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Levitte S, Nilkant R, Jensen AR, Zhang KY. Unlocking the promise of mesenchymal stem cells and extracorporeal photopheresis to address rejection and graft failure in intestinal transplant recipients. Hum Immunol 2024; 85:111160. [PMID: 39471538 DOI: 10.1016/j.humimm.2024.111160] [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: 06/27/2024] [Revised: 10/03/2024] [Accepted: 10/13/2024] [Indexed: 11/01/2024]
Abstract
INTRODUCTION In patients with irreversible intestinal failure, intestinal transplant has become a standard treatment option. Graft failure secondary to acute or chronic cellular rejection continues to be a significant challenge following transplant. Even with optimal immune suppression, some patients continue to struggle with refractory rejection. Both extracorporeal photopheresis (ECP) and extracellular vesicles derived from mesenchymal stem cells (EVs) have been used to treat refractory rejection following intestinal transplantation, although their use remains limited and consistent treatment protocols are lacking. METHODS Intestinal transplant recipients who received ECP only or ECP and EVs as rescue therapy for acute cellular rejection or chronic inflammation between 2016 and 2022 were included in this single-center retrospective analysis. Baseline demographics, pre- and post-treatment histopathology, endoscopic and biochemical findings, and long-term transplant outcomes were analyzed. RESULTS Three patients (two pediatric and one adult) with acute steroid- and biologic-refractory rejection were treated with ECP and/or EVs, as was one patient (pediatric) with chronic graft rejection and inflammation. Patients received twice weekly ECP for 4 weeks and once weekly thereafter. EVs were administered in three doses each separated by 72 h. Immunosuppression at the time of treatment initiation included high-dose tacrolimus and sirolimus. Histologic resolution of rejection was achieved in all patients over 12-16 weeks. Steroids were weaned to low-dose or withdrawn in every patient within 4 weeks of ECP/EV treatment. C-reactive protein decreased from an average of 14.75 to 1.6 mg/dL post-treatment and fecal calprotectin decreased from average 800 mg/g to 31 mg/g. Donor-induced cytotoxic T cell populations were quantified for two of the patients with acute rejection, and in both cases decreased dramatically following treatment. There were no complications associated with either treatment. CONCLUSION Both ECP and EVs present novel opportunities to address graft rejection and inflammation in bowel transplant recipients. More work will be needed to define the optimal therapeutic parameters for each treatment modality.
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Affiliation(s)
- Steven Levitte
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, CA, USA
| | - Riya Nilkant
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA
| | - Amanda R Jensen
- Department of Transplantation Surgery, Stanford University, Palo Alto, CA, USA
| | - Ke-You Zhang
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Stanford University, Palo Alto, CA, USA.
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2
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Assadiasl S, Nicknam MH. Intestinal transplantation: Significance of immune responses. Arab J Gastroenterol 2024; 25:330-337. [PMID: 39289083 DOI: 10.1016/j.ajg.2024.08.001] [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: 03/05/2024] [Revised: 07/06/2024] [Accepted: 08/02/2024] [Indexed: 09/19/2024]
Abstract
Intestinal allografts, with many resident immune cells and as a destination for circulating lymphocytes of the recipient, appear to be the most challenging solid organ transplants. The high incidence of acute rejection and frequent reports of fatal graft-versus-host disease (GvHD) after intestinal transplantation call for more research to describe the molecular mechanisms involved in the immunopathogenesis of post-transplant complications to define new therapeutic targets. In addition, according to the rapid development of immunosuppressive agents, it is time to consider novel therapeutic approaches in managing treatment-refractory patients with rejection or severe GvHD. Herein, the main immunological challenges before and after intestinal transplant including, brain-dead donor inflammation, acute rejection, antibody-mediated, and chronic rejections, as well as GvHD have been described. Besides, the new immune-based therapies used in experimental and clinical settings to improve tolerance toward intestinal allograft, and cases of operational tolerance have been reviewed.
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Affiliation(s)
- Sara Assadiasl
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Iranian Tissue Bank and Research Center, Tehran University of Medical Science, Tehran, Iran.
| | - Mohammad Hossein Nicknam
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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3
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Mönch D, Reinders MEJ, Dahlke MH, Hoogduijn MJ. How to Make Sense out of 75,000 Mesenchymal Stromal Cell Publications? Cells 2022; 11:cells11091419. [PMID: 35563725 PMCID: PMC9101744 DOI: 10.3390/cells11091419] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 02/01/2023] Open
Abstract
Mesenchymal stromal cells have been the subject of an expanding number of studies over the past decades. Today, over 75,000 publications are available that shine light on the biological properties and therapeutic effects of these versatile cells in numerous pre-clinical models and early-phase clinical trials. The massive number of papers makes it hard for researchers to comprehend the whole field, and furthermore, they give the impression that mesenchymal stromal cells are wonder cells that are curative for any condition. It is becoming increasingly difficult to dissect how and for what conditions mesenchymal stromal cells exhibit true and reproducible therapeutic effects. This article tries to address the question how to make sense of 75,000, and still counting, publications on mesenchymal stromal cells.
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Affiliation(s)
- Dina Mönch
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany;
- University of Tübingen, 72074 Tübingen, Germany
| | - Marlies E. J. Reinders
- Erasmus MC Transplant Institute, Department of Internal Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands;
| | - Marc H. Dahlke
- Department of Surgery, Robert-Bosch-Hospital, 70376 Stuttgart, Germany;
| | - Martin J. Hoogduijn
- Erasmus MC Transplant Institute, Department of Internal Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands;
- Correspondence:
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Merola J, Shamim A, Weiner J. Update on immunosuppressive strategies in intestinal transplantation. Curr Opin Organ Transplant 2022; 27:119-125. [PMID: 35232925 PMCID: PMC8915446 DOI: 10.1097/mot.0000000000000958] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW The intestine is the most immunologically complex solid organ allograft with the greatest risk of both rejection and graft-versus-host disease (GVHD). High levels of immunosuppression are required, further increasing morbidity. Due to low volume of transplants and few centers with experience, there is paucity of evidence-based, standardized, and effective therapeutic regimens. We herein review the most recent data about immunosuppression, focusing on novel and emerging therapies. RECENT FINDINGS Recent data are moving the field toward increasing use of basilixumab and consideration of alemtuzumab for induction and inclusion of mammalian target of rapamycin inhibitors and antimetabolites for maintenance. For rejection, we highlight novel roles for tumor necrosis factor-α inhibition, α4β7 integrin inhibition, microbiome modulation, desensitization protocols, and tolerance induction strategies. We also highlight emerging novel therapies for GVHD, especially the promising role of Janus kinase inhibition. SUMMARY New insights into immune pathways associated with rejection and GVHD in intestinal allografts have led to an evolution of therapies from broad-based immunosuppression to more targeted strategies that hold promise for reducing morbidity from infection, rejection, and GVHD. These should be the focus of further study to facilitate their widespread use.
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Affiliation(s)
- Jonathan Merola
- Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032
| | - Abrar Shamim
- Columbia University College of Dental Medicine, New York, NY 10032
- Columbia Center for Translational Immunology, Columbia University Vagelos College of Physicians & Surgeons, New York, NY 10032
| | - Joshua Weiner
- Department of Surgery, Columbia University Irving Medical Center, New York, NY 10032
- Columbia Center for Translational Immunology, Columbia University Vagelos College of Physicians & Surgeons, New York, NY 10032
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5
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Burke JR, Helliwell J, Wong J, Quyn A, Herrick S, Jayne D. The use of mesenchymal stem cells in animal models for gastrointestinal anastomotic leak: A systematic review. Colorectal Dis 2021; 23:3123-3140. [PMID: 34363723 DOI: 10.1111/codi.15864] [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] [Received: 05/20/2021] [Revised: 07/29/2021] [Accepted: 07/29/2021] [Indexed: 02/08/2023]
Abstract
AIM Anastomotic leak is the most feared complication of gastrointestinal surgery. Mesenchymal stem cell technology is used clinically to promote wound healing; however, the safety and efficacy of this technology on anastomotic healing has yet to be defined. The aim of this study was to investigate whether mesenchymal stem cells confer any benefit when applied to animal models for gastrointestinal anastomotic leak, identify the methodology and how efficacy is assessed. METHODS The MEDLINE, EMBASE, WebofScience and Cochrane Library databases were interrogated between 1 January1947 to 1 May 2020. All studies where mesenchymal stem cells were applied to laboratory animal leak models to demonstrate a healing effect were considered. All experimental and histological outcomes were examined. Compliance to ARRIVE and current International Consensus was assessed. RESULTS A total of 1205 studies were screened. Twelve studies reported on 438 gastrointestinal anastomoses in four species using 11 models; seven in the colon. No studies utilised a model with a known leak rate. Significant variance was observed in histological outcomes with efficacy demonstrated in five out of 12 studies. One study demonstrated a benefit in leak rate. Colorectal studies had a greater median ARRIVE compliance, 60.8% (IQR 63.2-64.5) compared to noncolorectal 45.4% (IQR 43.8-49.0). CONCLUSIONS Mesenchymal stem cell delivery to an animal anastomosis is safe and feasible. Use may confer benefit but findings are currently limited to surrogate histological outcomes. There is consistency in outcome measures reported but variance in how this is assessed. Poor compliance to ARRIVE but good compliance to current international consensus in leak models of the colon was observed.
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Affiliation(s)
- Joshua Richard Burke
- The John Goligher Colorectal Surgery Unit, St. James's University Hospital, Leeds Teaching Hospital Trust, Leeds, UK
| | - Jack Helliwell
- The John Goligher Colorectal Surgery Unit, St. James's University Hospital, Leeds Teaching Hospital Trust, Leeds, UK
| | - Jason Wong
- Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Aaron Quyn
- The John Goligher Colorectal Surgery Unit, St. James's University Hospital, Leeds Teaching Hospital Trust, Leeds, UK
| | - Sarah Herrick
- Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - David Jayne
- The John Goligher Colorectal Surgery Unit, St. James's University Hospital, Leeds Teaching Hospital Trust, Leeds, UK
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Podestà MA, Remuzzi G, Casiraghi F. Mesenchymal Stromal Cell Therapy in Solid Organ Transplantation. Front Immunol 2021; 11:618243. [PMID: 33643298 PMCID: PMC7902912 DOI: 10.3389/fimmu.2020.618243] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 12/29/2020] [Indexed: 12/29/2022] Open
Abstract
Transplantation is the gold-standard treatment for the failure of several solid organs, including the kidneys, liver, heart, lung and small bowel. The use of tailored immunosuppressive agents has improved graft and patient survival remarkably in early post-transplant stages, but long-term outcomes are frequently unsatisfactory due to the development of chronic graft rejection, which ultimately leads to transplant failure. Moreover, prolonged immunosuppression entails severe side effects that severely impact patient survival and quality of life. The achievement of tolerance, i.e., stable graft function without the need for immunosuppression, is considered the Holy Grail of the field of solid organ transplantation. However, spontaneous tolerance in solid allograft recipients is a rare and unpredictable event. Several strategies that include peri-transplant administration of non-hematopoietic immunomodulatory cells can safely and effectively induce tolerance in pre-clinical models of solid organ transplantation. Mesenchymal stromal cells (MSC), non-hematopoietic cells that can be obtained from several adult and fetal tissues, are among the most promising candidates. In this review, we will focus on current pre-clinical evidence of the immunomodulatory effect of MSC in solid organ transplantation, and discuss the available evidence of their safety and efficacy in clinical trials.
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Affiliation(s)
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Bergamo, Italy
| | - Federica Casiraghi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Aldo & Cele Daccò Clinical Research Center for Rare Diseases, Bergamo, Italy
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7
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Andres AM, Stringa P, Talayero P, Santamaria M, García-Arranz M, García Gómez-Heras S, Largo-Aramburu C, Aras-Lopez RM, Vallejo-Cremades MT, Guerra Pastrián L, Vega L, Encinas JL, Lopez-Santamaria M, Hernández-Oliveros F. Graft infusion of adipose-derived mesenchymal stromal cells to prevent rejection in experimental intestinal transplantation: A feasibility study. Clin Transplant 2021; 35:e14226. [PMID: 33465824 DOI: 10.1111/ctr.14226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/30/2020] [Accepted: 01/12/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Mesenchymal stromal cells (MSC) have been proposed as a promising complement to standard immunosuppression in solid organ transplantation because of their immunomodulatory properties. The present work addresses the role of adipose-derived MSC (Ad-MSC) in an experimental model of acute rejection in small bowel transplantation (SBT). MATERIAL/METHODS Heterotopic allogeneic SBT was performed. A single dose of 1.5x106 Ad-MSC was intra-arterially delivered just before graft reperfusion. Animals were divided into CONTROL (CTRL), CONTROL+Ad-MSC (CTRL_MSC), tacrolimus (TAC), and TAC+Ad-MSC (TAC_MSC) groups. Each Ad-MSC groups was subdivided in autologous and allogeneic third-party groups. RESULTS Rejection rate and severity were similar in MSC-treated and untreated animals. CTRL_MSC animals showed a decrease in macrophages, T-cell (CD4, CD8, and Foxp3 subsets) and B-cell counts in the graft compared with CTRL, this decrease was attenuated in TAC_MSC animals. Pro- and anti-inflammatory cytokines and some chemokines and growth factors increased in CTRL_MSC animals, especially in the allogeneic group, whereas milder changes were seen in the TAC groups. CONCLUSION Ad-MSC did not prevent rejection when administered just before reperfusion. However, they showed immunomodulatory effects that could be relevant for a longer-term outcome. Interference between tacrolimus and the MSC effects should be addressed in further studies.
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Affiliation(s)
- Ane M Andres
- Pediatric Surgery Department, La Paz University Hospital, Madrid, Spain.,Idipaz Institute, La Paz University Hospital, Madrid, Spain.,TransplantChild ERN, Idipaz Institute, La Paz University Hospital, Madrid, Spain
| | - Pablo Stringa
- Institute for Immunological and Physiopathological Studies (IIFP-CONICET-UNLP), National University of La Plata, Buenos Aires, Argentina
| | - Paloma Talayero
- Immunology Department, 12 de Octubre University Hospital, Madrid, Spain.,imas12 Research Institute, 12 de Octubre University Hospital, Madrid, Spain
| | - Monica Santamaria
- Experimental Transplant Department, Alfonso X University, Madrid, Spain
| | | | | | | | - Rosa M Aras-Lopez
- Research Institute, Idipaz Institute, La Paz University Hospital, Madrid, Spain
| | | | | | - Luz Vega
- Health Research Institute, Fundación Jimenez Diaz, Madrid, Spain
| | - Jose Luis Encinas
- Pediatric Surgery Department, La Paz University Hospital, Madrid, Spain
| | | | - Francisco Hernández-Oliveros
- TransplantChild ERN, Idipaz Institute, La Paz University Hospital, Madrid, Spain.,Health Research Institute, Fundación Jimenez Diaz, Madrid, Spain.,Pediatric Surgery Department EOC TransplantChild ERN, La Paz University Hospital, Madrid, Spain
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8
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Hoogduijn MJ, Issa F, Casiraghi F, Reinders MEJ. Cellular therapies in organ transplantation. Transpl Int 2021; 34:233-244. [PMID: 33207013 PMCID: PMC7898347 DOI: 10.1111/tri.13789] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/15/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023]
Abstract
Cellular therapy is a promising tool for improving the outcome of organ transplantation. Various cell types with different immunoregulatory and regenerative properties may find application for specific transplant rejection or injury-related indications. The current era is crucial for the development of cellular therapies. Preclinical models have demonstrated the feasibility of efficacious cell therapy in transplantation, early clinical trials have shown safety of several of these therapies, and the first steps towards efficacy studies in humans have been made. In this review, we address the current state of the art of cellular therapies in clinical transplantation and discuss monitoring tools and endpoints for these studies.
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Affiliation(s)
- Martin J. Hoogduijn
- Nephrology and TransplantationDepartment of Internal MedicineErasmus University Medical CenterErasmus Medical CenterRotterdamThe Netherlands
| | - Fadi Issa
- Transplantation Research and Immunology GroupNuffield Department of Surgical SciencesJohn Radcliffe HospitalUniversity of OxfordOxfordUK
| | | | - Marlies E. J. Reinders
- Nephrology and TransplantationDepartment of Internal MedicineErasmus University Medical CenterErasmus Medical CenterRotterdamThe Netherlands
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9
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Abstract
Over the past decade, the clinical application of mesenchymal stromal cells (MSCs) has generated growing enthusiasm as an innovative cell-based approach in solid organ transplantation (SOT). These expectations arise from a significant number of both transplant- and non-transplant-related experimental studies investigating the complex anti-inflammatory, immunomodulatory, and tissue-repair properties of MSCs. Promising preclinical results have prompted clinical trials using MSC-based therapy in SOT. In the present review, the general properties of MSCs are summarized, with a particular emphasis on MSC-mediated impact on the immune system and in the ischemic conditioning strategy. Next, we chronologically detail all clinical trials using MSCs in the field of SOT. Finally, we envision the challenges and perspectives of MSC-based cell therapy in SOT.
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10
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Abstract
PURPOSE Hirschsprung's disease-related short bowel syndrome (HDSBS) is characterized by aganglionosis that extends orally to 75 cm from Treitz's band. The condition is reported be associated with a high mortality rate of 50-80%. This retrospective study aimed to survey the current trends in HDSBS treatment in Japan. METHODS Patient data were extracted from the results of a nationwide survey we conducted, resulting in the retrospective collection of the data of 1087 HD patients from 2008 to 2012 in Japan. RESULTS A total of 11 (0.9%) cases of HDSBS were noted. All patients underwent jejunostomy as neonates. Radical procedures performed in five patients (A-colon patch method in four, Duhamel's procedure in one). Ziegler's myotomy-myectomy and serial transverse enteroplasty (STEP) were performed in each patient as palliative procedures. No radical operations were performed in 4 of the 11 cases. The mortality rate was 36.4%. Four patients died, 1 patient who underwent STEP and 3 patients who received no radical procedures. The causes of death were sepsis due to enterocolitis or central intravenous catheter infection, and hepatic failure. All patients who underwent radical procedures survived and showed satisfactory outcomes. CONCLUSION HDSBS still showed a high mortality rate, although surgical approaches such as the A-colon patch method resulted in satisfactory outcomes.
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11
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Current status of graft-versus-host disease after intestinal transplantation. Curr Opin Organ Transplant 2019; 24:199-206. [DOI: 10.1097/mot.0000000000000624] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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12
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Clouse JW, Kubal CA, Fridell JA, Pearsall EJ, Mangus RS. Post-intestine transplant graft-vs-host disease associated with inclusion of a liver graft and with a high mortality risk. Clin Transplant 2018; 33:e13409. [PMID: 30222903 DOI: 10.1111/ctr.13409] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 04/19/2018] [Accepted: 09/10/2018] [Indexed: 12/20/2022]
Abstract
INTRODUCTION This study reports the incidence, anatomic location, and outcomes of graft-vs-host disease (GVHD) at a single active intestine transplant center. METHODS Records were reviewed for all patients receiving an intestine transplant from 2003 to 2015. Pathology reports and pharmacy records were reviewed to establish the diagnosis, location, and therapeutic interventions for GVHD. RESULTS A total of 236 intestine transplants were performed during the study period, with 37 patients (16%) developing GVHD. The median time to onset of disease was 83 days, with 89% of affected patients diagnosed in the first year post-transplant. Mortality for affected patients was 54% in the 1 year after GVHD diagnosis. Skin lesions were the most common manifestation of GVHD. Other sites of disease included lungs, bone marrow, oral mucosa, large intestine, and brain. The incidence of GVHD was 16% in adult patients, and slightly lower in pediatric recipients (13%). In adults, increasing graft volume (isolated vs multi-organ) and liver inclusion were associated with increasing risk of GVHD, though this was not seen in pediatric patients. CONCLUSION Overall, 16% of intestine transplant recipients developed GVHD. GVHD is associated with high mortality, and disease in the lungs, brain, and bone marrow was universally fatal.
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Affiliation(s)
- Jared W Clouse
- Department of Surgery, Transplant Division, Indiana University School of Medicine, Indianapolis, Indiana
| | - Chandrashekhar A Kubal
- Department of Surgery, Transplant Division, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jonathan A Fridell
- Department of Surgery, Transplant Division, Indiana University School of Medicine, Indianapolis, Indiana
| | - E Jordan Pearsall
- Department of Surgery, Transplant Division, Indiana University School of Medicine, Indianapolis, Indiana
| | - Richard S Mangus
- Department of Surgery, Transplant Division, Indiana University School of Medicine, Indianapolis, Indiana
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13
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Gürkan A. Advances in small bowel transplantation. Turk J Surg 2017; 33:135-141. [PMID: 28944322 DOI: 10.5152/turkjsurg.2017.3544] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Accepted: 10/17/2016] [Indexed: 12/13/2022]
Abstract
Small bowel transplantation is a life-saving surgery for patients with intestinal failure. The biggest problem in intestinal transplantation is graft rejection. Graft rejection is the main reason for morbidity and mortality. Rejection has a negative effect on the survival of the graft. While 50%-75% of small bowel transplantation patients experience acute rejection, chronic rejection occurs in approximately 15% of patients. Immune monitoring is crucial after small bowel transplantation. Unlike other types of transplantation, there are no non-invasive or reliable markers to predict rejection in small bowel transplantation. The diagnosis of AR is confirmed by clinical symptoms, endoscopic appearance, and pathological specimens taken by endoscopy. Thus, histopathological examinations obtained by protocol biopsies remain as the gold standard for intestinal graft monitoring; however, biopsies have some complications, especially in small grafts. In addition to the high complication rate, biopsies are non-diagnostic; thus, multiple biopsies should be performed to exclude rejection. Therefore, auxiliary assays, such as measurements of citrulline and calprotectin in the blood, cytofluorographic examination of peripheral blood immune cells, cytokine profiling, and distinct gene-set-change measurements, are increasingly being used in small bowel transplantation. Developments in the understanding of genes seem to be promising that limited gene sets, taken from blood or from intestinal biopsies, will enhance pathological diagnosis. Bone marrow mesenchymal stem cell transplantation with SBT and tissue engineering are also promising procedures.
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Affiliation(s)
- Alp Gürkan
- Department of General Surgery, Çamlıca Medicana Hospital, İstanbul, Turkey.,Department of General Surgery, İstanbul Aydın University School of Medicine, İstanbul, Turkey
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14
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Diagnostic Lessons from a Complex Case of Postintestinal Transplantation Enteropathy. Case Rep Transplant 2017; 2017:2498423. [PMID: 28845319 PMCID: PMC5563400 DOI: 10.1155/2017/2498423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Revised: 06/04/2017] [Accepted: 07/04/2017] [Indexed: 11/20/2022] Open
Abstract
Recent advances in the field of intestinal transplantation have been mitigated by the incidence of allograft rejection. In such events, early identification and appropriate timing of antirejection therapy are crucial in retaining graft function. We present the case of a patient who suffered severe postintestinal transplantation allograft enteropathy, primarily characterized by extensive mucosal ulcerations, and was refractory to all conventional therapy. This progressed as chronic rejection; however crucially this was not definitively diagnosed until allograft function had irreversibly diminished. We argue that the difficulties encountered in this case can be attributed to the inability of our current array of investigative studies and diagnostic guidelines to provide adequate clinical guidance. This case illustrates the importance of developing reliable and specific markers for guiding the diagnosis of rejection and the use of antirejection therapeutics in this rapidly evolving field of transplant surgery.
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15
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Li A, Tao Y, Kong D, Zhang N, Wang Y, Wang Z, Wang Y, Wang J, Xiao J, Jiang Y, Liu X, Zheng C. Infusion of umbilical cord mesenchymal stem cells alleviates symptoms of ankylosing spondylitis. Exp Ther Med 2017; 14:1538-1546. [PMID: 28781629 PMCID: PMC5526206 DOI: 10.3892/etm.2017.4687] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 03/17/2017] [Indexed: 02/06/2023] Open
Abstract
The current study evaluated 5 patients with ankylosing spondylitis (AS). Patients received intravenous transfusions of umbilical cord mesenchymal stem cells (uMSCs). All therapeutic and adverse responses were assessed and recorded during uMSC therapy. No severe adverse reactions were observed in any of the patients, although a slight transient fever was observed in 3 patients within 2–6 h of intravenous administration of uMSCs. Following treatment, the Bath Ankylosing Spondylitis Disease Activity and Bath Ankylosing Spondylitis Metrology Indices decreased, however the Bath Ankylosing Spondylitis Functional Index increased. The erythrocyte sedimentation rate in 3 patients was reduced and C-reactive protein levels in 1 patient were markedly reduced. The symptoms of AS were alleviated in all patients. The present study indicates that intravenous transfusion of uMSCs is safe and well tolerated by patients and that it effectively alleviates disease activity and clinical symptoms. In the future, a larger cohort of patients with AS should be recruited to enable the systemic evaluation of uMSC therapy.
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Affiliation(s)
- Ai Li
- Department of Hematology and Cellular Therapy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China.,Shandong University-Karolinska Institute Collaborative Laboratory For Stem Cell Research, Jinan, Shandong 250033, P.R. China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Yuan Tao
- Department of Hematology and Cellular Therapy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China.,Shandong University-Karolinska Institute Collaborative Laboratory For Stem Cell Research, Jinan, Shandong 250033, P.R. China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Dexiao Kong
- Department of Hematology and Cellular Therapy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China.,Shandong University-Karolinska Institute Collaborative Laboratory For Stem Cell Research, Jinan, Shandong 250033, P.R. China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Ni Zhang
- Department of Hematology and Cellular Therapy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China
| | - Yongjing Wang
- Department of Hematology and Cellular Therapy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China.,Shandong University-Karolinska Institute Collaborative Laboratory For Stem Cell Research, Jinan, Shandong 250033, P.R. China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Zhilun Wang
- Department of Hematology and Cellular Therapy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China.,Shandong University-Karolinska Institute Collaborative Laboratory For Stem Cell Research, Jinan, Shandong 250033, P.R. China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Yingxue Wang
- Department of Hematology and Cellular Therapy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China.,Shandong University-Karolinska Institute Collaborative Laboratory For Stem Cell Research, Jinan, Shandong 250033, P.R. China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Juandong Wang
- Department of Hematology and Cellular Therapy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China.,Shandong University-Karolinska Institute Collaborative Laboratory For Stem Cell Research, Jinan, Shandong 250033, P.R. China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Juan Xiao
- Department of Hematology and Cellular Therapy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China.,Shandong University-Karolinska Institute Collaborative Laboratory For Stem Cell Research, Jinan, Shandong 250033, P.R. China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Yang Jiang
- Department of Hematology and Cellular Therapy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China.,Shandong University-Karolinska Institute Collaborative Laboratory For Stem Cell Research, Jinan, Shandong 250033, P.R. China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Xiaoli Liu
- Department of Hematology and Cellular Therapy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China.,Shandong University-Karolinska Institute Collaborative Laboratory For Stem Cell Research, Jinan, Shandong 250033, P.R. China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, Shandong 250033, P.R. China
| | - Chengyun Zheng
- Department of Hematology and Cellular Therapy, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China.,Shandong University-Karolinska Institute Collaborative Laboratory For Stem Cell Research, Jinan, Shandong 250033, P.R. China.,Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, Shandong 250033, P.R. China
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16
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Yang L, Shen ZY, Wang RR, Yin ML, Zheng WP, Wu B, Liu T, Song HL. Effects of heme oxygenase-1-modified bone marrow mesenchymal stem cells on microcirculation and energy metabolism following liver transplantation. World J Gastroenterol 2017; 23:3449-3467. [PMID: 28596681 PMCID: PMC5442081 DOI: 10.3748/wjg.v23.i19.3449] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 01/23/2017] [Accepted: 02/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effects of heme oxygenase-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) on the microcirculation and energy metabolism of hepatic sinusoids following reduced-size liver transplantation (RLT) in a rat model.
METHODS BMMSCs were isolated and cultured in vitro using an adherent method, and then transduced with HO-1-bearing recombinant adenovirus to construct HO-1/BMMSCs. A rat acute rejection model following 50% RLT was established using a two-cuff technique. Recipients were divided into three groups based on the treatment received: normal saline (NS), BMMSCs and HO-1/BMMSCs. Liver function was examined at six time points. The levels of endothelin-1 (ET-1), endothelial nitric-oxide synthase (eNOS), inducible nitric-oxide synthase (iNOS), nitric oxide (NO), and hyaluronic acid (HA) were detected using an enzyme-linked immunosorbent assay. The portal vein pressure (PVP) was detected by Power Lab ML880. The expressions of ET-1, iNOS, eNOS, and von Willebrand factor (vWF) protein in the transplanted liver were detected using immunohistochemistry and Western blotting. ATPase in the transplanted liver was detected by chemical colorimetry, and the ultrastructural changes were observed under a transmission electron microscope.
RESULTS HO-1/BMMSCs could alleviate the pathological changes and rejection activity index of the transplanted liver, and improve the liver function of rats following 50% RLT, with statistically significant differences compared with those of the NS group and BMMSCs group (P < 0.05). In term of the microcirculation of hepatic sinusoids: The PVP on POD7 decreased significantly in the HO-1/BMMSCs and BMMSCs groups compared with that of the NS group (P < 0.01); HO-1/BMMSCs could inhibit the expressions of ET-1 and iNOS, increase the expressions of eNOS and inhibit amounts of NO production, and maintain the equilibrium of ET-1/NO (P < 0.05); and HO-1/BMMSCs increased the expression of vWF in hepatic sinusoidal endothelial cells (SECs), and promoted the degradation of HA, compared with those of the NS group and BMMSCs group (P < 0.05). In term of the energy metabolism of the transplanted liver, HO-1/BMMSCs repaired the damaged mitochondria, and improved the activity of mitochondrial aspartate aminotransferase (ASTm) and ATPase, compared with the other two groups (P <0.05).
CONCLUSION HO-1/BMMSCs can improve the microcirculation of hepatic sinusoids significantly, and recover the energy metabolism of damaged hepatocytes in rats following RLT, thus protecting the transplanted liver.
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17
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Zorzopulos J, Opal SM, Hernando-Insúa A, Rodriguez JM, Elías F, Fló J, López RA, Chasseing NA, Lux-Lantos VA, Coronel MF, Franco R, Montaner AD, Horn DL. Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy. World J Stem Cells 2017; 9:45-67. [PMID: 28396715 PMCID: PMC5368622 DOI: 10.4252/wjsc.v9.i3.45] [Citation(s) in RCA: 9] [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: 07/12/2016] [Revised: 10/12/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
The immune responses of humans and animals to insults (i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell (MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.
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18
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Xiang H, Zhang X, Yang C, Xu W, Ge X, Zhang R, Qiu Y, Sun W, Li F, Xiang T, Chen H, Wang Z, Zeng Q. Autologous bone marrow stem cell transplantation for the treatment of ulcerative colitis complicated with herpes zoster: a case report. Front Med 2016; 10:522-526. [PMID: 27896624 DOI: 10.1007/s11684-016-0485-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2015] [Accepted: 08/17/2016] [Indexed: 12/27/2022]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with continuous or recurrent symptoms. A 42-year-old male patient with intermittent diarrhea accompanied by bloody mucopurulent stools was admitted to our hospital. The diagnosis of UC was confirmed by a combination of laboratory examination, colonoscopy, and histological assay. The patient developed herpes zoster in the hospital, which challenged traditional treatments. Therefore, we performed an autologous bone marrow cells to modulate the immune system with his permission. Autologous bone marrow mononuclear cells were collected and injected locally into the bowel mucosa, and subsequently injected systemically through a peripheral vein. After the patient underwent auto bone marrow mononuclear cells transplantations twice, the patient's symptoms were alleviated. Furthermore, he recovered from hematochezia, and his hypersensitive C reactive protein decreased. Colonoscopy results showed reduced lesions and decreased areas with bleeding and edema in the sigmoid colon and rectum. No recurrence occurred in the subsequent two years, but long-time monitoring is still necessary for the prophylaxis of colorectal cancer.
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Affiliation(s)
- Hang Xiang
- Institute of Health Management, Institute of Geriatrics, Beijing Key Laboratory of Normal Aging and Geriatrics, Department of Gerontal Gastroenterology, Chinese PLA General Hospital, Beijing, 100853, China
| | - Xiaomei Zhang
- Institute of Health Management, Institute of Geriatrics, Beijing Key Laboratory of Normal Aging and Geriatrics, Department of Gerontal Gastroenterology, Chinese PLA General Hospital, Beijing, 100853, China
| | - Chao Yang
- Department of Blood Transfusion, Department of Hematology, The General Hospital of the PLA Rocket Force, Beijing, 100088, China
| | - Wenhuan Xu
- Institute of Health Management, Institute of Geriatrics, Beijing Key Laboratory of Normal Aging and Geriatrics, Department of Gerontal Gastroenterology, Chinese PLA General Hospital, Beijing, 100853, China
| | - Xin Ge
- Galactophore Department of the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Rong Zhang
- Department of Blood Transfusion, Department of Hematology, The General Hospital of the PLA Rocket Force, Beijing, 100088, China
| | - Ya Qiu
- Institute of Health Management, Institute of Geriatrics, Beijing Key Laboratory of Normal Aging and Geriatrics, Department of Gerontal Gastroenterology, Chinese PLA General Hospital, Beijing, 100853, China
| | - Wanjun Sun
- Department of Blood Transfusion, Department of Hematology, The General Hospital of the PLA Rocket Force, Beijing, 100088, China
| | - Fan Li
- Institute of Health Management, Institute of Geriatrics, Beijing Key Laboratory of Normal Aging and Geriatrics, Department of Gerontal Gastroenterology, Chinese PLA General Hospital, Beijing, 100853, China
| | - Tianyuan Xiang
- Geriatrics Institute of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Haixu Chen
- Institute of Health Management, Institute of Geriatrics, Beijing Key Laboratory of Normal Aging and Geriatrics, Department of Gerontal Gastroenterology, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Zheng Wang
- Department of Biotherapy of PLA 455 Hospital, Shanghai, 200052, China.
| | - Qiang Zeng
- Institute of Health Management, Institute of Geriatrics, Beijing Key Laboratory of Normal Aging and Geriatrics, Department of Gerontal Gastroenterology, Chinese PLA General Hospital, Beijing, 100853, China.
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19
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Yang Y, Song HL, Zhang W, Wu BJ, Fu NN, Dong C, Shen ZY. Heme oxygenase-1-transduced bone marrow mesenchymal stem cells in reducing acute rejection and improving small bowel transplantation outcomes in rats. Stem Cell Res Ther 2016; 7:164. [PMID: 27866474 PMCID: PMC5116370 DOI: 10.1186/s13287-016-0427-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 09/22/2016] [Accepted: 10/20/2016] [Indexed: 12/13/2022] Open
Abstract
Background We determined whether bone marrow mesenchymal stem cells (BMMSCs) transduced with heme oxygenase-1 (HO-1), a cytoprotective and immune-protective factor, could improve outcomes for small bowel transplantation (SBTx) in rats. Methods We performed heterotopic SBTx from Brown Norway rats to Lewis rats, before infusing Ad/HO-1-transduced BMMSCs (Ad/HO-1/BMMSCs) through the superficial dorsal veins of the penis. Respective infusions with Ad/BMMSCs, BMMSCs, and normal saline served as controls. The animals were sacrificed after 1, 5, 7, or 10 days. At each time point, we measured small bowel histology and apoptosis, HO-1 protein and mRNA expression, natural killer (NK) cell activity, cytokine concentrations in serum and intestinal graft, and levels of regulatory T (Treg) cells. Results The saline-treated control group showed aggravated acute cellular rejection over time, with mucosal destruction, increased apoptosis, NK cell activation, and upregulation of proinflammatory and immune-related mediators. Both the Ad/BMMSC-treated group and the BMMSC-treated group exhibited attenuated acute cellular rejection at an early stage, but the effects receded 7 days after transplantation. Strikingly, the Ad/HO-1/BMMSC-treated group demonstrated significantly attenuated acute cellular rejection, reduced apoptosis and NK cell activity, and suppressed concentrations of inflammation and immune-related cytokines, and upregulated expression of anti-inflammatory cytokine mediators and increased Treg cell levels. Conclusion Our data suggest that Ad/HO-1-transduced BMMSCs have a reinforced effect on reducing acute rejection and protecting the outcome of SBTx in rats.
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Affiliation(s)
- Yang Yang
- Department of Organ Transplantation, Tianjin First Central Hospital, 24# Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China
| | - Hong Li Song
- Department of Organ Transplantation, Tianjin First Central Hospital, 24# Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China. .,Tianjin Key Laboratory of Organ Transplantation, 24# Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China.
| | - Wen Zhang
- Department of Organ Transplantation, Tianjin First Central Hospital, 24# Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China
| | - Ben Juan Wu
- Department of Organ Transplantation, Tianjin First Central Hospital, 24# Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China
| | - Nan Nan Fu
- Department of Organ Transplantation, Tianjin First Central Hospital, 24# Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China
| | - Chong Dong
- Department of Organ Transplantation, Tianjin First Central Hospital, 24# Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China
| | - Zhong Yang Shen
- Department of Organ Transplantation, Tianjin First Central Hospital, 24# Fukang Road, Nankai District, Tianjin, 300192, People's Republic of China.
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20
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Green T, Hind J. Graft-versus-host disease in paediatric solid organ transplantation: A review of the literature. Pediatr Transplant 2016; 20:607-18. [PMID: 27198497 DOI: 10.1111/petr.12721] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/24/2016] [Indexed: 12/23/2022]
Abstract
GvHD is a rare and serious complication of organ transplantation. The literature is sparse following solid organ transplantation. The aim of this report was to review the literature of GvHD in paediatric solid organ transplantation. We searched PubMed for English-language full-text manuscripts between 1990 and 2015 for eligible studies. A total of 28 publications were found pertaining to paediatric GvHD following solid organ transplantation. GvHD had a mean incidence of 11% (range 8.3-13.4%) following SBTx and 1.5% following liver transplantation. Where described, the most common sites for presentation of GvHD were the skin (87%), the native GI tract (43%), the lungs (7%), the eyes (4%), HA (4%), and the kidneys (1%). Diagnosis was confirmed with biopsy (93%) and/or chimerism (41%). Treatments used include steroids (80%), of which 75% showed partial or complete resolution. Mortality was 33.3% (range 0-100%). Novel therapies include ECP and MSC therapy. GvHD is a rare but serious disease with high mortality. Novel therapies may offer hope in the future, but currently there is limited evidence for their efficacy in the context of intestinal or liver transplantation.
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Affiliation(s)
- Thomas Green
- King's College London - GKT School of Medical Education, London, UK
| | - Jonathan Hind
- King's College Hospital - Paediatric Liver, GI and Nutrition Centre, London, UK
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21
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Abstract
Despite recent therapeutic advances, patients with Crohn's disease (CD) continue to experience high recurrence with cumulative structural damage and ultimate loss of nutritional autonomy. With short bowel syndrome, strictures, and enteric fistulae being the underlying pathology, CD is the second common indication for home parenteral nutrition (HPN). With development of intestinal failure, nutritional management including HPN is required as a rescue therapy. Unfortunately, some patients do not escape the HPN-associated complications. Therefore, the concept of gut rehabilitation has evolved as part of the algorithmic management of these patients, with transplantation being the ultimate life-saving therapy. With type 2 intestinal failure, comprehensive rehabilitative measures including nutritional care, pharmacologic manipulation, autologous reconstruction, and bowel lengthening is often successful, particularly in patients with quiescent disease. With type 3 intestinal failure, transplantation is the only life-saving treatment for patients with HPN failure and intractable disease. With CD being the second common indication for transplantation in adults, survival outcome continues to improve because of surgical innovation, novel immunosuppression, and better postoperative care. Despite being a rescue therapy, the procedure has achieved survival rates similar to other solid organs, and comparable to those who continue to receive HPN therapy. With similar technical, immunologic, and infectious complications, survival is similar in the CD and non-CD recipients. Full nutritional autonomy is achievable in most survivors with better quality of life and long-term cost-effectiveness. CD recurrence is rare with no impact on graft function. Further progress is anticipated with new insights into the pathogenesis of CD and mechanisms of transplant tolerance.
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22
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Houston BL, Yan M, Tinckam K, Kamel-Reid S, Chang H, Kuo KHM, Tsien C, Seftel MD, Avitzur Y, Grant D, Cserti-Gazdewich CM. Extracorporeal photopheresis in solid organ transplant-associated acute graft-versus-host disease. Transfusion 2016; 56:962-9. [PMID: 26892365 DOI: 10.1111/trf.13467] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 10/18/2015] [Accepted: 10/19/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND Extracorporeal photopheresis (ECP) culls pathogenic T lymphocytes, be these the clones of cutaneous T-cell lymphoma, or mediators of chronic graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT-GVHD). Whether or not ECP may have an effect in the rarer instances of solid organ transplantation-associated GVHD (SOT-GVHD) is unclear. Mortality rates in SOT-GVHD rival those of transfusion-associated GVHD, with fatalities preceded by pancytopenia and peripheral blood chimerism (PBC) levels exceeding 20%. ECP has been described in two SOT-GVHD cases to date, with one surviving. STUDY DESIGN AND METHODS Clinicolaboratory features (including HLA relationships) in a case of multivisceral transplantation were reviewed from the time of surgery to the onset and progression of SOT-GVHD. ECP, which was introduced as a less immunosuppressive and more selective intervention, was assessed for its effect on serial PBC (as measured by short-tandem-repeat analysis) and clinical outcome. RESULTS Multivisceral SOT-GVHD manifested with erythroderma, neutropenic sepsis, and PBC increasing from 6% on Posttransplant Day (PTD) 38 to 78% by PTD 60 (at a doubling time of 6 days despite corticosteroids). ECP was administered on PTDs 62 and 67 and was associated with the first evidence of PBC decay to 67% on PTD 69. Death nevertheless ensued on the last day of salvage antithymocyte globulin (PTDs 69-73) despite further PBC reduction to 41%. CONCLUSION Further study is needed to determine if the sooner or more frequent application of ECP might attenuate the high case fatality rates of SOT-GVHD.
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Affiliation(s)
| | - Matthew Yan
- Department of Medical Oncology and Hematology, University of Toronto
| | - Kathryn Tinckam
- Department of Medicine.,Laboratory Medicine Program, University Health Network and University of Toronto, Toronto, Ontario
| | - Suzanne Kamel-Reid
- Laboratory Medicine Program, University Health Network and University of Toronto, Toronto, Ontario
| | - Hong Chang
- Laboratory Medicine Program, University Health Network and University of Toronto, Toronto, Ontario
| | - Kevin H M Kuo
- Department of Medicine.,Department of Medical Oncology and Hematology, University of Toronto
| | | | - Matthew D Seftel
- Department of Medical Oncology and Hematology, CancerCare Manitoba, and Section of Hematology/Oncology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba
| | - Yaron Avitzur
- Department of Paediatrics, Hospital for Sick Children, Toronto
| | - David Grant
- Department of Surgery, University Health Network and University of Toronto, Toronto, Ontario, Canada
| | - Christine M Cserti-Gazdewich
- Department of Medicine.,Department of Medical Oncology and Hematology, University of Toronto.,Laboratory Medicine Program, University Health Network and University of Toronto, Toronto, Ontario
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