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Madill-Thomsen KS, Abouljoud M, Bhati C, Ciszek M, Durlik M, Feng S, Foroncewicz B, Francis I, Grąt M, Jurczyk K, Klintmalm G, Krasnodębski M, McCaughan G, Miquel R, Montano-Loza A, Moonka D, Mucha K, Myślak M, Pączek L, Perkowska-Ptasińska A, Piecha G, Reichman T, Sanchez-Fueyo A, Tronina O, Wawrzynowicz-Syczewska M, Więcek A, Zieniewicz K, Halloran PF. The molecular phenotypes of injury, steatohepatitis, and fibrosis in liver transplant biopsies in the INTERLIVER study. Am J Transplant 2022; 22:909-926. [PMID: 34780106 DOI: 10.1111/ajt.16890] [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: 06/01/2021] [Revised: 10/19/2021] [Accepted: 10/21/2021] [Indexed: 01/25/2023]
Abstract
To extend previous molecular analyses of rejection in liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov #NCT03193151), the present study aimed to define the gene expression selective for parenchymal injury, fibrosis, and steatohepatitis. We analyzed genome-wide microarray measurements from 337 liver transplant biopsies from 13 centers. We examined expression of genes previously annotated as increased in injury and fibrosis using principal component analysis (PCA). PC1 reflected parenchymal injury and related inflammation in the early posttransplant period, slowly regressing over many months. PC2 separated early injury from late fibrosis. Positive PC3 identified a distinct mildly inflamed state correlating with histologic steatohepatitis. Injury PCs correlated with liver function and histologic abnormalities. A classifier trained on histologic steatohepatitis predicted histologic steatohepatitis with cross-validated AUC = 0.83, and was associated with pathways reflecting metabolic abnormalities distinct from fibrosis. PC2 predicted histologic fibrosis (AUC = 0.80), as did a molecular fibrosis classifier (AUC = 0.74). The fibrosis classifier correlated with matrix remodeling pathways with minimal overlap with those selective for steatohepatitis, although some biopsies had both. Genome-wide assessment of liver transplant biopsies can not only detect molecular changes induced by rejection but also those correlating with parenchymal injury, steatohepatitis, and fibrosis, offering potential insights into disease mechanisms for primary diseases.
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Affiliation(s)
| | | | - Chandra Bhati
- Virginia Commonwealth University, Richmond, Virginia, USA
| | - Michał Ciszek
- Department of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Magdalena Durlik
- Department of Transplant Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Sandy Feng
- University of California San Francisco, San Francisco, California, USA
| | - Bartosz Foroncewicz
- Department of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | | | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof Jurczyk
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland
| | | | - Maciej Krasnodębski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Geoff McCaughan
- Centenary Research Institute, Australian National Liver Transplant Unit, Royal Prince Alfred Hospital, The University of Sydney, Sydney, New South Wales, Australia
| | | | | | | | - Krzysztof Mucha
- Department of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Marek Myślak
- Department of Clinical Interventions, Department of Nephrology and Kidney Transplantation SPWSZ Hospital, Pomeranian Medical University, Szczecin, Poland
| | - Leszek Pączek
- Department of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | | | - Grzegorz Piecha
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland
| | | | | | - Olga Tronina
- Department of Transplant Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Marta Wawrzynowicz-Syczewska
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland
| | - Andrzej Więcek
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland
| | - Krzysztof Zieniewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
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2
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Richards J, Gimson A, Joh Y, Watson CJE, Neuberger J. Trials & Tribulations of Liver Transplantation- are trials now prohibitive without surrogate endpoints? Liver Transpl 2021; 27:747-755. [PMID: 33462951 DOI: 10.1002/lt.25988] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 01/03/2021] [Accepted: 01/06/2021] [Indexed: 01/13/2023]
Abstract
During the past 5 decades, liver transplantation has moved from its pioneering days where success was measured in days to a point where it is viewed as a routine part of medical care. Despite this progress, there are still significant unmet needs and outstanding questions that need addressing in clinical trials to improve outcomes for patients. The traditional endpoint for trials in liver transplantation has been 1-year patient survival, but with rates now approaching 95%, this endpoint now poses a number of significant financial and logistical barriers to conducting trials because of the large numbers of participants required to demonstrate only an incremental improvement. Here, we suggest the following solutions to this challenge: adoption of validated surrogate endpoints; bigger and better collaborative multiarm, multiphase studies; recognition by funders and institutions that work on larger collaborative research projects is potentially more important than smaller, self-led bodies of work; ringfenced areas of research within trial frameworks where individuals can take a lead; and fair funding structures using both industry and public sector money across national and international borders.
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Affiliation(s)
- James Richards
- Department of Surgery Addenbrooke's HospitalUniversity of Cambridge Cambridge UK The National Institute of Health Research Blood and Transplant Research Unit at the University of Cambridge in collaboration with Newcastle University and in partnership with National Health Service Blood and Transplant Cambridge UK The National Institute of Health Research Cambridge Biomedical Research Centre Cambridge UK Department of Medicine Cambridge University HospitalsAddenbrooke's Hospital Cambridge UK Department of Hepatopancreatobiliary and Transplant Surgery Singapore General Hospital Singapore University Hospital Birmingham NHS Foundation Trust Birmingham UK
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3
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Precise immune tolerance for hPSC derivatives in clinical application. Cell Immunol 2017; 326:15-23. [PMID: 28866278 DOI: 10.1016/j.cellimm.2017.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 08/03/2017] [Accepted: 08/04/2017] [Indexed: 11/22/2022]
Abstract
Human pluripotent stem cells (hPSCs) promise a foreseeing future for regeneration medicine and cell replacement therapy with their abilities to produce almost any types of somatic cells of the body. The complicated immunogenicity of hPSC derivatives and context dependent responses in variable transplantations greatly hurdle the practical application of hPSCs in clinic. Especially for applications of hPSCs, induction of immune tolerance at the same time increases the risks of tumorigenesis. Over the past few years, thanks to the progress in immunology and practices in organ transplantation, endeavors on exploring strategies to induce long term protection of allogeneic transplants have shed light on overcoming this barrier. Novel genetic engineering techniques also allow to precisely cradle the immune response of transplantation. Here we reviewed the current understanding on immunogenicity, and efforts have been attempted on inducing immune tolerance for hPSC derivatives, with extra focus on modifying the graft cells. We also glimpse on employing cutting-edge genome editing technologies for this purpose, which will potentially endow hPSC derivatives with the nature of wide spectrum drugs for therapy.
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Trotter JF, Levy G. Sotrastaurin in liver transplantation: has it had a fair trial? Am J Transplant 2015; 15:1137-8. [PMID: 25677186 DOI: 10.1111/ajt.13179] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 12/10/2014] [Accepted: 12/11/2014] [Indexed: 01/25/2023]
Affiliation(s)
- J F Trotter
- Baylor University Medical Center, Dallas, TX
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5
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Adams DH, Sanchez-Fueyo A, Samuel D. From immunosuppression to tolerance. J Hepatol 2015; 62:S170-85. [PMID: 25920086 DOI: 10.1016/j.jhep.2015.02.042] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 02/25/2015] [Accepted: 02/28/2015] [Indexed: 12/14/2022]
Abstract
The past three decades have seen liver transplantation becoming a major therapeutic approach in the management of end-stage liver diseases. This is due to the dramatic improvement in survival after liver transplantation as a consequence of the improvement of surgical and anaesthetic techniques, of post-transplant medico-surgical management and of prevention of disease recurrence and other post-transplant complications. Improved use of post-transplant immunosuppression to prevent acute and chronic rejection is a major factor in these improved results. The liver has been shown to be more tolerogenic than other organs, and matching of donor and recipients is mainly limited to ABO blood group compatibility. However, long-term immunosuppression is required to avoid severe acute and chronic rejection and graft loss. With the current immunosuppression protocols, the risk of acute rejection requiring additional therapy is 10-40% and the risk of chronic rejection is below 5%. However, the development of histological lesions in the graft in long-term survivors suggest atypical forms of graft rejection may develop as a consequence of under-immunosuppression. The backbone of immunosuppression remains calcineurin inhibitors (CNI) mostly in association with steroids in the short-term and mycophenolate mofetil or mTOR inhibitors (everolimus). The occurrence of post-transplant complications related to the immunosuppressive therapy has led to the development of new protocols aimed at protecting renal function and preventing the development of de novo cancer and of dysmetabolic syndrome. However, there is no new class of immunosuppressive drugs in the pipeline able to replace current protocols in the near future. The aim of a full immune tolerance of the graft is rarely achieved since only 20% of selected patients can be weaned successfully off immunosuppression. In the future, immunosuppression will probably be more case oriented aiming to protect the graft from rejection and at reducing the risk of disease recurrence and complications related to immunosuppressive therapy. Such approaches will include strategies aiming to promote stable long-term immunological tolerance of the liver graft.
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Affiliation(s)
- David H Adams
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, University of Birmingham and Queen Elizabeth Hospital, Edgbaston Birmingham B152TT, United Kingdom
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, MRC Centre for Transplantation, King's College London, London SE5 9RS, United Kingdom
| | - Didier Samuel
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire; Inserm, Research Unit 1193; Université Paris-Sud, Villejuif F-94800, France.
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Rong Z, Wang M, Hu Z, Stradner M, Zhu S, Kong H, Yi H, Goldrath A, Yang YG, Xu Y, Fu X. An effective approach to prevent immune rejection of human ESC-derived allografts. Cell Stem Cell 2014; 14:121-30. [PMID: 24388175 DOI: 10.1016/j.stem.2013.11.014] [Citation(s) in RCA: 182] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 10/07/2013] [Accepted: 11/15/2013] [Indexed: 01/03/2023]
Abstract
Human embryonic stem cells (hESCs) hold great promise for cell therapy as a source of diverse differentiated cell types. One key bottleneck to realizing such potential is allogenic immune rejection of hESC-derived cells by recipients. Here, we optimized humanized mice (Hu-mice) reconstituted with a functional human immune system that mounts a vigorous rejection of hESCs and their derivatives. We established knockin hESCs that constitutively express CTLA4-Ig and PD-L1 before and after differentiation, denoted CP hESCs. We then demonstrated that allogenic CP hESC-derived teratomas, fibroblasts, and cardiomyocytes are immune protected in Hu-mice, while cells derived from parental hESCs are effectively rejected. Expression of both CTLA4-Ig, which disrupts T cell costimulatory pathways, and PD-L1, which activates T cell inhibitory pathway, is required to confer immune protection, as neither was sufficient on their own. These findings are instrumental for developing a strategy to protect hESC-derived cells from allogenic immune responses without requiring systemic immune suppression.
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Affiliation(s)
- Zhili Rong
- Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA
| | - Meiyan Wang
- Shenzhen Children's Hospital, Shenzhen, Guangdong 518026, China; Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA
| | - Zheng Hu
- First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Martin Stradner
- Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA
| | - Shengyun Zhu
- Shenzhen Children's Hospital, Shenzhen, Guangdong 518026, China; Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA
| | - Huijuan Kong
- Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA
| | - Huanfa Yi
- First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Ananda Goldrath
- Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA
| | - Yong-Guang Yang
- First Hospital of Jilin University, Changchun, Jilin 130021, China; Columbia Center for Translational Immunology, Columbia University Medical School, New York, NY 10032, USA
| | - Yang Xu
- Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
| | - Xuemei Fu
- Shenzhen Children's Hospital, Shenzhen, Guangdong 518026, China; Children's Hospital, Chongqing Medical University, Chongqing 400016, China.
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Zarrinpar A, Busuttil RW. Immunomodulating options for liver transplant patients. Expert Rev Clin Immunol 2013; 8:565-78; quiz 578. [PMID: 22992151 DOI: 10.1586/eci.12.47] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Much has changed since the early years of liver transplantation. Improvements in post-transplant survival are largely due to more selective and less toxic immunosuppression regimens and advances in operative and perioperative care. This has allowed liver transplantation to become an extremely successful treatment option for patients with endstage liver disease. Beginning with cyclosporine, a cyclic endecapeptide of fungal origin and the first of the calcineurin inhibitors to find widespread use, immunosuppressive regimens have evolved to include additional calcineurin inhibitors, steroids, mTOR inhibitors, antimetabolites and antibodies, mostly targeting T-cell activation. This review will present currently available immunosuppressive agents used in the perioperative period of liver transplantation, as well as maintenance treatments, tailoring therapeutic strategies for specific populations, and advances in immune monitoring and tolerance.
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Affiliation(s)
- Ali Zarrinpar
- Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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Ghanekar A, Kashfi A, Cattral M, Selzner N, McGilvray I, Selzner M, Renner E, Lilly L, Levy G, Grant D, Greig P. Routine induction therapy in living donor liver transplantation prevents rejection but may promote recurrence of hepatitis C. Transplant Proc 2012; 44:1351-6. [PMID: 22664014 DOI: 10.1016/j.transproceed.2012.01.117] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Accepted: 01/25/2012] [Indexed: 12/15/2022]
Abstract
BACKGROUND Routine induction therapy in living donor liver transplantation (LDLT) has not been well described. METHODS We reviewed outcomes of induction therapy with rabbit antithymocyte globulin (rATG) or basiliximab within 1 year of LDLT. RESULTS Between 2002 and 2007, 184 adults underwent LDLT and received induction therapy in addition to standard immunosuppression. Acute cellular rejection (ACR) developed in 17 of 130 patients (13.1%) who received rATG and 13 of 54 patients (24.1%) who received basiliximab (P = .066). The interval between transplantation and rejection as well as rejection severity was similar in patients who received rATG and those who received basiliximab. Hepatitis C (HCV) recurrence requiring initiation of antiviral therapy was more common in patients who received rATG compared with basiliximab (34.5% vs 8.7%; P = .021), and in those who received induction combined with tacrolimus as opposed to cyclosporine (38.5% vs 3.9%; P = .001). rATG and basiliximab were associated with excellent patient and graft survivals well as low rates of opportunistic infections and malignancies. CONCLUSION Induction with rATG or basiliximab was well tolerated and highly effective at preventing ACR within 1 year of LDLT, but may be associated with a higher risk of clinically significant HCV recurrence in some patients.
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Affiliation(s)
- A Ghanekar
- University of Toronto Liver Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada.
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Meadows HB, Taber DJ, Pilch NA, Tischer SM, Baliga PK, Chavin KD. The impact of early corticosteroid withdrawal on graft survival in liver transplant recipients. Transplant Proc 2012; 44:1323-8. [PMID: 22664009 DOI: 10.1016/j.transproceed.2012.01.110] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Accepted: 01/21/2012] [Indexed: 01/13/2023]
Abstract
BACKGROUND There has been increased interest in recent years in reducing or eliminating steroids from the immunosuppression regimen of transplant recipients to reduce adverse effects associated with their use. The purpose of this study was to compare clinical outcomes between early versus late steroid withdrawal after liver transplant to determine the optimal duration of steroid use in this population. METHODS This large-scale, retrospective analysis of liver transplants occurred at our institution between 2000 and 2009. Patients were excluded if they were <18 years old, received a multiorgan transplant, or remained on steroids for >1 year. The early steroid withdrawal group had steroids eliminated by 3 months posttransplant; late steroid withdrawal patients had steroids withdrawn between 3 and 12 months posttransplant. RESULTS A total of 586 liver transplants occurred during the study period; 330 patients were included in the analysis. Graft survival was significantly lower in the early steroid withdrawal group. There was no difference in patient survival or overall acute rejection. However, the late steroid withdrawal group had a significantly higher rate of early acute rejection episodes. There was no difference with regard to new-onset diabetes after transplant, hyperlipidemia, or cardiovascular events between groups. CONCLUSION The results of this study suggest that late corticosteroid withdrawal is associated with better long-term graft survival without increasing the rates of diabetes, hyperlipidemia, or cardiovascular events in liver transplant recipients. A prospective study is warranted to confirm these findings.
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Affiliation(s)
- H B Meadows
- Medical University of South Carolina, Charleston, South Carolina 29425, USA.
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Elsharkawy AM, Hudson M. The future developments in hepatology: no need for a jaundiced view. Frontline Gastroenterol 2012; 3:i47-i52. [PMID: 28839693 PMCID: PMC5551950 DOI: 10.1136/flgastro-2012-100153] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/10/2012] [Indexed: 02/04/2023] Open
Abstract
There have been major advances in the diagnosis and management of all forms of liver disease since the British Society of Gastroenterology first came into existence 75 years ago. In this review some of the exciting developments that are likely to enter into routine clinical practice over the next 5 years are highlighted. It is suggested that some critical changes need to take place in UK hepatology over the next decade to ensure that the management of liver disease in this country continues to be among the best in the world.
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Affiliation(s)
- Ahmed Mohamed Elsharkawy
- Liver Unit, University Hospitals Birmingham, Birmingham, UK,Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK
| | - Mark Hudson
- British Association for the Study of the Liver, London, UK
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11
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Gao LL, Guan FX, Zheng PY, Yang B, Chi LK, Liang S, Zou RQ, Liu ZQ. Therapeutic effect of transplantation of human amniotic membrane- and umbilical cord-derived mesenchymal stem cells on hepatic cirrhosis in rats. Shijie Huaren Xiaohua Zazhi 2012; 20:916-922. [DOI: 10.11569/wcjd.v20.i11.916] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the therapeutic effect of transplantation of human amniotic membrane-derived mesenchymal stem cells (hAM-MSCs) and human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on carbon tetrachloride (CCl4)-induced hepatic cirrhosis in rats.
METHODS: hAM-MSCs and hUC-MSCs were isolated and analyzed by flow cytometry for detection of expression of CD44, CD29 and CD34. Hepatic cirrhosis was induced in rats with CCl4. At week 8, five rats were killed to conduct pathological examination to confirm successful induction of hepatic cirrhosis, and 30 rats with hepatic cirrhosis were randomly and equally divided into three groups: hAM-MSCs group, hUC-MSCs group and control group. The hAM-MSCs and hUC-MSCs groups were infused wit 2×106 MSCs in 2 mL of saline via the tail vein, while the control group was given equal volume of saline. Liver function was examined before cell transplantation and 4 wk after cell transplantation. HE staining and Masson dyeing were performed to observe pathological changes in the liver. The expression of alpha-smooth muscle actin (α-SMA) in the liver was determined by immunohistochemistry.
RESULTS: Both isolated hAM-MSCs and hUC-MSCs expressed CD29 and CD44, but did not express CD34. After cell transplantation, liver function parameters were markedly improved (all P < 0.05) and the expression of α-SMA was reduced in the hAM-MSCs and hUC-MSCs groups compared to the control group (130.6 ± 3.0, 127.0 ± 2.6 vs 152.2 ± 5.4, both P < 0.05). There were no statistically significant differences in liver function parameters and α-SMA expression between the hAM-MSCs and hUC-MSCs groups.
CONCLUSION: Transplantation of hAM-MSCs and hUC-MSCs could efficiently improve liver functions and inhibit liver fibrosis in rats.
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Pan Q, Tilanus HW, Metselaar HJ, Janssen HLA, van der Laan LJW. Virus-drug interactions--molecular insight into immunosuppression and HCV. Nat Rev Gastroenterol Hepatol 2012; 9:355-62. [PMID: 22508161 PMCID: PMC7097508 DOI: 10.1038/nrgastro.2012.67] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Liver transplantation is an effective treatment for end-stage liver disease that is attributable to chronic HCV infection. However, long-term outcomes are compromised by universal virological recurrence in the graft. Reinfection that occurs after transplantation has increased resistance to current interferon-based antiviral therapy and often leads to accelerated development of cirrhosis. Important risk factors for severe HCV recurrence are linked to immunosuppression. Owing to the lack of good randomized, controlled trials, the optimal choice of immunosuppressants is still debated. By contrast, much progress has been made in the understanding of HCV biology and the antiviral action of interferons. These new insights have greatly expanded our knowledge of the molecular interplay between HCV and immunosuppressive drugs. In this article, we explore the effect of different immunosuppressants on the complex cellular events involved in HCV infection and interferon signalling. Potential implications for clinical practice and future drug development are discussed.
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Affiliation(s)
- Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, sGravendijkwal 230, Room L458, Rotterdam, 3015 CE The Netherlands
| | - Hugo W. Tilanus
- Department of Surgery and Laboratory of Experimental Transplantation and Intestinal Surgery, Erasmus MC-University Medical Center, sGravendijkwal 230, Room L458, Rotterdam, 3015 CE The Netherlands
| | - Herold J. Metselaar
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, sGravendijkwal 230, Room L458, Rotterdam, 3015 CE The Netherlands
| | - Harry L. A. Janssen
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, sGravendijkwal 230, Room L458, Rotterdam, 3015 CE The Netherlands
| | - Luc J. W. van der Laan
- Department of Surgery and Laboratory of Experimental Transplantation and Intestinal Surgery, Erasmus MC-University Medical Center, sGravendijkwal 230, Room L458, Rotterdam, 3015 CE The Netherlands
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Immune modulation of inflammatory conditions: regulatory T cells for treatment of GvHD. Immunol Res 2012; 53:200-12. [DOI: 10.1007/s12026-012-8267-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Fosby B, Karlsen TH, Melum E. Recurrence and rejection in liver transplantation for primary sclerosing cholangitis. World J Gastroenterol 2012; 18:1-15. [PMID: 22228965 PMCID: PMC3251800 DOI: 10.3748/wjg.v18.i1.1] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2011] [Revised: 06/15/2011] [Accepted: 06/22/2011] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic progressive inflammatory disease affecting the bile ducts, leading to fibrosis and eventually cirrhosis in most patients. Its etiology is unknown and so far no effective medical therapy is available. Liver transplantation (LTX) is the only curative treatment and at present PSC is the main indication for LTX in the Scandinavian countries. Close to half of the PSC patients experience one or more episodes of acute cellular rejection (ACR) following transplantation and approximately 1/5 of the transplanted patients develop recurrent disease in the graft. In addition, some reports indicate that ACR early after LTX for PSC can influence the risk for recurrent disease. For these important post-transplantation entities affecting PSC patients, we have reviewed the current literature on epidemiology, pathogenesis, treatment and the possible influence of rejection on the risk of recurrent disease in the allograft.
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15
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Current world literature. Curr Opin Organ Transplant 2011; 16:650-60. [PMID: 22068023 DOI: 10.1097/mot.0b013e32834dd969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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16
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Durand F. Hot-topic debate on kidney function: renal-sparing approaches are beneficial. Liver Transpl 2011; 17 Suppl 3:S43-9. [PMID: 21796759 DOI: 10.1002/lt.22392] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
1. Renal function is frequently compromised in candidates for transplantation with advanced cirrhosis. These patients frequently have chronic and irreversible kidney changes at the time of transplantation. 2. The accumulated incidence of chronic renal failure is high in liver transplant recipients. Chronic renal failure has a deleterious impact on the outcome. 3. Calcineurin inhibitor (CNI)-based immunosuppression is highly effective at preventing rejection. However, CNI nephrotoxicity has a central role in the occurrence of chronic renal failure. 4. Renal function impairment frequently occurs within the first year after transplantation. Once renal function is significantly impaired [glomerular filtration rate (GFR) < 60 mL/minute/1.73 m(2) ], any intervention is unlikely to result in a return to normal renal function. Early interventions are needed to prevent chronic and irreversible kidney injury. 5. De novo CNI minimization has been proven to be effective at reducing the rate of impaired renal function after transplantation. The reduction in the CNI doses should be offset by the addition of mycophenolate mofetil or enteric-coated mycophenolate sodium. 6. Delayed CNI minimization in patients with established renal insufficiency may result in a significant improvement in the GFR, even though the increase in the GFR after minimization is generally modest. 7. Mammalian target of rapamycin (mTOR) inhibitors are considered nonnephrotoxic immunosuppressive agents. They may be an option for improving renal function in liver transplant recipients. However, not all patients with renal dysfunction benefit from a switch to mTOR inhibitors. In addition, the benefits in terms of renal function should be balanced against specific side effects. 8. New immunosuppressive agents without intrinsic nephrotoxicity are currently under development for solid organ transplantation. These agents could help to reduce the burden of impaired renal function in transplantation in the near future.
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Affiliation(s)
- François Durand
- Department of Hepatology and Liver Intensive Care, Beaujon Hospital, and Bichat-Beaujon Center of Biomedical Research (National Institute of Health and Medical Research Unit 773), University of Paris VII, Clichy, France.
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Lake JR. Hot-topic debate on kidney function: renal-sparing approaches are ineffective. Liver Transpl 2011; 17 Suppl 3:S50-3. [PMID: 21898771 DOI: 10.1002/lt.22429] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
1. Both acute kidney injury and chronic renal disease are common in patients undergoing liver transplantation. The etiologies are mixed. 2. The incidence of chronic renal failure after liver transplantation is unacceptable, and it has a significant impact on long-term outcomes after liver transplantation. 3. The role of calcineurin inhibitors (CNIs) in the development of posttransplant chronic renal failure is likely overrated. 4. The use of CNIs in the early posttransplant period is currently essential. 5. Whether new agents will be able to provide effective immunosuppression as primary immunosuppressives remains to be proven.
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Affiliation(s)
- John R Lake
- Division of Gastroenterology and Hepatology, University of Minnesota, Minneapolis, MN 55455, USA.
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Investigation of hepatoprotective activity of induced pluripotent stem cells in the mouse model of liver injury. J Biomed Biotechnol 2011; 2011:219060. [PMID: 21808596 PMCID: PMC3144694 DOI: 10.1155/2011/219060] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2011] [Accepted: 05/27/2011] [Indexed: 01/14/2023] Open
Abstract
To date liver transplantation is the only effective treatment for end-stage liver diseases. Considering the potential of pluripotency and differentiation into tridermal lineages, induced pluripotent stem cells (iPSCs) may serve as an alternative of cell-based therapy. Herein, we investigated the effect of iPSC transplantation on thioacetamide- (TAA-) induced acute/fulminant hepatic failure (AHF) in mice. Firstly, we demonstrated that iPSCs had the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) that expressed various hepatic markers, including albumin, α-fetoprotein, and hepatocyte nuclear factor-3β, and exhibited biological functions. Intravenous transplantation of iPSCs effectively reduced the hepatic necrotic area, improved liver functions and motor activity, and rescued TAA-treated mice from lethal AHF. 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate cell labeling revealed that iPSCs potentially mobilized to the damaged liver area. Taken together, iPSCs can effectively rescue experimental AHF and represent a potentially favorable cell source of cell-based therapy.
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