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1
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Stasik K, Filip R. The Complex Relationship between Mechanisms Underlying Inflammatory Bowel Disease, Its Treatment, and the Risk of Lymphomas: A Comprehensive Review. Int J Mol Sci 2024; 25:4241. [PMID: 38673824 PMCID: PMC11049907 DOI: 10.3390/ijms25084241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 04/06/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Patients with inflammatory bowel disease may be at higher risk of developing lymphomas and other cancers of the gastrointestinal tract. In addition, there may be a link between the use of thiopurines or anti-tumor necrosis factor drugs (anti-TNF) and these pathologies. The treatment of patients with Crohn's disease who have previously been diagnosed with lymphoma is a challenge for gastroenterologists. In this report, we examine important clinical issues related to the treatment of patients with inflammatory bowel disease with active lymphoma, as well as of patients with hematological cancer history. In this discussion, we take into account most of the available treatments for inflammatory bowel disease, as well as the impact of chronic inflammation and viral infections. In addition, we try to find common ground for the development of lymphoproliferative disorders and autoimmune diseases. Patients with inflammatory bowel disease may be at higher risk of developing lymphomas and other cancers of the gastrointestinal tract. Chronic inflammatory processes and viral infections play an important role in carcinogenesis. In addition, there may be a link between the use of thiopurines or anti-TNF drugs and these pathologies. A significant risk of the development of lymphoma in people undergoing each therapy should be considered, and it should be estimated how much greater this risk will be in patients with a history of lymphoproliferative disorders. The following review is an attempt to answer which therapy would be the most appropriate for patients with Crohn's disease and a history of lymphoma treatment. A lack of clear guidelines creates great challenges for doctors.
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Affiliation(s)
- Katarzyna Stasik
- Department of Gastroenterology with IBD Unit, Clinical Hospital No. 2, 35-301 Rzeszow, Poland;
| | - Rafał Filip
- Faculty of Medicine, University of Rzeszow, 35-959 Rzeszow, Poland
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2
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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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3
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Eiro N, Fraile M, González-Jubete A, González LO, Vizoso FJ. Mesenchymal (Stem) Stromal Cells Based as New Therapeutic Alternative in Inflammatory Bowel Disease: Basic Mechanisms, Experimental and Clinical Evidence, and Challenges. Int J Mol Sci 2022; 23:ijms23168905. [PMID: 36012170 PMCID: PMC9408403 DOI: 10.3390/ijms23168905] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are an example of chronic diseases affecting 40% of the population, which involved tissue damage and an inflammatory process not satisfactorily controlled with current therapies. Data suggest that mesenchymal stem cells (MSC) may be a therapeutic option for these processes, and especially for IBD, due to their multifactorial approaches such as anti-inflammatory, anti-oxidative stress, anti-apoptotic, anti-fibrotic, regenerative, angiogenic, anti-tumor, or anti-microbial. However, MSC therapy is associated with important limitations as safety issues, handling difficulties for therapeutic purposes, and high economic cost. MSC-derived secretome products (conditioned medium or extracellular vesicles) are therefore a therapeutic option in IBD as they exhibit similar effects to their parent cells and avoid the issues of cell therapy. In this review, we proposed further studies to choose the ideal tissue source of MSC to treat IBD, the implementation of new standardized production strategies, quality controls and the integration of other technologies, such as hydrogels, which may improve the therapeutic effects of derived-MSC secretome products in IBD.
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Affiliation(s)
- Noemi Eiro
- Research Unit, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
- Correspondence: (N.E.); (F.J.V.); Tel.: +34-98-5320050 (ext. 84216) (N.E.); Fax: +34-98-531570 (N.E.)
| | - Maria Fraile
- Research Unit, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
| | | | - Luis O. González
- Department of Anatomical Pathology, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
| | - Francisco J. Vizoso
- Research Unit, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
- Department of Surgery, Fundación Hospital de Jove, Av. de Eduardo Castro, 161, 33290 Gijón, Spain
- Correspondence: (N.E.); (F.J.V.); Tel.: +34-98-5320050 (ext. 84216) (N.E.); Fax: +34-98-531570 (N.E.)
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4
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Cassinotti A, Passamonti F, Segato S. CELL THERAPY IN INFLAMMATORY BOWEL DISEASE. Pharmacol Res 2021; 163:105247. [PMID: 33069755 DOI: 10.1016/j.phrs.2020.105247] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [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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Affiliation(s)
| | | | - Sergio Segato
- Gastroenterology Unit, ASST Sette Laghi, Varese Italy
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5
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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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6
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Ruiz MA, Junior RLK, Piron-Ruiz L, Saran PS, Castiglioni L, Quadros LGD, Pinho TS, Burt RK. Medical, ethical, and legal aspects of hematopoietic stem cell transplantation for Crohn’s disease in Brazil. World J Stem Cells 2020; 12:1113-1123. [PMID: 33178395 PMCID: PMC7596442 DOI: 10.4252/wjsc.v12.i10.1113] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 07/08/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023] Open
Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease that can affect any part of the gastrointestinal tract. The etiology of CD is unknown; however, genetic, epigenetic, environmental, and lifestyle factors could play an essential role in the onset and establishment of the disease. CD results from immune dysregulation due to loss of the healthy symbiotic relationship between host and intestinal flora and or its antigens. It affects both sexes equally with a male to female ratio of 1.0, and its onset can occur at any age, but the diagnosis is most commonly observed in the range of 20 to 40 years of age. CD diminishes quality of life, interferes with social activities, traumatizes due to the stigma of incontinence, fistulae, strictures, and colostomies, and in severe cases, affects survival when compared to the general population. Symptoms fluctuate between periods of remission and activity in which complications such as fistulas, strictures, and the need for bowel resection, surgery, and colostomy implantation make up the most severe aspects of the disease. CD can be progressive and the complications recurrent despite treatment with anti-inflammatory drugs, corticosteroids, immunosuppressants, and biological agents. However, over time many patients become refractory without treatment alternatives, and in this scenario, hematopoietic stem cell transplantation (HSCT) has emerged as a potential treatment option. The rationale for the use of HSCT for CD is anchored in animal studies and human clinical trials where HSCT could reset a patient's immune system by eliminating disease-causing effector cells and upon immune recovery increase regulatory and suppressive immune cells. Autologous HSCT using a non-myeloablative regimen of cyclophosphamide and anti-thymocyte globulin without CD34+ selection has been to date the most common transplant conditioning regimen adopted. In this review we will address the current situation regarding CD treatment with HSCT and emphasize the medical, ethical, and legal aspects that permeate the procedure in Brazil.
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Affiliation(s)
- Milton Artur Ruiz
- Department of Bone Marrow Transplant, Beneficência Portuguesa Hospital, São José do Rio Preto 15090 470, Brazil
| | | | - Lilian Piron-Ruiz
- Department of Bone Marrow Transplantation, Beneficência Portuguesa Hospital, São José do Rio Preto 15090 470, Brazil
| | - Priscila Samara Saran
- Department of Bone Marrow Transplantation, Beneficência Portuguesa Hospital, São José do Rio Preto 15090 470, Brazil
| | - Lilian Castiglioni
- Genetics and Molecular Biology, FAMERP- Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto 15090 470 Brazil
| | - Luiz Gustavo de Quadros
- Department of Endoscopy, Beneficência Portuguesa Hospital, ABC Medical School, São Bernardo 15015 110, Brazil
| | - Tainara Souza Pinho
- Department of Bone Marrow Transplantation, Beneficência Portuguesa Hospital, São José do Rio Preto 15090 470, Brazil
| | - Richard K Burt
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
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7
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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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8
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Chen L, Gao Y, Zhang Z, Sun M, Yang W, Liu Z, Jiang X. Umbilical cord blood mononuclear cell therapy induces clinical remission of steroid-dependent or -resistant ulcerative colitis patients. Oncotarget 2018; 9:15027-15035. [PMID: 29599923 PMCID: PMC5871094 DOI: 10.18632/oncotarget.24541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 11/16/2017] [Indexed: 11/25/2022] Open
Abstract
To compare the efficacy and safety of umbilical cord blood mononuclear cells (CBMNC) and azathioprine (AZA) in the treatment of patients with steroid-dependent or -resistant ulcerative colitis. One hundred and six patients diagnosed with steroid-dependent or -resistant ulcerative colitis were studied retrospectively, including 36 patients treated with CBMNC and 70 treated with AZA. To reduce confounding bias due to retrospective nature of this study, the propensity score matching system was applied to equipoise the pretreatment data of two groups. After matching, 35 matched pairs (1:1) were created. The ratios of clinical remission, clinical response and endoscopic mucosal healing, Mayo score, and major complications were compared between two groups at weeks 8, 16, and 36 after treatment. The results demonstrated that the ratios of clinical remission (80% vs. 57%, P < 0.05) and mucosal healing (74% vs. 51%, P < 0.05) were significantly higher in CBMNC-treated patients compared with those in AZA-treated patients at week 8. The erythrocyte sedimentation rate was significantly decreased in CBMNC group compared with that in AZA-treated group (14.5 ± 3.9 mm/h vs. 18.0 ± 5.7 mm/h, P < 0.01) at week 8. In AZA group, 2 patients had neutropenia and 3 patients had elevated alanine aminotransferase levels, whereas no obvious side-effects were observed in CBMNC-treated group. Our results reveal that CBMNC therapy appears to be an effective and safe strategy for patients with steroid-dependent or -resistant ulcerative colitis. Further prospective studies are needed to define the potential roles and mechanisms of CBMNC in the treatment of refractory ulcerative colitis.
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Affiliation(s)
- Liang Chen
- Department of Gastroenterology, The Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
- Department of Gastroenterology, Chinese PLA General Hospital of Jinan Military Command, Jinan, China
| | - Yuan Gao
- Department of Gastroenterology, Chinese PLA General Hospital of Jinan Military Command, Jinan, China
| | - Zongmei Zhang
- Department of Gastroenterology, Chinese PLA General Hospital of Jinan Military Command, Jinan, China
| | - Mingming Sun
- Department of Gastroenterology, The Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Wenjing Yang
- Department of Gastroenterology, The Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Zhanju Liu
- Department of Gastroenterology, The Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Xueliang Jiang
- Department of Digestive Center, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
- Department of Gastroenterology, Chinese PLA General Hospital of Jinan Military Command, Jinan, China
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9
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DiNicola CA, Zand A, Hommes DW. Autologous hematopoietic stem cells for refractory Crohn's disease. Expert Opin Biol Ther 2017; 17:555-564. [PMID: 28326848 DOI: 10.1080/14712598.2017.1305355] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Autologous hematopoietic stem cells are gaining ground as an effective and safe treatment for treating severe refractory Crohn's disease (CD). Autologous hematopoietic stem cell therapy (AHSCT) induces resetting of the immune system by de novo regeneration of T-cell repertoire and repopulation of epithelial cells by bone-marrow derived cells to help patients achieve clinical and endoscopic remission. Areas covered: Herein, the authors discuss the use of AHSCT in treating patients with CD. Improvements in disease activity have been seen in patients with severe autoimmune disease and patients with severe CD who underwent AHSCT for a concomitant malignant hematological disease. Clinical and endoscopic remission has been achieved in patients treated with AHSCT for CD. The only randomized trial published to date, the ASTIC Trial, did not support further use of AHSCT to treat CD. Yet, critics of this trial have deemed AHSCT as a promising treatment for severe refractory CD. Expert opinion: Even with the promising evidence presented for HSCT for refractory CD, protocols need to be refined through the collaboration of GI and hemato-oncology professionals. The goal is to incorporate safe AHSCT and restore tolerance by delivering an effective immune 'cease fire' as a treatment option for severe refractory CD.
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Affiliation(s)
- C A DiNicola
- a Department of Medicine , UCLA Center for Inflammatory Bowel Diseases , Los Angeles , CA , USA.,b Vatche & Tamar Manoukian Divison of Digestive Diseases , University of California , Los Angeles , CA , USA
| | - A Zand
- a Department of Medicine , UCLA Center for Inflammatory Bowel Diseases , Los Angeles , CA , USA.,b Vatche & Tamar Manoukian Divison of Digestive Diseases , University of California , Los Angeles , CA , USA
| | - D W Hommes
- a Department of Medicine , UCLA Center for Inflammatory Bowel Diseases , Los Angeles , CA , USA.,b Vatche & Tamar Manoukian Divison of Digestive Diseases , University of California , Los Angeles , CA , USA
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10
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Annese V, Beaugerie L, Egan L, Biancone L, Bolling C, Brandts C, Dierickx D, Dummer R, Fiorino G, Gornet JM, Higgins P, Katsanos KH, Nissen L, Pellino G, Rogler G, Scaldaferri F, Szymanska E, Eliakim R. European Evidence-based Consensus: Inflammatory Bowel Disease and Malignancies. J Crohns Colitis 2015; 9:945-965. [PMID: 26294789 DOI: 10.1093/ecco-jcc/jjv141] [Citation(s) in RCA: 315] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 08/10/2015] [Indexed: 02/07/2023]
Affiliation(s)
- Vito Annese
- University Hospital Careggi, Department of Gastroenterology, Florence, Italy
| | - Laurent Beaugerie
- Department of Gastroenterology, AP-HP Hôpital Saint-Antoine, and UPMC Univ Paris 06, Paris, France
| | - Laurence Egan
- Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland
| | - Livia Biancone
- University Tor Vergata of Rome, GI Unit, Department of Systems Medicine, Rome, Italy
| | - Claus Bolling
- Agaplesion Markus Krankenhaus, Medizinische Klinik I, Frankfurt am Main, Germany
| | - Christian Brandts
- Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt am Main, Germany
| | - Daan Dierickx
- Department of Haematology, University Hospital Leuven, Leuven, Belgium
| | - Reinhard Dummer
- Department of Dermatology, University Zürich, Zürich, Switzerland
| | - Gionata Fiorino
- Gastroenterology Department, Humanitas Research Hospital, Rozzano, Italy
| | - Jean Marc Gornet
- Service d'hépatogastroentérologie, Hopital Saint-Louis, Paris, France
| | - Peter Higgins
- University of Michigan, Department of Internal Medicine, Ann Arbor, USA
| | | | - Loes Nissen
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Gianluca Pellino
- Second University of Naples, Unit of Colorectal Surgery, Department of Medical, Surgical, Neurological, Metabolic and Ageing Sciences, Naples, Italy
| | - Gerhard Rogler
- Klinik für Gastroenterologie und Hepatologie, UniversitätsSpital Zürich, Zürich, Switzerland
| | - Franco Scaldaferri
- Università Cattolica del Sacro Cuore, Department of Internal Medicine, Gastroenterology Division, Roma, Italy
| | - Edyta Szymanska
- Department of Pediatrics, Nutrition and Metabolic Disorders, Children's Memorial Health Institute, Warsaw, Poland
| | - Rami Eliakim
- Department of Gastroenterology and Hepatology, Sheba Medical Center & Sackler School of Medicine, Israel
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11
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Abstract
Inflammatory bowel disease (IBD) could be curable by "immune rest" and correction of the genetic predisposition inherent in allogeneic hematopoietic stem cell transplantation. However, balancing risks against benefits remains challenging. The application of mesenchymal stem cells (MSCs) serving as a site-regulated "drugstore" is a recent concept, which suggests the possibility of an alternative treatment for many intractable diseases such as IBD. Depending on the required function of MSC, such as a cell provider, immune moderator, and/or trophic resource, MSC therapy should be optimized to maximize its therapeutic benefit. Therapeutic effects do not always require full engraftment of MSCs. Therefore, optimization of pleiotropic gut trophic factors produced by MSCs, which favoring not only regulating immune responses but also promoting tissue repair, must directly enhance new drug discoveries for treatment of IBD. Stem cell biology holds great promise for a new era of cell-based therapy, sparking considerable interest among scientists, clinicians, and patients. However, the translational arm of stem cell science remains in a relatively primitive state. Although several clinical studies using MSCs have been initiated, early results suggest several inherent problems. In each study, optimization of MSC therapy appears to be the most urgent problem, and can be resolved only by scientifically unveiling the mechanisms of therapeutic action. In the present review, the authors outline how such information would facilitate the critical steps in the paradigm shift from basic research on stem cell biology to clinical practice of regenerative medicine for conquering IBD in the near future.
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12
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Martínez-Montiel MDP, Gómez-Gómez GJ, Flores AI. Therapy with stem cells in inflammatory bowel disease. World J Gastroenterol 2014; 20:1211-1227. [PMID: 24574796 PMCID: PMC3921504 DOI: 10.3748/wjg.v20.i5.1211] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/23/2013] [Accepted: 01/06/2014] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) affects a part of the young population and has a strong impact upon quality of life. The underlying etiology is not known, and the existing treatments are not curative. Furthermore, a significant percentage of patients are refractory to therapy. In recent years there have been great advances in our knowledge of stem cells and their therapeutic applications. In this context, autologous hematopoietic stem cell transplantation (HSCT) has been used in application to severe refractory Crohn's disease (CD), with encouraging results. Allogenic HSCT would correct the genetic defects of the immune system, but is currently not accepted for the treatment of IBD because of its considerable risks. Mesenchymal stem cells (MSCs) have immune regulatory and regenerative properties, and low immunogenicity (both autologous and allogenic MSCs). Based on these properties, MSCs have been used via the systemic route in IBD with promising results, though it is still too soon to draw firm conclusions. Their local administration in perianal CD is the field where most progress has been made in recent years, with encouraging results. The next few years will be decisive for defining the role of such therapy in the management of IBD.
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Panés J, Ordás I, Ricart E. Stem cell treatment for Crohn’s disease. Expert Rev Clin Immunol 2014; 6:597-605. [DOI: 10.1586/eci.10.27] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Abstract
BACKGROUND The Autologous Stem Cell Transplantation International Crohn's Disease (ASTIC) trial is a randomised controlled evaluation of the proposition that immunoablation and haemopoietic stem cell transplantation improves the course of Crohn's disease. Recruitment of all 48 patients in the trial will be completed in early 2012 and the results to date are descriptively presented here. METHODS Patients with an impaired quality of life due to active Crohn's disease, despite the administration of at least 3 immunosuppressive agents, all received mobilisation treatment (cyclophosphamide 4 g/m(2) over 2 days followed by recombinant human granulocyte colony stimulating factor (filgrastim) 10 µg/kg daily before randomisation to immediate (after 1 month) or delayed (after 1 year) immunoablation and stem cell transplantation. The conditioning regime was cyclophosphamide 50 mg/kg/day for 4 days, anti-thymocyte globulin 2.5 mg/kg/day and methylprednisolone 1 mg/kg on days 3-5. The bone marrow was reconstituted by the infusion of an unselected graft of 3-8 × 10(6)/kg CD34-positive stem cells. Results were compared 1 year after mobilisation alone or after transplantation. RESULTS Twelve months after stem cell transplantation (early or delayed) the Crohn's Disease Activity Index (CDAI) fell from 324 (median, interquartile range 229-411) to 161 (85-257, n = 17) compared to 351 (287-443) to 272 (214-331) following mobilisation alone (n = 11). Six patients had a normal CDAI after transplantation versus 1 after mobilisation. C-reactive protein fell from 16.6 (6.7-32.0) to 6.5 (3.5-12.5) mg/l versus 14 (8.0-27.0) to 9.0 (2.0-23.4) mg/l following mobilisation alone. The Crohn's Disease Endoscopic Index of Severity (CDEIS) (aggregate for upper and lower endoscopy) fell from 18 (10-25) to 5 (1-11) following transplantation versus 14 (12-16) to 9 (4-22) following mobilisation. Three patients achieved the goal of a normal CDAI, no drug therapy and normal upper and lower endoscopy 1 year after transplantation, but so did 1 patient following mobilisation alone. Serious adverse events were common (n = 100 to date) with 42 infective episodes requiring or prolonging hospitalisation, following both mobilisation and conditioning and transplantation. There were 7 episodes of viral (re)activation. Temporary flare of Crohn's disease activity or a need for surgery occurred in 8 patients. CONCLUSIONS Immunoablation and haemopoietic stem cell transplantation appear to be an effective treatment for some patients with Crohn's disease, although full results will be required for a firm conclusion. The risks are significant, making it potentially suitable for only a limited number of patients. Data from the whole trial will be needed to judge whether mobilisation alone has any benefits.
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Affiliation(s)
- C J Hawkey
- Nottingham Digestive Diseases Centre, Nottingham, UK. cj.hawkey @ nottingham.ac.uk
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Kotlarz D, Beier R, Murugan D, Diestelhorst J, Jensen O, Boztug K, Pfeifer D, Kreipe H, Pfister ED, Baumann U, Puchalka J, Bohne J, Egritas O, Dalgic B, Kolho KL, Sauerbrey A, Buderus S, Güngör T, Enninger A, Koda YKL, Guariso G, Weiss B, Corbacioglu S, Socha P, Uslu N, Metin A, Wahbeh GT, Husain K, Ramadan D, Al-Herz W, Grimbacher B, Sauer M, Sykora KW, Koletzko S, Klein C. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 2012; 143:347-355. [PMID: 22549091 DOI: 10.1053/j.gastro.2012.04.045] [Citation(s) in RCA: 342] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Revised: 04/06/2012] [Accepted: 04/18/2012] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Homozygous loss of function mutations in interleukin-10 (IL10) and interleukin-10 receptors (IL10R) cause severe infantile (very early onset) inflammatory bowel disease (IBD). Allogeneic hematopoietic stem cell transplantation (HSCT) was reported to induce sustained remission in 1 patient with IL-10R deficiency. We investigated heterogeneity among patients with very early onset IBD, its mechanisms, and the use of allogeneic HSCT to treat this disorder. METHODS We analyzed 66 patients with early onset IBD (younger than 5 years of age) for mutations in the genes encoding IL-10, IL-10R1, and IL-10R2. IL-10R deficiency was confirmed by functional assays on patients' peripheral blood mononuclear cells (immunoblot and enzyme-linked immunosorbent assay analyses). We assessed the therapeutic effects of standardized allogeneic HSCT. RESULTS Using a candidate gene sequencing approach, we identified 16 patients with IL-10 or IL-10R deficiency: 3 patients had mutations in IL-10, 5 had mutations in IL-10R1, and 8 had mutations in IL-10R2. Refractory colitis became manifest in all patients within the first 3 months of life and was associated with perianal disease (16 of 16 patients). Extraintestinal symptoms included folliculitis (11 of 16) and arthritis (4 of 16). Allogeneic HSCT was performed in 5 patients and induced sustained clinical remission with a median follow-up time of 2 years. In vitro experiments confirmed reconstitution of IL-10R-mediated signaling in all patients who received the transplant. CONCLUSIONS We identified loss of function mutations in IL-10 and IL-10R in patients with very early onset IBD. These findings indicate that infantile IBD patients with perianal disease should be screened for IL-10 and IL-10R deficiency and that allogeneic HSCT can induce remission in those with IL-10R deficiency.
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Affiliation(s)
- Daniel Kotlarz
- Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
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Arimura Y, Nagaishi K, Naishiro Y, Yamashita K, Shinomura Y, Imai K. Regenerative medicine for inflammatory bowel disease. Inflamm Regen 2012. [DOI: 10.2492/inflammregen.32.061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Annaloro C, Onida F, Lambertenghi Deliliers G. Autologous hematopoietic stem cell transplantation in autoimmune diseases. Expert Rev Hematol 2011; 2:699-715. [PMID: 21082959 DOI: 10.1586/ehm.09.60] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The term 'autoimmune diseases' encompasses a spectrum of diseases whose clinical manifestations and, possibly, biological features vary widely. The results of conventional treatment are considered unsatisfactory in aggressive forms, with subsets of patients having short life expectancies. Relying on wide experimental evidence and more feeble clinical data, some research groups have used autologous hematopoietic stem cell transplantation (HSCT) in the most disabling autoimmune diseases with the aim of resetting the patient's immune system. Immunoablative conditioning regimens are preferred over their myeloablative counterparts, and some form of in vivo and/or ex vivo T-cell depletion is generally adopted. Despite 15 years' experience, published controlled clinical trials are still lacking, with the evidence so far available coming from pilot studies and registry surveys. In multiple sclerosis, clinical improvement, or at least lasting disease stabilization, can be achieved in the majority of the patients; nevertheless, the worst results are observed in patients with progressive disease, where no benefit can be expected from conventional therapy. Concerning rheumatologic diseases, wide experience has been acquired in systemic sclerosis, with long-term improvements in cutaneous disease being frequently reported, although visceral involvement remains unchanged at best. Autografting has proved to be barely effective in rheumatoid arthritis and quite toxic in juvenile idiopathic arthritis, whereas it leads to clinical remission and the reversal of visceral impairment in the majority of patients with systemic lupus erythematosus. A promising indication is Crohn's disease, in which long-term endoscopic remission is frequently observed. Growing experience with autologous HCST in autoimmune diseases has progressively reduced concerns about transplant-related mortality and secondary myelodysplasia/leukemia. Therefore, a sustained complete remission seems to be within the reach of autografting in some autoimmune diseases; in others, the indications, risks and benefits of autografting need to be better defined. Consequently, the search for new drugs should also be encouraged.
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Affiliation(s)
- Claudio Annaloro
- Bone Marrow Transplantation Center-Hematology I, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Via Francesco Sforza 35, Milan, Italy
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García-Bosch O, Ricart E, Panés J. Review article: stem cell therapies for inflammatory bowel disease - efficacy and safety. Aliment Pharmacol Ther 2010; 32:939-52. [PMID: 20804451 DOI: 10.1111/j.1365-2036.2010.04439.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Drugs available for the treatment of inflammatory bowel disease fail to induce and maintain remission in a significant number of patients. AIM To assess the value of stem cell therapies for treatment of inflammatory bowel disease based on published studies. METHODS Publications were identified through a MEDLINE search using the Medical Subject Heading terms: inflammatory bowel diseases, or Crohn's disease, or ulcerative colitis, and stem cell, or stromal cell or transplant. RESULTS Haematopoietic stem cell therapy as a primary treatment for inflammatory bowel disease was originally supported by animal experiments, and by remissions in patients undergoing transplant for haematological disorders. Later, transplantation specifically performed for patients with refractory Crohn's disease showed long-lasting clinical remission and healing of inflammatory intestinal lesions. Use of autologous nonmyeloablative regimens and concentration of the procedures in centres with large experience are key in reducing treatment-related mortality. Initial trials of mesenchymal stem cell therapy with local injection in Crohn's perianal fistulas had positive results. CONCLUSIONS Autologous haematopoietic stem cell transplant changes the natural course of Crohn's disease, and may be a therapeutic option in patients with refractory disease if surgery is not feasible due to disease location or extension.
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Affiliation(s)
- O García-Bosch
- Department of Gastroenterology, Hospital Clínic de Barcelona, CiBERehd, Spain
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Westbrook AM, Szakmary A, Schiestl RH. Mechanisms of intestinal inflammation and development of associated cancers: lessons learned from mouse models. Mutat Res 2010; 705:40-59. [PMID: 20298806 PMCID: PMC2878867 DOI: 10.1016/j.mrrev.2010.03.001] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2009] [Revised: 02/21/2010] [Accepted: 03/08/2010] [Indexed: 12/15/2022]
Abstract
Chronic inflammation is strongly associated with approximately 1/5th of all human cancers. Arising from combinations of factors such as environmental exposures, diet, inherited gene polymorphisms, infections, or from dysfunctions of the immune response, chronic inflammation begins as an attempt of the body to remove injurious stimuli; however, over time, this results in continuous tissue destruction and promotion and maintenance of carcinogenesis. Here we focus on intestinal inflammation and its associated cancers, a group of diseases on the rise and affecting millions of people worldwide. Intestinal inflammation can be widely grouped into inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and celiac disease. Long-standing intestinal inflammation is associated with colorectal cancer and small-bowel adenocarcinoma, as well as extraintestinal manifestations, including lymphomas and autoimmune diseases. This article highlights potential mechanisms of pathogenesis in inflammatory bowel diseases and celiac disease, as well as those involved in the progression to associated cancers, most of which have been identified from studies utilizing mouse models of intestinal inflammation. Mouse models of intestinal inflammation can be widely grouped into chemically induced models; genetic models, which make up the bulk of the studied models; adoptive transfer models; and spontaneous models. Studies in these models have lead to the understanding that persistent antigen exposure in the intestinal lumen, in combination with loss of epithelial barrier function, and dysfunction and dysregulation of the innate and adaptive immune responses lead to chronic intestinal inflammation. Transcriptional changes in this environment leading to cell survival, hyperplasia, promotion of angiogenesis, persistent DNA damage, or insufficient repair of DNA damage due to an excess of proinflammatory mediators are then thought to lead to sustained malignant transformation. With regards to extraintestinal manifestations such as lymphoma, however, more suitable models are required to further investigate the complex and heterogeneous mechanisms that may be at play.
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Affiliation(s)
- Aya M. Westbrook
- Molecular Toxicology Interdepartmental Program, UCLA School of Medicine and School of Public Health, University of California at Los Angeles, Los Angeles, CA 90095
- Department of Pathology and Lab Medicine, UCLA School of Medicine and School of Public Health, University of California at Los Angeles, Los Angeles, CA 90095
| | - Akos Szakmary
- Institute for Cancer Research, Medical University of Vienna, Austria
| | - Robert H. Schiestl
- Molecular Toxicology Interdepartmental Program, UCLA School of Medicine and School of Public Health, University of California at Los Angeles, Los Angeles, CA 90095
- Department of Pathology and Lab Medicine, UCLA School of Medicine and School of Public Health, University of California at Los Angeles, Los Angeles, CA 90095
- Institute for Cancer Research, Medical University of Vienna, Austria
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Takitani K, Inoue A, Kawakami C, Miyazaki H, Aomatsu T, Yoden A, Suzuki K, Tamai H. Reduced plasma all-transretinoic acid level in a patient with Crohn's disease with acute promyelocytic leukemia. Leuk Lymphoma 2009; 50:300-2. [DOI: 10.1080/10428190802617797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Lanzoni G, Roda G, Belluzzi A, Roda E, Bagnara GP. Inflammatory bowel disease: Moving toward a stem cell-based therapy. World J Gastroenterol 2008. [PMID: 18698675 DOI: 10.3748/wjp.14.4616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The incidence and prevalence of Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel diseases (IBD), are rising in western countries. The modern hygienic lifestyle is probably at the root of a disease where, in genetically susceptible hosts, the intestinal commensal flora triggers dysregulated immune and inflammatory responses. Current therapies ranging from anti-inflammatory drugs to immunosuppressive regimens, remain inadequate. Advances in our understanding of the cell populations involved in the pathogenetic processes and recent findings on the regenerative, trophic and immunoregulatory potential of stem cells open new paths in IBD therapy. Hematopoietic and mesenchymal stem cells are catalyzing the attention of IBD investigators. This review highlights the pivotal findings for stem cell-based approaches to IBD therapy and collects the encouraging results coming in from clinical trials.
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Affiliation(s)
- Giacomo Lanzoni
- Department of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, Bologna, Italy
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22
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Lanzoni G, Roda G, Belluzzi A, Roda E, Bagnara GP. Inflammatory bowel disease: Moving toward a stem cell-based therapy. World J Gastroenterol 2008; 14:4616-26. [PMID: 18698675 PMCID: PMC2738785 DOI: 10.3748/wjg.14.4616] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2008] [Revised: 07/09/2008] [Accepted: 07/16/2008] [Indexed: 02/06/2023] Open
Abstract
The incidence and prevalence of Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel diseases (IBD), are rising in western countries. The modern hygienic lifestyle is probably at the root of a disease where, in genetically susceptible hosts, the intestinal commensal flora triggers dysregulated immune and inflammatory responses. Current therapies ranging from anti-inflammatory drugs to immunosuppressive regimens, remain inadequate. Advances in our understanding of the cell populations involved in the pathogenetic processes and recent findings on the regenerative, trophic and immunoregulatory potential of stem cells open new paths in IBD therapy. Hematopoietic and mesenchymal stem cells are catalyzing the attention of IBD investigators. This review highlights the pivotal findings for stem cell-based approaches to IBD therapy and collects the encouraging results coming in from clinical trials.
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23
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Stem cells as potential novel therapeutic strategy for inflammatory bowel disease. J Crohns Colitis 2008; 2:99-106. [PMID: 21172199 DOI: 10.1016/j.crohns.2007.12.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2007] [Accepted: 12/21/2007] [Indexed: 02/08/2023]
Abstract
Hematopoietic stem cell transplantation and mesenchymal stromal cell therapy are currently under investigation as novel therapies for inflammatory bowel diseases. Hematopoietic stem cells (HSC) are thought to repopulate the immune system and reset the immunological response to luminal antigens. Mesenchymal stromal cells (MSC) are cells that have the capacity to differentiate into wide variety of distinct cell lineages and suppress immune responses in vitro and in vivo. Recent results from animal models and early human experience in graft-versus-host disease but also Crohn's Disease suggest that ex vivo expanded MSCs may have clinically useful immunomodulatory effects.
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von Roon AC, Reese G, Teare J, Constantinides V, Darzi AW, Tekkis PP. The risk of cancer in patients with Crohn's disease. Dis Colon Rectum 2007; 50:839-55. [PMID: 17308939 DOI: 10.1007/s10350-006-0848-z] [Citation(s) in RCA: 193] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE The risk of cancer in patients with Crohn's disease is not well defined. Using meta-analytical techniques, the present study was designed to quantify the risk of intestinal, extraintestinal, and hemopoietic malignancies in such patients. METHODS A literature search identified 34 studies of 60,122 patients with Crohn's disease. The incidence and relative risk of cancer were calculated for patients with Crohn's disease and compared with the baseline population of patients without Crohn's disease. Overall pooled estimates, with 95 percent confidence intervals, were obtained, using a random-effects model. RESULTS The relative risk of small bowel, colorectal, extraintestinal cancer, and lymphoma compared with the baseline population was 28.4 (95 percent confidence interval, 14.46-55.66), 2.4 (95 percent confidence interval, 1.56-4.36), 1.27 (95 percent confidence interval, 1.1-1.47), and 1.42 (95 percent confidence interval, 1.16-1.73), respectively. On subgroup analysis, patients with Crohn's disease had an increased risk of colon cancer (relative risk, 2.59; 95 percent confidence interval, 1.54-4.36) but not of rectal cancer (relative risk, 1.46; 95 percent confidence interval, 0.8-2.55). There was significant association between the anatomic location of the diseased bowel and the risk of cancer in that segment. The risk of small bowel cancer and colorectal cancer was found to be higher in North America and the United Kingdom than in Scandinavian countries with no evidence of temporal changes in the cancer incidence. CONCLUSIONS The present meta-analysis demonstrated an increased risk of small bowel, colon, extraintestinal cancers, and lymphoma in patients with Crohn's disease. Patients with extensive colonic disease that has been present from a young age should be candidates for endoscopic surveillance; however, further data are required to evaluate the risk of neoplasia over time.
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Affiliation(s)
- Alexander C von Roon
- Department of Biosurgery and Surgical Technology, Imperial College, St. Mary's Hospital, London, W2 1NY, UK
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Leung Y, Geddes M, Storek J, Panaccione R, Beck PL. Hematopoietic cell transplantation for Crohn’s disease; is it time? World J Gastroenterol 2006; 12:6665-73. [PMID: 17075981 PMCID: PMC4125673 DOI: 10.3748/wjg.v12.i41.6665] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To review all studies in the literature that have assessed Hematopoietic cell transplantation (HCT) and Crohn’s disease (CD) with the ultimate aims of determining if this is a viable treatment option for those with CD. A secondary aim was to review the above literature and determine if the studies shed further light on the mechanisms involved in the pathogenesis of CD.
METHODS: An extensive Medline search was performed on all articles from 1970 to 2005 using the keywords; bone marrow transplant, stem cell, hematopoietic cell, Crohn’s disease and inflammatory bowel disease.
RESULTS: We identified one case in which a patient developed CD following an allogeneic HCT from a sibling suffering with CD. Evidence for transfer of the genetic predisposition to develop CD was also identified with report of a patient that developed severe CD following an allogeneic HCT. Following HCT it was found that the donor (that had no signs or symptoms of CD) and the recipient had several haplotype mismatches in HLA class III genes in the IBD3 locus including a polymorphism of NOD2/CARD15 that has been associated with CD. Thirty three published cases of patients with CD who underwent either autologous or allogeneic HCT were identified. At the time of publication 29 of these 33 patients were considered to be in remission. The median follow-up time was seven years, and twenty months for allogeneic and autologous HCT respectively. For patients who underwent HCT primarily for treatment of their CD there have been no mortalities related to transplant complications.
CONCLUSION: Overall these preliminary data suggest that both allogeneic and autologous HCT may be effective in inducing remission in refractory CD. This supports the hypothesis that the hemolymphatic cells play a key role in CD and that resetting of the immune system may be a critical approach in the management or cure of CD.
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Affiliation(s)
- Y Leung
- Department of Medicine, University of Calgary, Health Sciences Center, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada
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Oliver JW, Farnsworth B, Tonk VS. Juvenile myelomonocytic leukemia in a child with Crohn disease. ACTA ACUST UNITED AC 2006; 167:70-3. [PMID: 16682290 DOI: 10.1016/j.cancergencyto.2005.09.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2005] [Revised: 09/09/2005] [Accepted: 09/13/2005] [Indexed: 11/17/2022]
Abstract
Intestinal adenocarcinoma is a well-known complication of inflammatory bowel disease. Hematologic malignancies, most commonly lymphoma or acute myeloid leukemia, represent a much less well-recognized complication of these disorders; these typically occur in adults with ulcerative colitis. We report a fatal case of juvenile myelomonocytic leukemia associated with monosomy 7 in a young child with a clinical history of Crohn disease. Neither the leukemia nor the cytogenetic aberration has been previously reported in a patient with inflammatory bowel disease. The aggressive disease course emphasizes the need for proper recognition and further study of this unusual complication.
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MESH Headings
- Biopsy
- Chromosome Aberrations
- Chromosomes, Human, Pair 7
- Crohn Disease/complications
- Crohn Disease/diagnosis
- Crohn Disease/genetics
- Crohn Disease/pathology
- Cytogenetic Analysis
- Drug Therapy
- Fatal Outcome
- Hematopoietic Stem Cells/cytology
- Humans
- Infant
- Leukemia, Myelomonocytic, Chronic/complications
- Leukemia, Myelomonocytic, Chronic/diagnosis
- Leukemia, Myelomonocytic, Chronic/genetics
- Leukemia, Myelomonocytic, Chronic/pathology
- Male
- Monosomy
- Stem Cell Transplantation
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Affiliation(s)
- Jeffrey W Oliver
- Department of Pathology, Texas Tech University Health Sciences Center, School of Medicine, 3601 4th Street, Lubbock, TX 79430-8115, USA.
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Hough RE, Snowden JA, Wulffraat NM. Haemopoietic stem cell transplantation in autoimmune diseases: a European perspective. Br J Haematol 2005; 128:432-59. [PMID: 15686452 DOI: 10.1111/j.1365-2141.2004.05298.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The potential of haemopoietic stem cell transplantation (HSCT) for the treatment of autoimmune and inflammatory diseases was originally supported by almost three decades of animal experiments and by the serendipitous remissions of autoimmune disease observed in patients undergoing transplantation for haematological disorders. Improved safety of both autologous and allogeneic HSCT over the last decade has been followed by increasing acceptance of HSCT as an experimental treatment for severe autoimmune diseases that are resistant to conventional treatment. International databases have collated over 700 procedures performed specifically for a variety of autoimmune diseases. Phase III clinical trials are in progress for some diseases. This review provides a comprehensive update on the efficacy and toxicity of HSCT in severe autoimmune disease. Future directions in the context of other evolving therapies are discussed.
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Affiliation(s)
- R E Hough
- Department of Haematology, Sheffield Teaching Hospitals NHS Trust, University of Sheffield, Sheffield, UK
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Kreisel W, Potthoff K, Bertz H, Schmitt-Graeff A, Ruf G, Rasenack J, Finke J. Complete remission of Crohn's disease after high-dose cyclophosphamide and autologous stem cell transplantation. Bone Marrow Transplant 2003; 32:337-340. [PMID: 12858208 DOI: 10.1038/sj.bmt.1704134] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2002] [Accepted: 02/17/2003] [Indexed: 12/13/2022]
Abstract
In a 36-year-old male with ileocolic Crohn's disease (CD) no long-lasting remission was obtained by treatment with corticosteroids, mesalazine, azathioprine and antibiotics. Surgical interventions due to relapsing fistulae and abscesses resulted in the removal of >1.5 m of small bowel and left only 40 cm of large bowel. In July 2000, a new fistula and abscess developed. The combination of corticosteroids, mesalazine, ciprofloxacin, metronidazol, azathioprine, formula diet and anti-TNF-alpha antibody largely reduced clinical activity, and resection of fistula and abscess were successful. Despite clinical remission, histology showed activity in the small bowel and the colon. In March 2001, stem cell mobilization chemotherapy with cyclophosphamide was performed. It induced an endoscopic remission for 9 months, which was maintained on azathioprine and corticosteroids. After relapse, in March 2002, high-dose chemotherapy with cyclophosphamide and reinfusion of T-cell-depleted autologous peripheral CD34+ blood stem cells were performed. This led to a complete clinical, endoscopical and histological remission for 9 months without any treatment. Thereafter, endoscopy showed initial aphthous lesions with minimal histological signs of inflammation. The patient is asymptomatic, but low-dose prednisolone and methotrexate are prophylactically given. Immunoablative chemotherapy followed by autologous peripheral blood stem cell transplantation may be a beneficial therapeutic option in complicated refractory CD.
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Affiliation(s)
- W Kreisel
- Medical Clinic, Department of Gastroenterology, Hepatology and Endocrinology, University of Freiburg, Freiburg, Germany
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Hinterberger W, Hinterberger-Fischer M, Marmont A. Clinically demonstrable anti-autoimmunity mediated by allogeneic immune cells favorably affects outcome after stem cell transplantation in human autoimmune diseases. Bone Marrow Transplant 2002; 30:753-9. [PMID: 12439698 DOI: 10.1038/sj.bmt.1703686] [Citation(s) in RCA: 81] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2002] [Accepted: 06/01/2002] [Indexed: 11/09/2022]
Abstract
To determine the role of allogeneic, autologous and syngeneic hemopoietic stem cell transplantation (SCTx) as a treatment for severe autoimmune disease (AID) we performed a literature search employing Medline, Cancer Lit and abstract books for reports on transplants for blood disorders and a concomitant AID. All reviews, case reports and abstracts available between June 1977 and September 2001 were used and attempts made to update them by e-mail by the corresponding authors. Disease-free survival (DFS) after allogeneic SCTx for 23 patients with severe aplastic anemia was 78% at 16 years and survival in unmaintained remission of concomitant AID was 64% at 13 years. DFS after allogeneic SCTx for 24 patients with hematologic malignancies was 87% at 15 years and survival in unmaintained remission for concomitant AID was 70% at 11 years. DFS after autologous SCTx for 24 patients with hematologic malignancies was 48% at 6 years and survival in unmaintained remission for concomitant AID was 29% at 3 years. Among 30 patients given allogeneic SCTx 19 developed graft-versus-host disease (GVHD) and 11 did not. Upon clinically justified discontinuation of all immunosuppressive therapy, 3/11 patients without GVHD relapsed with their concomitant AID (freedom of AID-relapse 69% at 9 years), whereas none of 19 patients with GVHD did so (log rank: P = 0.0135). Freedom of AID-relapse was superior after allo SCTx compared to autologous SCTx (89% at 18 years vs 38% at 5 years; log rank: P = 0.0002). Our data suggest that a graft-versus-autoimmunity effect after allogeneic hemopoietic SCTx mediates elimination of autoimmunity.
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Affiliation(s)
- W Hinterberger
- 2nd Department of Internal Medicine, Donauspital, and Ludwig Boltzmann Institute for Stem Cell Transplantation, Vienna, Austria
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Abstract
Scleroderma has a high mortality rate, especially in patients with early diffuse disease and poor prognostic features (such as high skin scores and internal organ involvement). In addition, there is no proven therapy for this disease. Finally, scleroderma has an autoimmune-related pathogenesis, particularly in early illness. In this setting, stem cell therapy is a reasonable potential choice. The rationale behind high-dose immunosuppressive therapy and stem cell transplantation in scleroderma, the regimens used, and the recent data from pilot studies are reviewed. The encouraging data, proper patient selection criteria, and appropriate therapy regimen make controlled studies appropriate, and such studies are currently under way in Europe and are soon to begin in the United States.
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Burt RK, Slavin S, Burns WH, Marmont AM. Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure? Int J Hematol 2002; 76 Suppl 1:226-47. [PMID: 12430858 DOI: 10.1007/bf03165251] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hematopoietic stem cells (HSCs) are the earliest cells of the immune system, giving rise to B and T lymphocytes, monocytes, tissue macrophages, and dendritic cells. In animal models, adoptive transfer of HSCs, depending on circumstances, may cause, prevent, or cure autoimmune diseases. Clinical trials have reported early remission of otherwise refractory autoimmune disorders after either autologous or allogeneic hematopoietic stem cell transplantation (HSCT). By percentage of transplantations performed, autoimmune diseases are the most rapidly expanding indication for stem cell transplantation. Although numerous editorials or commentaries have been previously published, no prior review has focused on the immunology of transplantation tolerance or development of phase 3 autoimmune HSCT trials. Results from current trials suggest that mobilization of HSCs, conditioning regimen, eligibility and exclusion criteria, toxicity, outcome, source of stem cells, and posttransplantation follow-up need to be disease specific. HSCT-induced remission of an autoimmune disease allows for a prospective analysis of events involved in immune tolerance not available in cross-sectional studies.
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Affiliation(s)
- Richard K Burt
- Northwestern University Medical Center, Division of Immune Therapy and Autoimmune Disease, Chicago, IL, USA
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Martí JL, Mayordomo JI, Isla MD, Saenz A, Escudero P, Tres A. PBSC autotransplant for inflammatory bowel disease (IBD): a case of ulcerative colitis. Bone Marrow Transplant 2001; 28:109-10. [PMID: 11498755 DOI: 10.1038/sj.bmt.1703103] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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