, hematopoietic stem cells (HSCs) and adult mesenchymal stem cells (MSCs) have shown efficacy in treating IBD. In addition, numerous clinical trials have evaluated the efficiency of MSCs in treating the disease. This review summarizes the current research progress on the safety and efficacy of SC-based therapy for IBD in both preclinical models and clinical trials. We discuss potential mechanisms of SC therapy, including tissue repair, paracrine effects, and the promotion of angiogenesis, immune regulation, and anti-inflammatory effects. We also summarize current SC engineering strategies aimed at enhancing the immunosuppressive and regenerative capabilities of SCs for treating intestinal diseases. Additionally, we highlight current limitations and future perspectives of SC-related therapy for IBD.
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Affiliation(s)
- Cheng-Mei Tian
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
- Department of Emergency, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, Guangdong, People’s Republic of China
| | - Mei-Feng Yang
- Department of Hematology, Yantian District People’s Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Hao-Ming Xu
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China
| | - Min-Zheng Zhu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Li-Sheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Yu-Jie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - De-Feng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
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13
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Maria ATJ, Campidelli A, Castilla-Llorente C, Lansiaux P, Marjanovic Z, Pugnet G, Torregrosa-Diaz JM, Terriou L, Algayres JP, Urbain F, Yakoub-Agha I, Farge D. [Vaccination before and after autologous hematopoietic cell transplantation for autoimmune diseases: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (MATHEC-SFGM-TC)]. Bull Cancer 2023; 110:S97-S107. [PMID: 36658011 DOI: 10.1016/j.bulcan.2022.11.005] [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: 06/24/2022] [Revised: 11/16/2022] [Accepted: 11/16/2022] [Indexed: 01/18/2023]
Abstract
The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 12th workshop on hematopoietic stem cell transplantation clinical practices harmonization procedures on September 2021 in Lille, France. In the absence of specific national or international recommendation, the French working group for autologous stem Cell transplantation in Auto-immune Diseases (MATHEC) proposed guidances for vaccinations of patients undergoing autologous hematopoietic stem cell transplantation for autoimmune disease, including in the context of SARS-Cov-2 pandemic.
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Affiliation(s)
- Alexandre Thibault Jacques Maria
- Médecine Interne & Immuno-Oncologie (MedI2O), Institute for Regenerative Medicine & Biotherapy (IRMB), Hôpital Saint Eloi, CHU de Montpellier, 80 avenue Augustin Fliche, Montpellier, France; IRMB, Inserm U1183, Hôpital Saint-Eloi, CHU de Montpellier, 34295, Montpellier, France
| | - Arnaud Campidelli
- CHRU Nancy, Service Hématologie Adulte, 54500 Vandoeuvre-lès-Nancy, France
| | - Cristina Castilla-Llorente
- Gustave Roussy Cancer Campus, Département d́Hématologie, 114 rue Edouard Vaillant, 94800 Villejuif, France
| | - Pauline Lansiaux
- Centre de Référence des Maladies auto-immunes systémiques Rares d'Ile-de-France MATHEC (FAI2R), AP-HP, Hôpital St-Louis, Unité de Médecine Interne: Maladies Auto-immunes et Pathologie Vasculaire (UF 04), 75010 Paris, France; Université de Paris Cité, Institut de recherche Saint Louis, Recherche clinique appliquée à l'hématologie, EA3518, 75010 Paris, France
| | - Zora Marjanovic
- Hôpital Saint Antoine (APHP), Service d'Hématologie et Thérapie cellulaire, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France
| | - Grégory Pugnet
- CHU Rangueil, Service de Médecine Interne et Immunologie Clinique, 1 avenue du Pr Jean Poulhès, 31059 Toulouse Cedex 9, France
| | | | - Louis Terriou
- Hôpital Claude Huriez, CHRU Lille, Service de médecine interne et immunologie clinique, rue Michel Polonovski, 59000 Lille, France
| | - Jean-Pierre Algayres
- Centre de Référence des Maladies auto-immunes systémiques Rares d'Ile-de-France MATHEC (FAI2R), AP-HP, Hôpital St-Louis, Unité de Médecine Interne: Maladies Auto-immunes et Pathologie Vasculaire (UF 04), 75010 Paris, France
| | - Fanny Urbain
- Hôpital Bicêtre, Groupe Hospitalier Universitaire Paris Sud, Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne et Immunologie Clinique, 94275 Le Kremlin-Bicêtre cedex, France; Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France
| | | | - Dominique Farge
- Centre de Référence des Maladies auto-immunes systémiques Rares d'Ile-de-France MATHEC (FAI2R), AP-HP, Hôpital St-Louis, Unité de Médecine Interne: Maladies Auto-immunes et Pathologie Vasculaire (UF 04), 75010 Paris, France; Université de Paris Cité, Institut de recherche Saint Louis, Recherche clinique appliquée à l'hématologie, EA3518, 75010 Paris, France; McGill University, Department of Medicine, H3A 1A1, Montreal, Canada.
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14
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Reider S, Binder L, Fürst S, Hatzl S, Blesl A. Hematopoietic Stem Cell Transplantation in Refractory Crohn's Disease: Should It Be Considered? Cells 2022; 11:3463. [PMID: 36359859 PMCID: PMC9656531 DOI: 10.3390/cells11213463] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 10/29/2022] [Accepted: 10/31/2022] [Indexed: 08/06/2023] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) is widely used in benign and malignant hematological diseases. During the last decade, HSCT, mainly autologous, also gained increasing attention in the treatment of refractory autoimmune diseases. Crohn's disease (CD) is an inflammatory bowel disease leading to transmural inflammation potentially affecting all parts of the luminal gastrointestinal tract. Despite improving therapeutic options, including various biologics, some patients are refractory to all lines of available conservative therapy, leading to increased morbidity and reduced quality of life. Apart from surgery, HSCT might be a reasonable treatment alternative for refractory CD patients. This review aims to describe the current role of HSCT in CD and discusses the procedure, the correct patient selection, the clinical efficacy from initial remission to following relapse rates, and complications of this treatment.
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Affiliation(s)
- Simon Reider
- Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University Linz, 4020 Linz, Austria
- Department of Internal Medicine 2 (Gastroenterology and Hepatology), Faculty of Medicine, Kepler University Hospital, Johannes Kepler University, 4020 Linz, Austria
| | - Lukas Binder
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Stefan Fürst
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Stefan Hatzl
- Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
- Division of Hematology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Andreas Blesl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
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15
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Hoang DM, Pham PT, Bach TQ, Ngo ATL, Nguyen QT, Phan TTK, Nguyen GH, Le PTT, Hoang VT, Forsyth NR, Heke M, Nguyen LT. Stem cell-based therapy for human diseases. Signal Transduct Target Ther 2022; 7:272. [PMID: 35933430 PMCID: PMC9357075 DOI: 10.1038/s41392-022-01134-4] [Citation(s) in RCA: 432] [Impact Index Per Article: 144.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 02/07/2023] Open
Abstract
Recent advancements in stem cell technology open a new door for patients suffering from diseases and disorders that have yet to be treated. Stem cell-based therapy, including human pluripotent stem cells (hPSCs) and multipotent mesenchymal stem cells (MSCs), has recently emerged as a key player in regenerative medicine. hPSCs are defined as self-renewable cell types conferring the ability to differentiate into various cellular phenotypes of the human body, including three germ layers. MSCs are multipotent progenitor cells possessing self-renewal ability (limited in vitro) and differentiation potential into mesenchymal lineages, according to the International Society for Cell and Gene Therapy (ISCT). This review provides an update on recent clinical applications using either hPSCs or MSCs derived from bone marrow (BM), adipose tissue (AT), or the umbilical cord (UC) for the treatment of human diseases, including neurological disorders, pulmonary dysfunctions, metabolic/endocrine-related diseases, reproductive disorders, skin burns, and cardiovascular conditions. Moreover, we discuss our own clinical trial experiences on targeted therapies using MSCs in a clinical setting, and we propose and discuss the MSC tissue origin concept and how MSC origin may contribute to the role of MSCs in downstream applications, with the ultimate objective of facilitating translational research in regenerative medicine into clinical applications. The mechanisms discussed here support the proposed hypothesis that BM-MSCs are potentially good candidates for brain and spinal cord injury treatment, AT-MSCs are potentially good candidates for reproductive disorder treatment and skin regeneration, and UC-MSCs are potentially good candidates for pulmonary disease and acute respiratory distress syndrome treatment.
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Affiliation(s)
- Duc M Hoang
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam.
| | - Phuong T Pham
- Department of Cellular Therapy, Vinmec High-Tech Center, Vinmec Healthcare System, Hanoi, Vietnam
| | - Trung Q Bach
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Anh T L Ngo
- Department of Cellular Therapy, Vinmec High-Tech Center, Vinmec Healthcare System, Hanoi, Vietnam
| | - Quyen T Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Trang T K Phan
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Giang H Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Phuong T T Le
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Van T Hoang
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Nicholas R Forsyth
- Institute for Science & Technology in Medicine, Keele University, Keele, UK
| | - Michael Heke
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Liem Thanh Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
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16
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Zhang HM, Yuan S, Meng H, Hou XT, Li J, Xue JC, Li Y, Wang Q, Nan JX, Jin XJ, Zhang QG. Stem Cell-Based Therapies for Inflammatory Bowel Disease. Int J Mol Sci 2022; 23:8494. [PMID: 35955628 PMCID: PMC9368934 DOI: 10.3390/ijms23158494] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 11/23/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, relapsing disease that severely affects patients' quality of life. The exact cause of IBD is uncertain, but current studies suggest that abnormal activation of the immune system, genetic susceptibility, and altered intestinal flora due to mucosal barrier defects may play an essential role in the pathogenesis of IBD. Unfortunately, IBD is currently difficult to be wholly cured. Thus, more treatment options are needed for different patients. Stem cell therapy, mainly including hematopoietic stem cell therapy and mesenchymal stem cell therapy, has shown the potential to improve the clinical disease activity of patients when conventional treatments are not effective. Stem cell therapy, an emerging therapy for IBD, can alleviate mucosal inflammation through mechanisms such as immunomodulation and colonization repair. Clinical studies have confirmed the effectiveness of stem cell transplantation in refractory IBD and the ability to maintain long-term remission in some patients. However, stem cell therapy is still in the research stage, and its safety and long-term efficacy remain to be further evaluated. This article reviews the upcoming stem cell transplantation methods for clinical application and the results of ongoing clinical trials to provide ideas for the clinical use of stem cell transplantation as a potential treatment for IBD.
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Affiliation(s)
- Hua-Min Zhang
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, China; (H.-M.Z.); (S.Y.); (J.-X.N.)
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Shuo Yuan
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, China; (H.-M.Z.); (S.Y.); (J.-X.N.)
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Huan Meng
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Xiao-Ting Hou
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Jiao Li
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
- Department of Immunology and Pathogenic Biology, College of Basic Medicine, Yanbian University, Yanji 133002, China
| | - Jia-Chen Xue
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
- Department of Immunology and Pathogenic Biology, College of Basic Medicine, Yanbian University, Yanji 133002, China
| | - You Li
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Qi Wang
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Ji-Xing Nan
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, China; (H.-M.Z.); (S.Y.); (J.-X.N.)
| | - Xue-Jun Jin
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, China; (H.-M.Z.); (S.Y.); (J.-X.N.)
| | - Qing-Gao Zhang
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
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Achini-Gutzwiller FR, Snowden JA, Corbacioglu S, Greco R. Haematopoietic stem cell transplantation for severe autoimmune diseases in children: A review of current literature, registry activity and future directions on behalf of the autoimmune diseases and paediatric diseases working parties of the European Society for Blood and Marrow Transplantation. Br J Haematol 2022; 198:24-45. [PMID: 37655707 DOI: 10.1111/bjh.18176] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 03/14/2022] [Accepted: 03/18/2022] [Indexed: 11/27/2022]
Abstract
Although modern clinical management strategies have improved the outcome of paediatric patients with severe autoimmune and inflammatory diseases over recent decades, a proportion will experience ongoing or recurrent/relapsing disease activity despite multiple therapies often leading to irreversible organ damage, and compromised quality of life, growth/development and long-term survival. Autologous and allogeneic haematopoietic stem cell transplantation (HSCT) have been used successfully to induce disease control and often apparent cure of severe treatment-refractory autoimmune diseases (ADs) in children. However, transplant-related outcomes are disease-dependent and long-term outcome data are limited in respect to efficacy and safety. Moreover, balancing risks of HSCT against AD prognosis with continually evolving non-transplant options is challenging. This review appraises published literature on HSCT strategies and outcomes in individual paediatric ADs. We also provide a summary of the European Society for Blood and Marrow Transplantation (EBMT) Registry, where 343 HSCT procedures (176 autologous and 167 allogeneic) have been reported in 326 children (<18 years) for a range of AD indications. HSCT is a promising treatment modality, with potential long-term disease control or cure, but therapy-related morbidity and mortality need to be reduced. Further research is warranted to establish the position of HSCT in paediatric ADs via registries and prospective clinical studies to support evidence-based interspeciality guidelines and recommendations.
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Affiliation(s)
- Federica R Achini-Gutzwiller
- Division of Paediatric Stem Cell Transplantation and Haematology, Children's Research Centre (CRC), University Children's Hospital of Zurich, Zurich, Switzerland
| | - John A Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK
| | - Selim Corbacioglu
- Department of Paediatric Oncology, Haematology and Stem Cell Transplantation, University Children's Hospital Regensburg, Regensburg, Germany
| | - Raffaella Greco
- Unit of Haematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
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El-Nakeep S, Shawky A, Abbas SF, Abdel Latif O. Stem cell transplantation for induction of remission in medically refractory Crohn's disease. Cochrane Database Syst Rev 2022; 5:CD013070. [PMID: 35556242 PMCID: PMC9099217 DOI: 10.1002/14651858.cd013070.pub2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND Crohn's disease (CD) is an inflammatory bowel disease that causes inflammation and stricture, of any part of the mucosa and the gut wall. It forms skip lesions, sparing the areas in between the affected parts of the gastrointestinal tract. Crohn's disease could have one of three complications; fistula, intestinal obstruction due to stricture, or gastrointestinal inflammation presenting as severe diarrhoea. Stem cell therapy (SCT) is an innovative treatment that has been recently used in CD. The exact role of SCT in CD is still unclear. Stem cells modify the immunity of the patients or act as a "reset tool" for the immune system as in the case of systemically-injected stem cells, or regenerate the affected area of necrotic and inflammatory tissue as in the case of local injection into the lesion. Stem cells are a wide variety of cells including pluripotent stem cells or differentiated stem cells. The hazards range from rejection to symptomatic manifestations as fever or increase infection. OBJECTIVES: The objective of this Cochrane systematic review is to assess the effects of stem cell transplantation compared to standard of care alone or with placebo on efficacy and safety outcomes in patients with refractory CD. SEARCH METHODS We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and clinical trial registries (Clinicaltrials.gov, World Health Organization-International Clinical Trials Registry Platform WHO ICTRP) from inception to 19 March 2021, without any language, publication year, or publication status restrictions. In addition, we searched references of included studies and review articles for further references. An update of the published studies was done during the writing of the review. SELECTION CRITERIA We included only randomised controlled trials (RCTs) that assessed the effectiveness and safety of SCT in refractory CD versus standard care alone (control) or with placebo. DATA COLLECTION AND ANALYSIS Two review authors (SEN and SFA) independently screened the studies retrieved from the search results for inclusion, extracted data and assessed the risk of bias. Any disagreement was resolved through a consensus between the authors. We used standard methodological procedures expected by Cochrane. MAIN RESULTS We conducted our search on 19 March 2021 and identified 639 records. We added two records by a manual search of the published reviews on the topic to a total of 641 records. The Covidence program removed 125 duplicates making a total of 516 reports. Two review authors (SEN and SFA) screened titles and abstracts and excluded 451 records with the remaining 65 for full-text records screened independently by the two authors; only 18 studies were considered for inclusion. We included seven RCTs with a total of 442 participants for the meta-analysis. The intervention group included 234 patients, and the control group included 208 patients. Nine trials are ongoing and, two abstracts are awaiting classification. All patients in the control and intervention groups received the standard therapy for CD. Only three studies used blinding methods for the control group in the form of a placebo, with one study of the three stated that the blinding method was inefficient. The patients and personnel were aware of the intervention in the rest of the four studies as they were open-label trials. However, the effect of unblinding was balanced by the low risk of detection bias in five of the included studies. The evidence is uncertain about the effect of SCT on achieving clinical remission as compared to control/placebo (risk ratio (RR) 1.88, 95% Confidence Interval (CI) 0.80 to 4.41; 3 studies; low-certainty evidence). The evidence is very uncertain about the effect of SCT on achieving Crohn's Disease Activity Index (CDAI) <150 at 24 weeks compared to control (RR1.02 95% CI 0.67 to 1.56; 4 studies; very-low certainty evidence). SCT is likely to achieve fistula closure as compared to the control/placebo both in the short term (RR 1.48, 95% CI 1.12 to 1.96); low-certainty evidence) and in the long term (RR 1.42, 95% CI 1.09 to 1.87; 4 studies; low-certainty evidence) follow-up. The evidence is very uncertain about the effect of SCT to cause no difference in the number of total adverse events as compared to the control/placebo (RR 0.99, 95% CI [0.88 to 1.13); 4 studies; very-low-certainty evidence). However, SCT is likely to increase the number of serious adverse events as compared to the control/placebo (RR 1.22, 95% CI 0.88 to 1.67; 7 studies; low-certainty evidence). The evidence is very uncertain about the effect of SCT to decrease the withdrawal due to adverse events as compared to the control/placebo (RR 0.78, 95% CI 0.32 to 1.89; 3 studies; very-low certainty evidence). Funding by pharmaceutical companies was found in three studies, with one including more than 50% of our studied population. AUTHORS' CONCLUSIONS SCT shows an uncertain effect on clinical remission with low certainty of evidence. SCT shows an uncertain effect on CDAI score to reach <150 after 24 weeks of treatment, with very low certainty evidence. SCT shows beneficial effects on fistula-closure during short and long-term follow-up with low-certainty evidence in both outcomes. There was no change in the total number of adverse events with SCT as compared to control, with very low certainty evidence. While there was a moderate effect on increasing the number of serious adverse events in the SCT group, as compared to the control with low-certainty evidence. Withdrawal due to adverse events was slightly higher in the control group with very low certainty evidence. All the participants were refractory to standard medical treatment, but the number of participants was small, this may limit the generalizability of the results. Further research is needed for validation. More objective outcomes are needed in the assessment of stem cell effectiveness in the treatment of Crohn's disease, especially the intestinal CD subtype; with standardization of the dose, methods of stem cell preparation, route of administration, and inclusion criteria to the studies to achieve clear results.
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Affiliation(s)
- Sarah El-Nakeep
- Gastroenterology and Hepatology Unit, Internal Medicine Department , Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ahmed Shawky
- Gastroenterology and Hepatology Unit, Internal Medicine Department , Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Sara F Abbas
- Extended Medical Program, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Osama Abdel Latif
- Allergy and Clinical Immunology Unit, Internal Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Binienda A, Ziolkowska S, Hauge IH, Salaga M. The Role of Immune and Epithelial Stem Cells in Inflammatory Bowel Disease Therapy. Curr Drug Targets 2021; 21:1405-1416. [PMID: 32364073 DOI: 10.2174/1389450121666200504074922] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 01/17/2020] [Accepted: 03/27/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Inflammatory Bowel Disease (IBD) is categorized as Crohn's disease (CD) and Ulcerative colitis (UC) and is characterized by chronic inflammation in the gastrointestinal (GI) tract. Relapsing symptoms, including abdominal pain, increased stool frequency, loss of appetite as well as anemia contribute to significant deterioration of quality of life. IBD treatment encompasses chemotherapy (e.g. corticosteroids, thiopurines) and biological agents (e.g. antibodies targeting tumour necrosis factor α, interleukin 12/23) and surgery. However, efficacy of these therapies is not satisfactory. Thus, scientists are looking for new options in IBD treatment that could induce and maintain remission. OBJECTIVE To summarize previous knowledge about role of different intestinal cells in IBD pathophysiology and application of stem cells in the IBD treatment. RESULTS Recent studies have emphasized an important role of innate lymphoid cells (ILCs) as well as intestinal epithelial cells (IECs) in the IBD pathophysiology suggesting that these types of cells can be new targets for IBD treatment. Moreover, last studies show that stem cells transplantation reduces inflammation in patients suffering from IBD, which are resistant to conventional therapies. CONCLUSION Both hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are able to restore damaged tissue and regulate the immune system. Autologous HSCs transplantation eliminates autoreactive cells and replace them with new T-cells resulting a long-time remission. Whereas MSCs transplantation is effective therapy in one of the major complications of IBD, perianal fistulas.
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Affiliation(s)
- Agata Binienda
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland
| | - Sylwia Ziolkowska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland
| | - Ingvild H Hauge
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland
| | - Maciej Salaga
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland
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Misselwitz B, Juillerat P, Sulz MC, Siegmund B, Brand S. Emerging Treatment Options in Inflammatory Bowel Disease: Janus Kinases, Stem Cells, and More. Digestion 2021; 101 Suppl 1:69-82. [PMID: 32570252 DOI: 10.1159/000507782] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 04/07/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Treatment of inflammatory bowel diseases (IBD) has tremendously improved during the last 20 years; however, a substantial fraction of patients does not respond to available therapies or lose response, and new strategies are needed. SUMMARY Two pharmacological principles have been successfully used for IBD treatment: inhibition of cellular signaling and interference with leukocyte trafficking. Besides tumor necrosis factor, interleukin (IL)-23 is a promising drug target, and antibodies for the combined inhibition of IL-23 and IL-12 (ustekinumab and briakinumab) or selective IL-23 inhibition (brazikumab, risankizumab, and mirikizumab) seem to be effective in Crohn's disease (CD) with emerging evidence also for ulcerative colitis (UC). Janus kinase (JAK) mediates intracellular signaling of a large number of cytokines. Tofacitinib is the first JAK inhibitor approved for UC, and the JAK inhibitors filgotinib and upadacitinib showed potential in CD. Leukocyte trafficking can be inhibited by interference with lymphocyte integrin-α4β7 or endothelial MadCAM-1. The α4β7 integrin inhibitor vedolizumab is an established treatment in IBD, and long-term data of pivotal studies are now available. Additional molecules with therapeutic potential are α4β7-specific abrilumab, β7-specific etrolizumab, and the α4-specific small molecule AJM300. PF-00547659, an antibody against endothelial MadCAM-1, also showed therapeutic potential in UC. Modulation of sphingosine-1-phosphate receptor (S1PR) activity is necessary for the egress of lymphocytes into the circulation, and S1PR modulation results in lymphocyte trapping in lymphatic organs. Ozanimod, an S1PR1 and S1PR5 inhibitor, has been successfully tested in initial studies in UC. Mesenchymal stem cell therapy has been approved for the treatment of complex, active CD fistula, and mesenchymal stem cell therapy might be a paradigm shift for this condition. Autologous stem cell transplantation (ASCT) has been successfully used in CD case series; however, in a randomized trial, a highly stringent endpoint was not met. However, considering positive effects in secondary endpoints, ASCT might be a future treatment of last resort in severe, refractory CD cases, provided that safer protocols can be provided. Key messages: New IBD treatments are successful for a significant fraction of patients. However, new strategies for patient selection, treatment combinations, and/or additional therapies must be developed to serve the need of all IBD patients.
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Affiliation(s)
- Benjamin Misselwitz
- Gastroenterology, Department of Visceral Surgery and Medicine, Inselspital Bern and Bern University, Bern, Switzerland,
| | - Pascal Juillerat
- Gastroenterology, Department of Visceral Surgery and Medicine, Inselspital Bern and Bern University, Bern, Switzerland
| | - Michael Christian Sulz
- Department of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Britta Siegmund
- Medical Department (Gastroenterology, Infectious Diseases, Rheumatology), Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Stephan Brand
- Department of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
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21
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Wang R, Yao Q, Chen W, Gao F, Li P, Wu J, Yu J, Cao H. Stem cell therapy for Crohn's disease: systematic review and meta-analysis of preclinical and clinical studies. Stem Cell Res Ther 2021; 12:463. [PMID: 34407875 PMCID: PMC8375136 DOI: 10.1186/s13287-021-02533-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
Background We explored whether stem cell therapy was effective for animal models and patients with Crohn’s disease (CD). Methods We searched five online databases. The relative outcomes were analyzed with the aid of GetData Graph Digitizer 2.26 and Stata 16.0 software. The SYRCLE risk of bias tool and the MINORS tool were used to assess study quality. Results We evaluated 46 studies including 28 animal works (n = 567) and 18 human trials (n = 360). In the animal studies, the disease activity index dramatically decreased in the mesenchymal stem cell (MSC) treatment groups compared to the control group. Rats and mice receiving MSCs exhibited longer colons [mice: standardized mean difference (SMD) 2.84, P = 0.000; rats: SMD 1.44, P = 0.029], lower histopathological scores (mice: SMD − 4.58, p = 0.000; rats: SMD − 1.41, P = 0.000) and lower myeloperoxidase levels (SMD − 6.22, P = 0.000). In clinical trials, stem cell transplantation reduced the CD activity index (SMD − 2.10, P = 0.000), the CD endoscopic index of severity (SMD − 3.40, P = 0.000) and simplified endoscopy score for CD (SMD − 1.71, P = 0.000) and improved the inflammatory bowel disease questionnaire score (SMD 1.33, P = 0.305) compared to control values. CD patients maintained high remission rates for 3–24 months after transplantation. Conclusions Stem cell transplantation is a valuable supplementary therapy for CD. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02533-0.
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Affiliation(s)
- Ruo Wang
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China.,National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Qigu Yao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China.,National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Wenyi Chen
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China.,National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Feiqiong Gao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China.,National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Pan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China.,National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Jian Wu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China.,National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China.,National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China. .,National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China. .,Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
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22
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Functional recovery by colon organoid transplantation in a mouse model of radiation proctitis. Biomaterials 2021; 275:120925. [PMID: 34171755 DOI: 10.1016/j.biomaterials.2021.120925] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 05/19/2021] [Accepted: 05/24/2021] [Indexed: 01/04/2023]
Abstract
Radiation proctitis is the collateral damage that occurs to healthy cells during radiation treatment of pelvic malignancies. Conservative treatment of radiation proctitis can mitigate inflammatory symptoms, but, to date, no therapeutic options are available for direct recovery of the damaged colonic epithelium. The present study assessed the ability of colon organoid-based regeneration to treat radiation proctitis. Radiation proctitis was induced in mice by irradiating their recta, followed by enema-based transplantation of mouse colon organoids. The transplanted colon organoids were found to successfully engraft onto the damaged rectal mucosa of the irradiated mice, reconstituting epithelial structure and integrity. Lgr5+ stem cells were shown to be pivotal to colon organoid mediated regeneration. Endoscopic examination showed the efficacy of localized transplantation of colon organoids with fibrin glue to irradiated sites. These findings provide useful insights into the use of colon organoid-based regenerative therapy for the treatment of radiation proctitis.
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23
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Koutroumpakis F, Phillips AE, Yadav D, Machicado JD, Ahsan M, Ramos Rivers C, Tan X, Schwartz M, Proksell S, Johnston E, Dueker J, Hashash JG, Barrie A, Harrison J, Dunn MA, Konnikova L, Hartman DJ, Din H, Babichenko D, Tang G, Binion DG. Serum IgG4 Subclass Deficiency Defines a Distinct, Commonly Encountered, Severe Inflammatory Bowel Disease Subtype. Inflamm Bowel Dis 2021; 27:855-863. [PMID: 32879976 DOI: 10.1093/ibd/izaa230] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Immunoglobulin G subclass 4 (IgG4) is hypothesized to play an immunomodulatory role, downregulating humoral immune responses. The role of this anti-inflammatory molecule in inflammatory bowel disease (IBD) has not been fully characterized. We sought to define alterations in serum IgG4 in patients with IBD and their association with multiyear disease severity. METHODS We analyzed metadata derived from curated electronic health records from consented patients with IBD prospectively followed at a tertiary center over a 10-year time period. Patients with IBD with IgG4 serum levels available formed the study population. Demographics and multiyear clinical data were collected and analyzed. We stratified patients with IBD with low, normal, or high serum IgG4 levels. RESULTS We found IgG4 characterized in 1193 patients with IBD and low IgG4 levels in 233 patients (20%) and elevated IgG4 levels in 61 patients (5%). An IgG4 deficiency did not significantly correlate with other antibody deficiencies. In a multiple Poisson regression analysis, low IgG4 was associated with more years on biologic agents (P = 0.002) and steroids (P = 0.049) and more hospital admissions (P < 0.001), clinic visits (P = 0.010), outpatient antibiotic prescriptions (P < 0.001), and CD-related surgeries (P = 0.011) during the study period after controlling for certain confounders. Elevated IgG4 was only associated with primary sclerosing cholangitis (P = 0.011). A cohort of patients with IgG4-deficient severe IBD received intravenous Ig replacement therapy, which benefited and was continued in 10 out of 11 individuals. CONCLUSIONS An IgG4 subclass deficiency, distinct from other antibody deficiencies, occurred commonly in a referral IBD population and was associated with multiple markers of disease severity. This is the first association of IgG4 subclass deficiency with an inflammatory disease process. Further work is needed to define the mechanistic role of IgG4 deficiency in this severe IBD subgroup.
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Affiliation(s)
- Filippos Koutroumpakis
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Anna Evans Phillips
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Dhiraj Yadav
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Jorge D Machicado
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic Health System, Eau Claire, Wisconsin, United States
| | - Maaz Ahsan
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Claudia Ramos Rivers
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Xiaoqing Tan
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
| | - Marc Schwartz
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Siobhan Proksell
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Elyse Johnston
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Jeffrey Dueker
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Jana G Hashash
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Arthur Barrie
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Janet Harrison
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Michael A Dunn
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Liza Konnikova
- Department of Pediatrics, Division of Newborn Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Douglas J Hartman
- Department of Pathology, Division of Anatomic Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Hasieb Din
- Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Dmitriy Babichenko
- School of Information Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
| | - Gong Tang
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
| | - David G Binion
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
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Hou Q, Huang J, Ayansola H, Masatoshi H, Zhang B. Intestinal Stem Cells and Immune Cell Relationships: Potential Therapeutic Targets for Inflammatory Bowel Diseases. Front Immunol 2021; 11:623691. [PMID: 33584726 PMCID: PMC7874163 DOI: 10.3389/fimmu.2020.623691] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/03/2020] [Indexed: 12/11/2022] Open
Abstract
The mammalian intestine is the largest immune organ that contains the intestinal stem cells (ISC), differentiated epithelial cells (enterocytes, Paneth cells, goblet cells, tuft cells, etc.), and gut resident-immune cells (T cells, B cells, dendritic cells, innate lymphoid cell, etc.). Inflammatory bowel disease (IBD), a chronic inflammatory disease characterized by mucosa damage and inflammation, threatens the integrity of the intestine. The continuous renewal and repair of intestinal mucosal epithelium after injury depend on ISCs. Inflamed mucosa healing could be a new target for the improvement of clinical symptoms, disease recurrence, and resection-free survival in IBD treated patients. The knowledge about the connections between ISC and immune cells is expanding with the development of in vitro intestinal organoid culture and single-cell RNA sequencing technology. Recent findings implicate that immune cells such as T cells, ILCs, dendritic cells, and macrophages and cytokines secreted by these cells are critical in the regeneration of ISCs and intestinal epithelium. Transplantation of ISC to the inflamed mucosa may be a new therapeutic approach to reconstruct the epithelial barrier in IBD. Considering the links between ISC and immune cells, we predict that the integration of biological agents and ISC transplantation will revolutionize the future therapy of IBD patients.
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Affiliation(s)
- Qihang Hou
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition & Feed Science, College of Animal Science & Technology, China Agricultural University, Haidian District, Beijing, China
| | - Jingxi Huang
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition & Feed Science, College of Animal Science & Technology, China Agricultural University, Haidian District, Beijing, China
| | - Hammed Ayansola
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition & Feed Science, College of Animal Science & Technology, China Agricultural University, Haidian District, Beijing, China
| | - Hori Masatoshi
- Department of Veterinary Pharmacology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Bingkun Zhang
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition & Feed Science, College of Animal Science & Technology, China Agricultural University, Haidian District, Beijing, China
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Oliveira MC, Elias JB, Moraes DAD, Simões BP, Rodrigues M, Ribeiro AAF, Piron-Ruiz L, Ruiz MA, Hamerschlak N. A review of hematopoietic stem cell transplantation for autoimmune diseases: multiple sclerosis, systemic sclerosis and Crohn's disease. Position paper of the Brazilian Society of Bone Marrow Transplantation. Hematol Transfus Cell Ther 2021; 43:65-86. [PMID: 32418777 PMCID: PMC7910166 DOI: 10.1016/j.htct.2020.03.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 03/19/2020] [Accepted: 03/23/2020] [Indexed: 12/16/2022] Open
Abstract
Autoimmune diseases are an important field for the development of bone marrow transplantation, or hematopoietic stem cell transplantation. In Europe alone, almost 3000 procedures have been registered so far. The Brazilian Society for Bone Marrow Transplantation (Sociedade Brasileira de Transplantes de Medula Óssea) organized consensus meetings for the Autoimmune Diseases Group, to review the available literature on hematopoietic stem cell transplantation for autoimmune diseases, aiming to gather data that support the procedure for these patients. Three autoimmune diseases for which there are evidence-based indications for hematopoietic stem cell transplantation are multiple sclerosis, systemic sclerosis and Crohn's disease. The professional stem cell transplant societies in America, Europe and Brazil (Sociedade Brasileira de Transplantes de Medula Óssea) currently consider hematopoietic stem cell transplantation as a therapeutic modality for these three autoimmune diseases. This article reviews the evidence available.
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Affiliation(s)
- Maria Carolina Oliveira
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil
| | - Juliana Bernardes Elias
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil
| | | | - Belinda Pinto Simões
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil
| | | | | | - Lilian Piron-Ruiz
- Associação Portuguesa de Beneficência de São José do Rio Preto, São José do Rio Preto, SP, Brazil
| | - Milton Arthur Ruiz
- Associação Portuguesa de Beneficência de São José do Rio Preto, São José do Rio Preto, SP, Brazil
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Indications de l’autogreffe de cellules hématopoïétiques dans la Maladie de Crohn : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire. Bull Cancer 2020; 107:S140-S150. [DOI: 10.1016/j.bulcan.2020.08.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 08/25/2020] [Accepted: 08/29/2020] [Indexed: 01/25/2023]
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CELL THERAPY IN INFLAMMATORY BOWEL DISEASE. Pharmacol Res 2020; 163:105247. [PMID: 33069755 DOI: 10.1016/j.phrs.2020.105247] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 10/06/2020] [Accepted: 10/07/2020] [Indexed: 12/14/2022]
Abstract
In recent years, cell-based therapies have been explored in various immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD). Cell therapy is the process of introducing new cells into an organism or tissue in order to treat a disease. The most studied cellular treatment in IBD was "stem cells-based therapy", which was explored according to different protocols in terms of type of donors, stem cells sources, study design and clinical endpoints. More recently, preliminary studies have also described the clinical use of "regulatory cells", which include T-reg and Tr1 cells, and "tolerogenic" dendritic cells. Finally, induced pluripotent stem cells are the subject of an intensive preclinical research program on animal models, including those related to colitis.
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Development of Colonic Organoids Containing Enteric Nerves or Blood Vessels from Human Embryonic Stem Cells. Cells 2020; 9:cells9102209. [PMID: 33003541 PMCID: PMC7600593 DOI: 10.3390/cells9102209] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023] Open
Abstract
The increased interest in organoid research in recent years has contributed to an improved understanding of diseases that are currently untreatable. Various organoids, including kidney, brain, retina, liver, and spinal cord, have been successfully developed and serve as potential sources for regenerative medicine studies. However, the application of organoids has been limited by their lack of tissue components such as nerve and blood vessels that are essential to organ physiology. In this study, we used three-dimensional co-culture methods to develop colonic organoids that contained enteric nerves and blood vessels. The development of enteric nerves and blood vessels was confirmed phenotypically and genetically by the use of immunofluorescent staining and Western blotting. Colonic organoids that contain essential tissue components could serve as a useful model for the study of colon diseases and help to overcome current bottlenecks in colon disease research.
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A pilot feasibility study of non-myeloablative allogeneic hematopoietic stem cell transplantation for refractory Crohn Disease. Bone Marrow Transplant 2020; 55:2343-2346. [PMID: 32467584 DOI: 10.1038/s41409-020-0953-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/05/2020] [Accepted: 05/14/2020] [Indexed: 01/21/2023]
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Okamoto R, Shimizu H, Suzuki K, Kawamoto A, Takahashi J, Kawai M, Nagata S, Hiraguri Y, Takeoka S, Sugihara HY, Yui S, Watanabe M. Organoid-based regenerative medicine for inflammatory bowel disease. Regen Ther 2020; 13:1-6. [PMID: 31970266 PMCID: PMC6961757 DOI: 10.1016/j.reth.2019.11.004] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/08/2019] [Accepted: 11/21/2019] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) consists of two major idiopathic gastrointestinal diseases: ulcerative colitis and Crohn's disease. Although a significant advance has been achieved in the treatment of IBD, there remains a particular population of patients that are refractory to the conventional treatments, including the biologic agents. Studies have revealed the importance of "mucosal healing" in improving the prognosis of those difficult-to-treat patients, which indicates the proper and complete regeneration of the damaged intestinal tissue. In this regard, organoid-based regenerative medicine may have the potential to dramatically promote the achievement of mucosal healing in refractory IBD patients, and thereby improve their long-term prognosis as well. So far, studies have shown that hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) may have some beneficial effect on IBD patients through their transplantation or transfusion. Recent advance in stem cell biology has added intestinal stem cells (ISCs) as a new player in this field. It has been shown that ISCs can be grown in vitro as organoids and that those ex-vivo cultured organoids can be employed as donor cells for transplantation studies. Further studies using mice colitis models have shown that ex-vivo cultured organoids can engraft onto the colitic ulcers and reconstruct the crypt-villus structures. Such transplantation of organoids may not only facilitate the regeneration of the refractory ulcers that may persist in IBD patients but may also reduce the risk of developing colitis-associated cancers. Endoscopy-assisted transplantation of organoids may, therefore, become one of the alternative therapies for refractory IBD patients.
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Affiliation(s)
- Ryuichi Okamoto
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hiromichi Shimizu
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kohei Suzuki
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Ami Kawamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Junichi Takahashi
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Mao Kawai
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Sayaka Nagata
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yui Hiraguri
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Sayaka Takeoka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hady Yuki Sugihara
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Shiro Yui
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Mamoru Watanabe
- Institute of Advanced Study, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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Qi D, Shi W, Black AR, Kuss MA, Pang X, He Y, Liu B, Duan B. Repair and regeneration of small intestine: A review of current engineering approaches. Biomaterials 2020; 240:119832. [PMID: 32113114 DOI: 10.1016/j.biomaterials.2020.119832] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 01/21/2020] [Accepted: 01/25/2020] [Indexed: 02/06/2023]
Abstract
The small intestine (SI) is difficult to regenerate or reconstruct due to its complex structure and functions. Recent developments in stem cell research, advanced engineering technologies, and regenerative medicine strategies bring new hope of solving clinical problems of the SI. This review will first summarize the structure, function, development, cell types, and matrix components of the SI. Then, the major cell sources for SI regeneration are introduced, and state-of-the-art biofabrication technologies for generating engineered SI tissues or models are overviewed. Furthermore, in vitro models and in vivo transplantation, based on intestinal organoids and tissue engineering, are highlighted. Finally, current challenges and future perspectives are discussed to help direct future applications for SI repair and regeneration.
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Affiliation(s)
- Dianjun Qi
- Department of General Practice, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China; Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA; Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Wen Shi
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA; Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Adrian R Black
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
| | - Mitchell A Kuss
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA; Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Xining Pang
- Department of General Practice, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China; Department of Academician Expert Workstation and Liaoning Province Human Amniotic Membrane Dressings Stem Cells and Regenerative Medicine Engineering Research Center, Shenyang Amnion Biological Engineering Technology Research and Development Center Co., Ltd, Shenyang, Liaoning, China
| | - Yini He
- Department of General Practice, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Bing Liu
- Department of Anorectal Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Bin Duan
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, USA; Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Department of Surgery, University of Nebraska Medical Center, Omaha, NE, USA; Department of Mechanical and Materials Engineering, University of Nebraska-Lincoln, Lincoln, NE, USA.
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32
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Song X, Li J, Wang Y, Zhou C, Zhang Z, Shen M, Xiang P, Zhang X, Zhao H, Yu L, Zuo L, Hu J. Clematichinenoside AR ameliorated spontaneous colitis in Il-10 -/- mice associated with improving the intestinal barrier function and abnormal immune responses. Life Sci 2019; 239:117021. [PMID: 31678552 DOI: 10.1016/j.lfs.2019.117021] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 10/21/2019] [Accepted: 10/26/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Clematichinenoside AR (AR) is a saponin extracted for traditional Chinese medicine with the effects of improving the expression of tight junction (TJ) proteins and mediating anti-inflammatory activities. However, its effect on Crohn's disease (CD) is still unknown. We aimed to investigate the impact of AR on CD-like colitis and determine the mechanism underlying its effects. METHODS Interleukin-10 gene knockout (Il-10-/-) mice (male, fifteen weeks old) with spontaneous colitis were allocated to the positive control and AR-treated (32 mg/kg AR administered every other day by gavage for 4 weeks) groups. Wild-type (WT) mice (male, fifteen weeks old) composed the negative control group. The effects of AR on intestinal barrier function and structure and T cell responses as well as the potential mechanisms underlying these effects were investigated. RESULTS AR treatment significantly improved spontaneous colitis in Il-10-/- mice as demonstrated by reductions in the inflammatory score, disease activity index (DAI) and levels of inflammatory factors. The effects of AR on colitis in Il-10-/- mice were related to protecting intestinal barrier function and maintaining immune system homeostasis (regulatory T cell (Treg)/T helper 17 (Th17) cell balance). The anticolitis effect of AR may partly act by downregulating PI3K/Akt signaling. CONCLUSIONS AR may have therapeutic potential for treating CD in humans.
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Affiliation(s)
- Xue Song
- Department of Central Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China; Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical College, Bengbu, China
| | - Jing Li
- Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical College, Bengbu, China; Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Yan Wang
- Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical College, Bengbu, China; Department of Clinical Medicine, Bengbu Medical College, Bengbu, China
| | - Changmin Zhou
- Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical College, Bengbu, China; Department of Clinical Medicine, Bengbu Medical College, Bengbu, China
| | - Zhichao Zhang
- Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical College, Bengbu, China; Department of Clinical Medicine, Bengbu Medical College, Bengbu, China
| | - Mengdi Shen
- Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical College, Bengbu, China; Department of Clinical Medicine, Bengbu Medical College, Bengbu, China
| | - Ping Xiang
- Department of Central Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Xiaofeng Zhang
- Department of Central Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China; Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical College, Bengbu, China
| | - Hao Zhao
- Department of Central Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Liang Yu
- Department of Central Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Lugen Zuo
- Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical College, Bengbu, China; Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Jianguo Hu
- Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical College, Bengbu, China; Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, China.
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Is it time to use hematopoietic stem cell transplantation for severe and refractory crohn's disease? Hematol Transfus Cell Ther 2019; 42:190-191. [PMID: 31601485 PMCID: PMC7248492 DOI: 10.1016/j.htct.2019.06.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 05/23/2019] [Accepted: 06/10/2019] [Indexed: 12/14/2022] Open
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Kotla NG, Rana S, Sivaraman G, Sunnapu O, Vemula PK, Pandit A, Rochev Y. Bioresponsive drug delivery systems in intestinal inflammation: State-of-the-art and future perspectives. Adv Drug Deliv Rev 2019; 146:248-266. [PMID: 29966684 DOI: 10.1016/j.addr.2018.06.021] [Citation(s) in RCA: 142] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 05/27/2018] [Accepted: 06/25/2018] [Indexed: 02/07/2023]
Abstract
Oral colon-specific delivery systems emerged as the main therapeutic cargos by making a significant impact in the field of modern medicine for local drug delivery in intestinal inflammation. The site-specific delivery of therapeutics (aminosalicylates, glucocorticoids, biologics) to the ulcerative mucus tissue can provide prominent advantages in mucosal healing (MH). Attaining gut mucosal healing and anti-fibrosis are main treatment outcomes in inflammatory bowel disease (IBD). The pharmaceutical strategies that are commonly used to achieve a colon-specific drug delivery system include time, pH-dependent polymer coating, prodrug, colonic microbiota-activated delivery systems and a combination of these approaches. Amongst the different approaches reported, the use of biodegradable polysaccharide coated systems holds great promise in delivering drugs to the ulcerative regions. The present review focuses on major physiological gastro-intestinal tract challenges involved in altering the pharmacokinetics of delivery systems, pathophysiology of MH and fibrosis, reported drug-polysaccharide cargos and focusing on conventional to advanced disease responsive delivery strategies, highlighting their limitations and future perspectives in intestinal inflammation therapy.
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Affiliation(s)
- Niranjan G Kotla
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway, Newcastle, Galway, Ireland.
| | - Shubhasmin Rana
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway, Newcastle, Galway, Ireland
| | - Gandhi Sivaraman
- Institute for Stem Cell Biology and Regenerative Medicine, GKVK Campus, Bengaluru 560062, India
| | - Omprakash Sunnapu
- Institute for Stem Cell Biology and Regenerative Medicine, GKVK Campus, Bengaluru 560062, India
| | - Praveen K Vemula
- Institute for Stem Cell Biology and Regenerative Medicine, GKVK Campus, Bengaluru 560062, India
| | - Abhay Pandit
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway, Newcastle, Galway, Ireland
| | - Yury Rochev
- Centre for Research in Medical Devices (CÚRAM), National University of Ireland Galway, Newcastle, Galway, Ireland; Sechenov First Moscow State Medical University, Institute for Regenerative Medicine, Moscow, Russian Federation.
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Snowden JA, Hawkey C, Hind D, Swaby L, Mellor K, Emsley R, Mandefield L, Lee E, Badoglio M, Polge E, Labopin M, Gribben J, Pockley AG, Foulds GA, Lobo A, Travis S, Parkes M, Satsangi J, Papaioannou D, Lindsay JO. Autologous stem cell transplantation in refractory Crohn's disease - low intensity therapy evaluation (ASTIClite): study protocols for a multicentre, randomised controlled trial and observational follow up study. BMC Gastroenterol 2019; 19:82. [PMID: 31151436 PMCID: PMC6544952 DOI: 10.1186/s12876-019-0992-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 05/01/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Intestinal inflammation in Crohn's disease (CD) is caused by mucosal immune system reactivity to luminal antigen and results in debilitating symptoms, reduced quality of life, impaired work productivity and significant health care costs. Not all patients respond to conventional and biologic therapies, with chronic inflammation ensuing. Although surgical resection may be required, disease frequently returns and surgery may not be an option, or may be declined. Case reports suggest potential benefit after haematopoietic stem cell transplant (HSCT) for patients with refractory CD. The ASTIC trial asked whether HSCT could cure CD. Few patients achieved the primary endpoint of clinical remission for 3 months, off all medication with no evidence of active disease, and there were a high number of adverse events (AEs) and serious adverse events (SAEs), including one patient death. However, beneficial effects were observed in some aspects of disease activity. The ASTIClite trial will investigate these potential benefits and safety using a lower intensity regimen than ASTIC. METHODS Ninety-nine participants will be recruited from secondary care IBD centres in the UK into a multicentre, randomised controlled trial (RCT, ASTIClite) and an observational follow-up, and randomised to autologous HSCT versus standard care (ratio 2:1). The primary endpoint is treatment success at week 48, defined as mucosal healing without surgery or death. Secondary endpoints relating to efficacy, safety and mechanistic analyses will be evaluated at week 8, 14, 24, 32, 40 and 48. Long-term safety of the low intensity HSCT regimen forms the primary endpoint for the EBMT follow-up study and will be assessed annually for 4-7 years. DISCUSSION ASTIClite will compare HSCTlite with standard care with respect to safety, efficacy and quality of life, and capture outcomes allowing findings to be generalised to current clinical practice in the UK. It will also provide significant mechanistic insights into the immunological consequences of HSCTlite and its impact on treatment outcomes. The observational follow-up will provide information, which is currently unavailable for this population. TRIAL REGISTRATION The ASTIClite RCT was registered on 31st October 2017 ( ISRCTN17160440 ) and the EBMT follow-up study on 19th January 2018 ( ISRCTN31981313 ).
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Affiliation(s)
- John A Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK
| | - Chris Hawkey
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
| | - Daniel Hind
- Clinical Trials Research Unit, ScHARR, University of Sheffield, Sheffield, UK
| | - Lizzie Swaby
- Clinical Trials Research Unit, ScHARR, University of Sheffield, Sheffield, UK.
| | - Katie Mellor
- Clinical Trials Research Unit, ScHARR, University of Sheffield, Sheffield, UK
| | - Richard Emsley
- Department of Biostatistics & Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Laura Mandefield
- Clinical Trials Research Unit, ScHARR, University of Sheffield, Sheffield, UK
| | - Ellen Lee
- Clinical Trials Research Unit, ScHARR, University of Sheffield, Sheffield, UK
| | - Manuela Badoglio
- European Society for Blood and Marrow Transplantation, Paris, France
| | - Emmanuelle Polge
- European Society for Blood and Marrow Transplantation, Paris, France
| | - Myriam Labopin
- European Society for Blood and Marrow Transplantation, Paris, France
| | - John Gribben
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, UK
| | - A Graham Pockley
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Gemma A Foulds
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Alan Lobo
- Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK
| | - Simon Travis
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, OX3 9DU, UK
| | - Miles Parkes
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Jack Satsangi
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, OX3 9DU, UK
| | - Diana Papaioannou
- Clinical Trials Research Unit, ScHARR, University of Sheffield, Sheffield, UK
| | - James O Lindsay
- Centre for Immunobiology, Barts and the London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, UK
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Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients. Blood Adv 2019; 2:126-141. [PMID: 29365321 DOI: 10.1182/bloodadvances.2017011072] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 11/18/2017] [Indexed: 02/06/2023] Open
Abstract
To evaluate the immunological mechanisms associated with clinical outcomes after autologous hematopoietic stem cell transplantation (AHSCT), focusing on regulatory T- (Treg) and B- (Breg) cell immune reconstitution, 31 systemic sclerosis (SSc) patients underwent simultaneous clinical and immunological evaluations over 36-month posttransplantation follow-up. Patients were retrospectively grouped into responders (n = 25) and nonresponders (n = 6), according to clinical response after AHSCT. Thymic function and B-cell neogenesis were respectively assessed by quantification of DNA excision circles generated during T- and B-cell receptor rearrangements. At the 1-year post-AHSCT evaluation of the total set of transplanted SSc patients, thymic rebound led to renewal of the immune system, with higher T-cell receptor (TCR) diversity, positive correlation between recent thymic emigrant and Treg counts, and higher expression of CTLA-4 and GITR on Tregs, when compared with pretransplant levels. In parallel, increased bone marrow output of newly generated naive B-cells, starting at 6 months after AHSCT, renovated the B-cell populations in peripheral blood. At 6 and 12 months after AHSCT, Bregs increased and produced higher interleukin-10 levels than before transplant. When the nonresponder patients were evaluated separately, Treg and Breg counts did not increase after AHSCT, and high TCR repertoire overlap between pre- and posttransplant periods indicated maintenance of underlying disease mechanisms. These data suggest that clinical improvement of SSc patients is related to increased counts of newly generated Tregs and Bregs after AHSCT as a result of coordinated thymic and bone marrow rebound.
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Autologous hematopoietic stem cell transplantation in autoimmune diseases - a brand new standard. Where do we go from here? Reumatologia 2019; 57:307-308. [PMID: 32226162 PMCID: PMC7091487 DOI: 10.5114/reum.2019.90824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 11/29/2019] [Indexed: 11/27/2022] Open
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38
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Ashton JJ, Mossotto E, Ennis S, Beattie RM. Personalising medicine in inflammatory bowel disease-current and future perspectives. Transl Pediatr 2019; 8:56-69. [PMID: 30881899 PMCID: PMC6382508 DOI: 10.21037/tp.2018.12.03] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Up to 25% of inflammatory bowel disease (IBD) presents during childhood, often with severe and extensive disease, leading to significant morbidity including delayed growth and nutritional impairment. The classical approach to management has centred on differentiation into Crohn's disease (CD) or ulcerative colitis (UC), with subsequent treatment based on symptoms, results and complications. However, IBD is a heterogeneous condition with substantial variation in phenotype, disease course and outcome, so whilst effective treatment exists one size does not fit all. The ability to predict disease course at diagnosis, alongside tailoring medications based on response gives the potential for a more 'personalised approach'. The move to a pre-emptive strategy to prevent IBD-related complications, whilst simultaneously minimising side effects and long-term toxicity from therapy, particularly in those with relatively indolent disease, has the potential to revolutionise care. In very early-onset IBD, personalised approaches to diagnosis and management have become the standard of treatment enabling clinicians to significantly alter the outcomes of the few children with monogenic disease. However, the promise of discoveries in genomics, microbiome and transcriptomics in paediatric IBD has not yet translated to clinical application for the vast majority of patients. Despite this, the opportunity presents itself to apply data gathered at diagnosis and follow-up to predict which patients are likely to progress to complicated disease, which will respond well and which will require additional therapy. Using complex mathematics and innovative, cutting-edge machine learning (ML) techniques gives the potential to use this data to develop personalised clinical care algorithms to treat patients more effectively, reduce toxicity and improve outcome. In this review, we will consider current management of paediatric IBD, discuss how precision medicine is making inroads into clinical practice already, examine the contemporary studies applying data to stratify patients and explore how future management may be revolutionised by personalisation with clinical, genomic and other multi-omic data.
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Affiliation(s)
- James J Ashton
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK.,Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK
| | - Enrico Mossotto
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK.,NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
| | - Sarah Ennis
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK
| | - R Mark Beattie
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
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39
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Turse EP, Dailey FE, Naseer M, Partyka EK, Bragg JD, Tahan V. Stem cells for luminal, fistulizing, and perianal inflammatory bowel disease: a comprehensive updated review of the literature. STEM CELLS AND CLONING-ADVANCES AND APPLICATIONS 2018; 11:95-113. [PMID: 30568468 PMCID: PMC6267708 DOI: 10.2147/sccaa.s135414] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Much research has been performed over the last decade on stem cell therapy as treatment for patients with inflammatory bowel disease. Hematopoietic and mesenchymal stem cells, both allogeneic (from someone else) and autologous (from own patient), have been studied with safe and efficacious results in the majority of patients treated for luminal, perianal, and/or fistulizing disease. Here in this review, we highlight all human trials that have been conducted utilizing stem cell therapy treatment in patients with inflammatory bowel disease.
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Affiliation(s)
- Erica P Turse
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri Health Center, Columbia, MO 65212, USA,
| | - Francis E Dailey
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri Health Center, Columbia, MO 65212, USA,
| | - Maliha Naseer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri Health Center, Columbia, MO 65212, USA,
| | - Edward K Partyka
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri Health Center, Columbia, MO 65212, USA,
| | - Jack D Bragg
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri Health Center, Columbia, MO 65212, USA,
| | - Veysel Tahan
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri Health Center, Columbia, MO 65212, USA,
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40
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Malmegrim KCR, Lima-Júnior JR, Arruda LCM, de Azevedo JTC, de Oliveira GLV, Oliveira MC. Autologous Hematopoietic Stem Cell Transplantation for Autoimmune Diseases: From Mechanistic Insights to Biomarkers. Front Immunol 2018; 9:2602. [PMID: 30505303 PMCID: PMC6250746 DOI: 10.3389/fimmu.2018.02602] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 10/23/2018] [Indexed: 12/20/2022] Open
Abstract
Phase I/II clinical trials of autologous hematopoietic stem cell transplantation (AHSCT) have led to increased safety and efficacy of this therapy for severe and refractory autoimmune diseases (AD). Recent phase III randomized studies have demonstrated that AHSCT induces long-term disease remission in most patients without any further immunosuppression, with superior efficacy when compared to conventional treatments. Immune monitoring studies have revealed the regeneration of a self-tolerant T and B cell repertoire, enhancement of immune regulatory mechanisms, and changes toward an anti-inflammatory milieu in patients that are responsive to AHSCT. However, some patients reactivate the disease after transplantation due to reasons not yet completely understood. This scenario emphasizes that additional specific immunological interventions are still required to improve or sustain therapeutic efficacy of AHSCT in patients with AD. Here, we critically review the current knowledge about the operating immune mechanisms or established mechanistic biomarkers of AHSCT for AD. In addition, we suggest recommendations for future immune monitoring studies and biobanking to allow discovery and development of biomarkers. In our view, AHSCT for AD has entered a new era and researchers of this field should work to identify robust predictive, prognostic, treatment-response biomarkers and to establish new guidelines for immune monitoring studies and combined therapeutic interventions to further improve the AHSCT protocols and their therapeutic efficacy.
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Affiliation(s)
- Kelen Cristina Ribeiro Malmegrim
- Department of Clinical Analysis, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.,Center for Cell-based Therapy, Regional Hemotherapy Center of Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - João Rodrigues Lima-Júnior
- Center for Cell-based Therapy, Regional Hemotherapy Center of Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Biosciences Applied to Pharmacy Program, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Lucas Coelho Marlière Arruda
- Division of Rheumatology, Allergy, Immunology and Immunotherapy, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Júlia Teixeira Cottas de Azevedo
- Division of Rheumatology, Allergy, Immunology and Immunotherapy, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Basic and Applied Immunology Program, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Gislane Lelis Vilela de Oliveira
- São Paulo State University (UNESP), Institute of Biosciences, Humanities and Exact Sciences (IBILCE), São Jose do Rio Preto, São Paulo, Brazil
| | - Maria Carolina Oliveira
- Center for Cell-based Therapy, Regional Hemotherapy Center of Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Division of Rheumatology, Allergy, Immunology and Immunotherapy, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
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41
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Ruiz MA, Kaiser Junior RL, Piron-Ruiz L, Peña-Arciniegas T, Saran PS, De Quadros LG. Hematopoietic stem cell transplantation for Crohn's disease: Gaps, doubts and perspectives. World J Stem Cells 2018; 10:134-137. [PMID: 30397423 PMCID: PMC6212546 DOI: 10.4252/wjsc.v10.i10.134] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 08/15/2018] [Accepted: 08/28/2018] [Indexed: 02/07/2023] Open
Abstract
Crohn's disease (CD) is an inflammatory bowel disease that can affect any site of the digestive system. It occurs due to an immunological imbalance and is responsible for intestinal mucosal lesions and complications such as fistulas and stenoses. Treatment aims to stabilize the disease, reducing the symptoms and healing intestinal lesions. Surgical procedures are common in patients. Cell therapy was initially used to treat this disease in patients who also suffered from lymphoma and leukemia and were considered to be good candidates for autologous and allogeneic transplantation. After transplantation, an improvement was also observed in their CD. In 2003, the procedure began to be used to treat the disease itself, and several case series and randomized studies have been published since then; this approach currently comprises a new option in the treatment of CD. However, considerable doubt along with significant gaps in our knowledge continue to exist in relation to cell therapy for CD. Cell therapy is currently restricted to the autologous modality of hematopoietic stem cell transplantation and, experimentally, to mesenchymal stromal cells to directly treat lesions of the anal mucosa. This article presents the supporting claims for transplantation as well as aspects related to the mobilization regime, conditioning and perspectives of cell therapy.
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Affiliation(s)
- Milton Artur Ruiz
- Bone Marrow Transplant Department, Associação Portuguesa de Beneficência, São José do Rio Preto, SP 15090 470, Brazil.
| | - Roberto Luiz Kaiser Junior
- Bone Marrow Transplant Department, Associação Portuguesa de Beneficência, São José do Rio Preto, SP 15090 470, Brazil
| | - Lilian Piron-Ruiz
- Bone Marrow Transplant Department, Associação Portuguesa de Beneficência, São José do Rio Preto, SP 15090 470, Brazil
| | - Tatiana Peña-Arciniegas
- Bone Marrow Transplant Department, Associação Portuguesa de Beneficência, São José do Rio Preto, SP 15090 470, Brazil
| | - Priscila Samara Saran
- Bone Marrow Transplant Department, Associação Portuguesa de Beneficência, São José do Rio Preto, SP 15090 470, Brazil
| | - Luiz Gustavo De Quadros
- Bone Marrow Transplant Department, Associação Portuguesa de Beneficência, São José do Rio Preto, SP 15090 470, Brazil
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Hernanz N, Sierra M, Volpato N, Núñez-Gómez L, Mesonero F, Herrera-Puente P, García-Gutiérrez V, Albillos A, López-San Román A. Autologous haematopoietic stem cell transplantation in refractory Crohn's disease: Experience in our centre. GASTROENTEROLOGIA Y HEPATOLOGIA 2018; 42:16-22. [PMID: 30337206 DOI: 10.1016/j.gastrohep.2018.08.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 07/16/2018] [Accepted: 08/21/2018] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Autologous haematopoietic stem cell transplantation (AHSCT) is an accepted treatment in refractory Crohn's disease (CD). MATERIAL AND METHODS Data on patients with refractory CD subjected to AHSCT are collected at the Hospital Universitario Ramón y Cajal in Madrid and the results obtained are described retrospectively. RESULTS Seven patients in total have received AHSCT due to refractory CD in our centre. Three patients (43%) presented with clinical and endoscopic remission; one patient (14%) clinical improvement without remission and three patients (43%) remained active with the need to restart treatment in the assessment of the initial response to the AHSCT (after six months). Symptoms recurred in five of the seven patients (71%) and all of them had to restart medical treatment after an average of 13.8 months (range: 3-30 months). Only one patient needed surgery after the AHSCT. At the end of the follow-up, after a mean of 48 months (range: 17-78 months), 5/7 (71%) of the patients were in clinical remission with or without treatment. CONCLUSION AHSCT may be a promising therapeutic option for patients with refractory CD. Its usefulness lies in the fact that it can produce clinical remission without treatment in some patients, but also that it can make the disease treatable, obtaining a response to certain treatments in patients who had previously lost it.
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Affiliation(s)
- Nerea Hernanz
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España
| | - María Sierra
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España
| | - Nadja Volpato
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España
| | - Laura Núñez-Gómez
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España
| | - Francisco Mesonero
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España
| | | | | | - Agustín Albillos
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España
| | - Antonio López-San Román
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España.
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43
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Brierley CK, Castilla-Llorente C, Labopin M, Badoglio M, Rovira M, Ricart E, Dierickx D, Vermeire S, Hasselblatt P, Finke J, Onida F, Cassinotti A, Satsangi J, Kazmi M, López-Sanromán A, Schmidt C, Farge D, Travis SPL, Hawkey CJ, Snowden JA. Autologous Haematopoietic Stem Cell Transplantation for Crohn's Disease: A Retrospective Survey of Long-term Outcomes From the European Society for Blood and Marrow Transplantation. J Crohns Colitis 2018; 12:1097-1103. [PMID: 29788233 PMCID: PMC6113702 DOI: 10.1093/ecco-jcc/jjy069] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 04/05/2018] [Accepted: 05/15/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Autologous haematopoietic stem cell transplantation [AHSCT] is a therapeutic option for patients with severe, treatment-refractory Crohn's disease [CD]. The evidence base for AHSCT for CD is limited, with one randomised trial [ASTIC] suggesting benefit. The aim of this study was to evaluate safety and efficacy for patients undergoing AHSCT for CD in Europe, outside the ASTIC trial. METHODS We identified 99 patients in the European Society for Blood and Marrow Transplantation [EBMT] registry, who were eligible for inclusion. Transplant and clinical outcomes were obtained for 82 patients from 19 centres in seven countries. RESULTS Median patient age was 30 years [range 20-65]. Patients had failed or been intolerant to a median of six lines of drug therapy; 61/82 [74%] had had surgery. Following AHSCT, 53/78 [68%] experienced complete remission or significant improvement in symptoms at a median follow-up of 41 months [range 6-174]; 22/82 [27%] required no medical therapy at any point post-AHSCT. In patients who had re-started medical therapy at latest follow-up, 57% [24/42] achieved remission or significant symptomatic improvement with therapies to which they had previously lost response or been non-responsive. Treatment-free survival at 1 year was 54%. On multivariate analysis, perianal disease was associated with adverse treatment-free survival (hazard ratio 2.34, 95% confidence interval [CI] 1.14-4.83, p = 0.02). One patient died due to infectious complications [cytomegalovirus disease] at Day +56. CONCLUSIONS In this multicentre retrospective analysis of European centres, AHSCT was relatively safe and appeared to be effective in controlling otherwise treatment-resistant Crohn's disease. Further prospective randomised controlled trials against standard of care are warranted.
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Affiliation(s)
- Charlotte K Brierley
- Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK,Corresponding author: Dr Charlotte Brierley, MA, MRCP, Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford OX3 7LE, UK.
| | - Cristina Castilla-Llorente
- Unité de transplantation des cellules souches, Département d’Hématologie Gustave Roussy, Villejuif, France
| | - Myriam Labopin
- EBMT Paris Study Office, Department of Haematology, Université Pierre et Marie Curie, Saint Antoine Hospital, Paris, France
| | - Manuela Badoglio
- EBMT Paris Study Office, Department of Haematology, Université Pierre et Marie Curie, Saint Antoine Hospital, Paris, France
| | - Montserrat Rovira
- BMT Unit, Haematology Department, Hospital Clínic of Barcelona, IDIBAPS, Institut Josep Carreras, Barcelona, Spain
| | - Elena Ricart
- Gastroenterology Department, Hospital Clínic of Barcelona, CIBER-EHD, IDIBAPS, Barcelona, Spain
| | - Daan Dierickx
- Department of Haematology, University Hospitals Leuven, Leuven, Belgium
| | - Severine Vermeire
- Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
| | - Peter Hasselblatt
- Department of Medicine II, Medical Faculty and University Hospital Freiburg, Freiburg, Germany
| | - Juergen Finke
- Department of Hematology, Oncology and Stem Cell Transplantation, Medical Faculty and University Hospital Freiburg, Freiburg, Germany
| | - Francesco Onida
- Haematology - BMT Centre, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | | | - Jack Satsangi
- Gastro-intestinal Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, UK
| | - Majid Kazmi
- Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust and King’s College Hospital, London, UK
| | | | - Carsten Schmidt
- Department of Gastroenterology, Medizinische Klinik II, Klinikum Fulda AG, Universitätsmedizin Marburg-Campus, Fulda, Germany
| | - Dominique Farge
- Internal Medicine, Autoimmune and Vascular Diseases Unit, UF 04, AP-HP Hôpital Saint-Louis, Centre de Référence des Maladies auto-immunes systémiques Rares d’Ile-de-France [site constitutif], Filière FAI2R Paris 7 University, France
| | - Simon P L Travis
- Translational Gastroenterology Unit, Oxford University Hospitals, Oxford, UK
| | - Chris J Hawkey
- Nottingham Digestive Diseases Centre, School of Clinical Sciences, Queen’s Medical Centre, Nottingham, UK
| | - John A Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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44
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El‐Nakeep S, Abdel Latif O, Shawky A, Nabhan AF. Stem cell transplantation for induction of remission in medically refractory Crohn’s disease. Cochrane Database Syst Rev 2018; 2018:CD013070. [PMCID: PMC6513462 DOI: 10.1002/14651858.cd013070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: The objective of this review is to assess the efficacy and safety of stem cell transplantation for induction of remission in active Crohn's disease.
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Affiliation(s)
- Sarah El‐Nakeep
- Faculty of Medicine, Ain Shams UniversityGastroenterology and Hepatology Unit, Department of Internal MedicineCairoEgypt
| | - Osama Abdel Latif
- Faculty of Medicine, Ain Shams UniversityAllergy and Clinical Immunology Unit, Department of Internal MedicineCairoEgypt
| | - Ahmed Shawky
- Faculty of Medicine, Ain Shams UniversityGastroenterology and Hepatology Unit, Department of Internal MedicineCairoEgypt
| | - Ashraf F Nabhan
- Ain Shams UniversityDepartment of Obstetrics and Gynaecology, Faculty of Medicine16 Ali Fahmi Kamel StreetHeliopolisCairoEgypt11351
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45
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Masaki T, Kishiki T, Kojima K, Asou N, Beniya A, Matsuoka H. Recent trends (2016-2017) in the treatment of inflammatory bowel disease. Ann Gastroenterol Surg 2018; 2:282-288. [PMID: 30003191 PMCID: PMC6036397 DOI: 10.1002/ags3.12177] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Accepted: 05/08/2018] [Indexed: 12/17/2022] Open
Abstract
Prevalence of inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease has dramatically increased in Asian countries in the last three decades. In this period, many new medical therapies were introduced for the treatment of IBD, such as immunosuppressants, anti-tumor necrosis factor agents, leukocyte apheresis, anti-integrin antibody, and so on, which have contributed to induce remission and to reduce complications in IBD. As for surgical techniques for Crohn's disease, a stapled functional end-to-end anastomosis and conventional end-to-end anastomosis have similar perianastomotic recurrence rate and reoperation rate. Prospective randomized controlled studies which compare Kono-S anastomosis and stapled side-to-side anastomosis are ongoing. Variant two-stage ileal pouch anal anastomosis (IPAA) and transanal IPAA are new concepts for surgical treatment of ulcerative colitis. Various endoscopic procedures, such as balloon dilation for stenosis or stricture, endoscopic fistulotomy, injection of filling agents, and clipping for fistulas or perforations will be new options in the treatment of Crohn's disease. Adverse effects of preoperative treatments on postoperative complications should also be taken into account to improve surgical outcomes in IBD patients.
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Affiliation(s)
| | | | | | | | - Ayumi Beniya
- Department of SurgeryKyorin UniversityTokyoJapan
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46
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Alexander T, Farge D, Badoglio M, Lindsay JO, Muraro PA, Snowden JA. Hematopoietic stem cell therapy for autoimmune diseases - Clinical experience and mechanisms. J Autoimmun 2018; 92:35-46. [PMID: 29934135 DOI: 10.1016/j.jaut.2018.06.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 06/07/2018] [Accepted: 06/08/2018] [Indexed: 12/13/2022]
Abstract
With accumulating evidence and improved outcomes along with recognition that modern biological therapies are not universally effective, require chronic administration and have high acquisition costs, hematopoietic stem cell transplantation (HSCT) has become an emerging direction for cell therapy in autoimmune diseases (ADs). The goal of this therapy is to induce medication-free remissions by resetting the immune system into a naïve and self-tolerant state through eradication of the autoreactive immunologic memory and profound re-configuration of the immune system induced by the transplant procedure. Safety of HSCT has generally improved by implementing internal quality management and external accreditation. Inter-disciplinary guidelines for patient selection, transplant technique and supportive care along with greater center experience should optimize safe and appropriate delivery of HSCT in specific ADs. In this review, we discuss the current role and future perspectives of HSCT in AD, focusing on recent published clinical and scientific studies and recommendations in the field.
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Affiliation(s)
- Tobias Alexander
- Department of Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, Germany.
| | - Dominique Farge
- Unité de Médecine Interne, Maladies Auto-immunes et Pathologie Vasculaire (UF 04), Hôpital St-Louis, AP-HP, 1 avenue Claude Vellefaux, 75010 Paris, Université Denis Diderot, France; Centre de Référence des Maladies auto-immunes systémiques Rares d'Ile-de-France (site constitutif), Filière FAI2R, France
| | - Manuela Badoglio
- EBMT Paris Study Office / CEREST-TC, Department of Haematology, Saint Antoine Hospital, INSERM UMR 938, Université Pierre et Marie Curie, Paris, France
| | - James O Lindsay
- The Royal London Hospital, Barts Health NHS Trust, London, E1 1BB UK; Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT, UK
| | - Paolo A Muraro
- Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK
| | - John A Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, S10 2JF, UK
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47
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Zhang XM, Zhang YJ, Wang W, Wei YQ, Deng HX. Mesenchymal Stem Cells to Treat Crohn's Disease with Fistula. Hum Gene Ther 2018; 28:534-540. [PMID: 28132518 DOI: 10.1089/hum.2016.095] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Crohn's disease, which mainly affects the gastrointestinal tract, is a refractory inflammatory disease that has clinical manifestations of abdominal pain, fever, bowel obstruction, and diarrhea with blood or mucus. Together, these symptoms can severely impair a patient's quality of life. Besides the common complication of intestinal obstruction, fistulas, particularly anorectal fistulas, are common in Crohn's disease patients. Since radical surgical cures can be difficult to achieve and relapse is common, Crohn's disease patients often seek other effective treatments in addition to surgery. Stem-cell therapies have recently been proposed as a method to address the challenges and prospective medical needs of Crohn's disease patients in general and those with fistulas. Several studies suggest that mesenchymal stem cells (MSCs) could improve Crohn's disease and Crohn's fistula. Moreover, studies concerning MSC transplantation or local rejection of stem cells derived from bone marrow or adipose tissue-derived stem cells have assessed stem cell-based treatments for refractory Crohn's disease. Many patients in these studies are now in remission. A number of clinical trials for refractory Crohn's disease have also evaluated transplantation of autologous or allogenic MSCs and showed that MSCs can be safely administered to Crohn's disease patients, with some achieving positive clinical responses.
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Affiliation(s)
- Xiao-Mei Zhang
- 1 State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu, P.R. China .,2 Laboratory Animal Center, Sichuan University , Chengdu, P.R. China
| | - Yu-Jing Zhang
- 1 State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu, P.R. China
| | - Wei Wang
- 1 State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu, P.R. China
| | - Yu-Quan Wei
- 1 State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu, P.R. China
| | - Hong-Xin Deng
- 1 State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu, P.R. China .,2 Laboratory Animal Center, Sichuan University , Chengdu, P.R. China
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48
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Pockley AG, Lindsay JO, Foulds GA, Rutella S, Gribben JG, Alexander T, Snowden JA. Immune Reconstitution After Autologous Hematopoietic Stem Cell Transplantation in Crohn's Disease: Current Status and Future Directions. A Review on Behalf of the EBMT Autoimmune Diseases Working Party and the Autologous Stem Cell Transplantation In Refractory CD-Low Intensity Therapy Evaluation Study Investigators. Front Immunol 2018; 9:646. [PMID: 29670622 PMCID: PMC5893785 DOI: 10.3389/fimmu.2018.00646] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Accepted: 03/15/2018] [Indexed: 12/13/2022] Open
Abstract
Patients with treatment refractory Crohn's disease (CD) suffer debilitating symptoms, poor quality of life, and reduced work productivity. Surgery to resect inflamed and fibrotic intestine may mandate creation of a stoma and is often declined by patients. Such patients continue to be exposed to medical therapy that is ineffective, often expensive and still associated with a burden of adverse effects. Over the last two decades, autologous hematopoietic stem cell transplantation (auto-HSCT) has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies have provided proof of concept that auto-HSCT can restore immunological tolerance in chronic autoimmunity via the eradication of pathological immune responses and a profound reconfiguration of the immune system. Herein, we review current experience of auto-HSCT for the treatment of CD as well as approaches that have been used to monitor immune reconstitution following auto-HSCT in patients with ADs, including CD. We also detail immune reconstitution studies that have been integrated into the randomized controlled Autologous Stem cell Transplantation In refractory CD-Low Intensity Therapy Evaluation trial, which is designed to test the hypothesis that auto-HSCT using reduced intensity mobilization and conditioning regimens will be a safe and effective means of inducing sustained control in refractory CD compared to standard of care. Immunological profiling will generate insight into the pathogenesis of the disease, restoration of responsiveness to anti-TNF therapy in patients with recurrence of endoscopic disease and immunological events that precede the onset of disease in patients that relapse after auto-HSCT.
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Affiliation(s)
- Alan Graham Pockley
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - James O Lindsay
- Centre for Immunobiology, Barts and the London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of London, London, United Kingdom
| | - Gemma A Foulds
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Sergio Rutella
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - John G Gribben
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Tobias Alexander
- Department of Rheumatology and Clinical Immunology, Charité - University Medicine, Berlin, Germany.,German Rheumatism Research Center Berlin (DRFZ) - a Leibniz Institute, Berlin, Germany
| | - John A Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
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Snowden JA, Panés J, Alexander T, Allez M, Ardizzone S, Dierickx D, Finke J, Hasselblatt P, Hawkey C, Kazmi M, Lindsay JO, Onida F, Salas A, Saccardi R, Vermeire S, Rovira M, Ricart E. Autologous Haematopoietic Stem Cell Transplantation (AHSCT) in Severe Crohn's Disease: A Review on Behalf of ECCO and EBMT. J Crohns Colitis 2018; 12:476-488. [PMID: 29325112 DOI: 10.1093/ecco-jcc/jjx184] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Accepted: 01/04/2018] [Indexed: 02/06/2023]
Abstract
Despite the major recent progress in the treatment of Crohn's disease [CD], there is a subset of patients in whom the disease runs an aggressive course with progressive tissue damage requiring early and repeated surgical management. Increasing evidence supports sustained and profound improvement in gastrointestinal parameters and quality of life following high-dose immunosuppressive therapy and autologous haematopoietic stem cell transplantation [AHSCT] compared to standard therapy in this context. In addition, international transplant registry data reflect the use of AHSCT in CD outside of trials in selected patients. However, AHSCT may be associated with significant treatment-related complications with risk of transplant-related mortality. In a joint initiative, the European Crohn's and Colitis Organisation [ECCO] and the European Society for Blood and Marrow Transplantation [EBMT] have produced a state-of-the-art review of the rationale, evaluation, patient selection, stem cell mobilization and transplant procedures and long-term follow up. Given the unique spectrum of issues, we recommend that AHSCT should only be performed in experienced centres with expertise in both haematological and gastroenterological aspects of the procedure. Where possible, patients should be enrolled on clinical trials and data registered centrally. Future development should be coordinated at both national and international levels.
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Affiliation(s)
- John A Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK
| | - Julián Panés
- Department of Gastroenterology, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Tobias Alexander
- Department of Rheumatology and Clinical Immunology, Charité - University Medicine, Berlin, Germany
| | - Matthieu Allez
- Department of Gastroenterology, Hôpital Saint Louis, APHP, INSERM U1160, Paris Diderot, Sorbonne Paris-Cité University, Paris, France
| | - Sandro Ardizzone
- DIBIC - ASST Fatebenefratelli Sacco - University of Milan, Italy
| | - Daan Dierickx
- Department of Haematology, University Hospitals, Leuven, Belgium
| | - Jürgen Finke
- Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
| | - Peter Hasselblatt
- Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
| | - Chris Hawkey
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
| | - Majid Kazmi
- Department of Haematology, Guys & St Thomas' NHS Foundation Trust, London, UK
| | - James O Lindsay
- The Royal London Hospital, Barts Health NHS Trust, London UK & Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Francesco Onida
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - University of Milan, Italy
| | - Azucena Salas
- Department of Gastroenterology, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Riccardo Saccardi
- Department of Haematology, Careggi University Hospital, Firenze, Italy
| | - Severine Vermeire
- Department of Gastroenterology - University Hospitals, Leuven, Belgium
| | - Montserrat Rovira
- BMT Unit, Hematology Department, IDIBAPS, Hospital Clinic. Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
| | - Elena Ricart
- Department of Gastroenterology, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain
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Rios Rodriguez V, Llop M, Poddubnyy D. Hematopoietic and mesenchymal stem cells: a promising new therapy for spondyloarthritis? Immunotherapy 2018; 9:899-911. [PMID: 29338611 DOI: 10.2217/imt-2017-0034] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
In the last years, a considerable progress has been made in the treatment of spondyloarthritides. Nonetheless, there remain a considerable number of patients who are unresponsive to all current therapies. Since the late 1990s, numerous trials have investigated the use of stem cell transplantation as a new approach for the treatment of autoimmune disease, particularly with hematopoietic stem cell transplantation. More recently, the research has focused on mesenchymal stem cell application due to their low immunogenicity and immunomodulatory properties. In this article, we summarize available data on hematopoietic stem cell and mesenchymal stem cell use for the treatment of spondyloarthritides and discuss the data gaps and possible research agenda in this area.
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Affiliation(s)
- Valeria Rios Rodriguez
- Department of Gastroenterology, Infectiology & Rheumatology, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Maria Llop
- Department of Rheumatology, Hospital Ramón y Cajal, Madrid, Spain
| | - Denis Poddubnyy
- Department of Gastroenterology, Infectiology & Rheumatology, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin, Germany
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