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Shahandeh N, Kim JS, Klomhaus AM, Tehrani DM, Hsu JJ, Nsair A, Khush KK, Fearon WF, Parikh RV. Comparison of cardiac allograft vasculopathy incidence between simultaneous multiorgan and isolated heart transplant recipients in the United States. J Heart Lung Transplant 2024; 43:1737-1746. [PMID: 38950666 DOI: 10.1016/j.healun.2024.06.014] [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: 08/19/2023] [Revised: 05/28/2024] [Accepted: 06/25/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND Prior studies have shown reduced development of cardiac allograft vasculopathy (CAV) in multiorgan transplant recipients. The aim of this study was to compare the incidence of CAV between isolated heart transplants and simultaneous multiorgan heart transplants in the contemporary era. METHODS We utilized the Scientific Registry of Transplant Recipients to perform a retrospective analysis of first-time adult heart transplant recipients between January 1, 2010 and December 31, 2019 in the United States. The primary end-point was the development of angiographic CAV within 5 years of follow-up. RESULTS Among 20,591 patients included in the analysis, 1,279 (6%) underwent multiorgan heart transplantation (70% heart-kidney, 16% heart-liver, 13% heart-lung, and 1% triple-organ), and 19,312 (94%) were isolated heart transplant recipients. The average age was 53 years, and 74% were male. There were no significant between-group differences in cold ischemic time. The incidence of acute rejection during the first year after transplant was significantly lower in the multiorgan group (18% vs 33%, p < 0.01). The 5-year incidence of CAV was 33% in the isolated heart group and 27% in the multiorgan group (p < 0.0001); differences in CAV incidence were seen as early as 1 year after transplant and persisted over time. In multivariable analysis, multiorgan heart transplant recipients had a significantly lower likelihood of CAV at 5 years (hazard ratio = 0.76, 95% confidence interval: 0.66-0.88, p < 0.01). CONCLUSIONS Simultaneous multiorgan heart transplantation is associated with a significantly lower long-term risk of angiographic CAV compared with isolated heart transplantation in the contemporary era.
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Affiliation(s)
- Negeen Shahandeh
- Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - Juka S Kim
- Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - Alexandra M Klomhaus
- Department of Medicine Statistics Core, University of California Los Angeles, Los Angeles, California
| | - David M Tehrani
- Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - Jeffrey J Hsu
- Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - Ali Nsair
- Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - Kiran K Khush
- Division of Cardiovascular Medicine, Stanford University, Stanford, California
| | - William F Fearon
- Division of Cardiovascular Medicine, Stanford University, Stanford, California; Division of Cardiology, VA Palo Alto Health Care Systems, Palo Alto, California
| | - Rushi V Parikh
- Division of Cardiology, Department of Medicine, University of California Los Angeles, Los Angeles, California.
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2
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Zhang IW, Lurje I, Lurje G, Knosalla C, Schoenrath F, Tacke F, Engelmann C. Combined Organ Transplantation in Patients with Advanced Liver Disease. Semin Liver Dis 2024; 44:369-382. [PMID: 39053507 PMCID: PMC11449526 DOI: 10.1055/s-0044-1788674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/27/2024]
Abstract
Transplantation of the liver in combination with other organs is an increasingly performed procedure. Over the years, continuous improvement in survival could be realized through careful patient selection and refined organ preservation techniques, in spite of the challenges posed by aging recipients and donors, as well as the increased use of steatotic liver grafts. Herein, we revisit the epidemiology, allocation policies in different transplant zones, indications, and outcomes with regard to simultaneous organ transplants involving the liver, that is combined heart-liver, liver-lung, liver-kidney, and multivisceral transplantation. We address challenges surrounding combined organ transplantation such as equity, utility, and logistics of dual organ implantation, but also advantages that come along with combined transplantation, thereby focusing on molecular mechanisms underlying immunoprotection provided by the liver to the other allografts. In addition, the current standing and knowledge of machine perfusion in combined organ transplantation, mostly based on center experience, will be reviewed. Notwithstanding all the technical advances, shortage of organs, and the lack of universal eligibility criteria for certain multi-organ combinations are hurdles that need to be tackled in the future.
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Affiliation(s)
- Ingrid Wei Zhang
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin, Berlin, Germany
- European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols Chair, Barcelona, Spain
| | - Isabella Lurje
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Georg Lurje
- Department of Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Christoph Knosalla
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Felix Schoenrath
- Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité, Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin, Berlin, Germany
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3
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Nuqali A, Bellumkonda L. Dual organ transplantation: when heart alone is not enough. Curr Opin Organ Transplant 2023; 28:370-375. [PMID: 37582057 DOI: 10.1097/mot.0000000000001093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/17/2023]
Abstract
PURPOSE OF REVIEW The number of dual organ transplantations (DOT) are steadily increasing over the past few years. This is both a reflection of increasing complexity and advanced disease process in the patients and greater transplant center experience with performing dual organ transplants. Due to lack of standardization of the process, there remains significant center-based variability in patient selection, perioperative and long-term management of these patients. RECENT FINDINGS Overall posttransplant outcomes for DOT have been acceptable with some immunological advantages because of partial tolerance offered by the second organ. These achievements should, however, be balanced with the ethical implications of bypassing the patients who are listed for single organ transplantation because of the preferential allocation of organs for DOT. SUMMARY The field of DOT is expanding rapidly, with good long-term outcomes. There is an urgent need for guidelines to standardize the process of patient selection and listing dual organ transplantation.
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Affiliation(s)
- Abdulelah Nuqali
- Division of Cardiology, Department of Medicine Yale University School of Medicine, New Haven, Connecticut, USA
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4
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Kittleson MM, Sharma K, Brennan DC, Cheng XS, Chow SL, Colvin M, DeVore AD, Dunlay SM, Fraser M, Garonzik-Wang J, Khazanie P, Korenblat KM, Pham DT. Dual-Organ Transplantation: Indications, Evaluation, and Outcomes for Heart-Kidney and Heart-Liver Transplantation: A Scientific Statement From the American Heart Association. Circulation 2023; 148:622-636. [PMID: 37439224 DOI: 10.1161/cir.0000000000001155] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/14/2023]
Abstract
Although heart transplantation is the preferred therapy for appropriate patients with advanced heart failure, the presence of concomitant renal or hepatic dysfunction can pose a barrier to isolated heart transplantation. Because donor organ supply limits the availability of organ transplantation, appropriate allocation of this scarce resource is essential; thus, clear guidance for simultaneous heart-kidney transplantation and simultaneous heart-liver transplantation is urgently required. The purposes of this scientific statement are (1) to describe the impact of pretransplantation renal and hepatic dysfunction on posttransplantation outcomes; (2) to discuss the assessment of pretransplantation renal and hepatic dysfunction; (3) to provide an approach to patient selection for simultaneous heart-kidney transplantation and simultaneous heart-liver transplantation and posttransplantation management; and (4) to explore the ethics of multiorgan transplantation.
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5
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Zhao K, Wang R, Kamoun M, Callans L, Bremner R, Rame E, McLean R, Cevasco M, Olthoff KM, Levine MH, Shaked A, Abt PL. Incidence of acute rejection and patient survival in combined heart-liver transplantation. Liver Transpl 2022; 28:1500-1508. [PMID: 35247292 DOI: 10.1002/lt.26448] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 02/06/2022] [Accepted: 02/13/2022] [Indexed: 01/13/2023]
Abstract
Combined heart-liver transplantation (CHLT) is indicated for patients with concomitant end-stage heart and liver disease or patients with amyloid heart disease where liver transplantation mitigates progression. Limited data suggest that the liver allograft provides immunoprotection for heart and kidney allografts in combined transplantation from the same donor. We hypothesized that CHLT reduces the incidence of acute cellular rejection (ACR) and the development of de novo donor-specific antibodies (DSAs) compared with heart-alone transplantation (HA). We conducted a retrospective analysis of 32 CHLT and 280 HA recipients in a single-center experience. The primary outcome was incidence of ACR based on protocol and for-cause myocardial biopsy. Rejection was graded by the International Society of Heart and Lung Transplantation guidelines with Grade 2R and higher considered significant. Secondary outcomes included the development of new DSAs, cardiac function, and patient and cardiac graft survival rates. Of CHLT patients, 9.7% had ACR compared with 45.3% of HA patients (p < 0.01). Mean pretransplant calculated panel reactive antibody (cPRA) levels were similar between groups (CHLT 9.4% vs. HA 9.5%; p = 0.97). Among patients who underwent testing, 26.9% of the CHLT and 16.7% of HA developed DSA (p = 0.19). Despite the difference in ACR, patient and cardiac graft survival rates were similar at 5 years (CHLT 82.1% vs. HA 80.9% [p = 0.73]; CHLT 82.1% vs. HA 80.9% [p = 0.73]). CHLT reduced the incidence of ACR in the cardiac allograft, suggesting that the liver offers immunoprotection against cellular mechanisms of rejection without significant impacts on patient and cardiac graft survival rates. CHLT did not reduce the incidence of de novo DSA, possibly portending similar long-term survival among cardiac allografts in CHLT and HA.
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Affiliation(s)
- Kai Zhao
- Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Roy Wang
- Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Malek Kamoun
- Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Lauren Callans
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Remy Bremner
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Eduardo Rame
- Department of Medicine, Jefferson University Hospital, Philadelphia, Pennsylvania, USA
| | - Rhondalyn McLean
- Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Marisa Cevasco
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Kim M Olthoff
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Matthew H Levine
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Abraham Shaked
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Peter L Abt
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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6
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Hilscher MB, Wells ML, Venkatesh SK, Cetta F, Kamath PS. Fontan-associated liver disease. Hepatology 2022; 75:1300-1321. [PMID: 35179797 DOI: 10.1002/hep.32406] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 12/21/2021] [Accepted: 12/27/2021] [Indexed: 12/13/2022]
Affiliation(s)
- Moira B Hilscher
- Division of Gastroenterology and HepatologyDepartment of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Michael L Wells
- Division of Abdominal ImagingDepartment of RadiologyMayo ClinicRochesterMinnesotaUSA
| | - Sudhakar K Venkatesh
- Division of Abdominal ImagingDepartment of RadiologyMayo ClinicRochesterMinnesotaUSA
| | - Frank Cetta
- Division of Pediatric CardiologyDepartment of Pediatric and Adolescent MedicineMayo ClinicRochesterMinnesotaUSA
| | - Patrick S Kamath
- Division of Gastroenterology and HepatologyDepartment of MedicineMayo ClinicRochesterMinnesotaUSA
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7
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Cotter TG, Wang J, Peeraphatdit T, Sandıkçı B, Ayoub F, Kim G, Te H, Jeevanandam V, Sabato D, Charlton M. Simultaneous Heart-Liver Transplantation for Congenital Heart Disease in the United States: Rapidly Increasing With Acceptable Outcomes. Hepatology 2021; 73:1464-1477. [PMID: 32559317 DOI: 10.1002/hep.31426] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/14/2020] [Accepted: 06/02/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS There are more adults than children living with congenital heart disease (CHD) in the United States, with a growing proportion requiring heart-liver transplantation (HLT). Our aim was to ascertain the frequency, outcomes, and prognostic factors in this patient population. APPROACH AND RESULTS United Network for Organ Sharing data on adult patients who underwent heart transplantation (HT) from 2009 through March 2020 were analyzed. The primary study outcome was patient survival. Cox proportional-hazards modeling assessed for mortality associations. There were 1,084 HT recipients: 817 (75.4%) CHD HTs only, 74 (6.8%) CHD HLTs, 179 (16.5%) non-CHD HLTs, and 14 (1.3%) heart-liver-kidney transplants. The number of CHD HLTs increased from a prior rate of 4/year to 21/year in 2019. Among patients with CHD, the 5-year survival rates were 74.1% and 73.6% in HTs only and HLTs, respectively (P = 0.865). There was a higher rate of allograft failure attributable to rejection in CHD HTs only compared with CHD HLTs (3.2% versus 0.4%; P = 0.014). Only 25 out of 115 HT-performing hospitals undertook CHD HLTs. Higher-volume centers (averaging one CHD HLT per year) had a 5-year patient survival rate of 83.0% compared with 61.3% in lower-volume centers (P = 0.079). Among HLT recipients, total bilirubin (hazard ratio [HR], 1.06; 95% confidence interval [CI], 1.01-1.12) and diabetes (HR = 2.97, 95% CI = 1.21-7.31) were independently associated with increased mortality risk, whereas CHD and age were not. CONCLUSIONS The rate of HLT for adult CHD in the United States is rising dramatically. The survival outcomes between CHD HT only and CHD HLT groups are comparable; however, the HLT group had lower rates of acute rejection. Among HLT recipients, diabetes and elevated bilirubin are associated with increased posttransplant mortality risk. An average of one CHD HLT per year could be considered a minimum quality metric at transplant centers.
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Affiliation(s)
- Thomas G Cotter
- Center for Liver Diseases, The University of Chicago Medicine, Chicago, IL
| | - Jennifer Wang
- Center for Liver Diseases, The University of Chicago Medicine, Chicago, IL
| | | | | | - Fares Ayoub
- Center for Liver Diseases, The University of Chicago Medicine, Chicago, IL
| | - Gene Kim
- Division of Cardiology, The University of Chicago Medicine, Chicago, IL
| | - Helen Te
- Center for Liver Diseases, The University of Chicago Medicine, Chicago, IL
| | | | - Diego Sabato
- Department of Surgery, The University of Chicago Medicine, Chicago, IL
| | - Michael Charlton
- Center for Liver Diseases, The University of Chicago Medicine, Chicago, IL
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8
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Kovac D, Choe J, Liu E, Scheffert J, Hedvat J, Anamisis A, Salerno D, Lange N, Jennings DL. Immunosuppression considerations in simultaneous organ transplant. Pharmacotherapy 2021; 41:59-76. [PMID: 33325558 DOI: 10.1002/phar.2495] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 10/21/2020] [Accepted: 12/01/2020] [Indexed: 12/12/2022]
Abstract
Solid organ transplantation is a life-saving procedure for patients in the end stage of heart, lung, kidney, and liver failure. For patients with more than one failing organ, simultaneous organ transplantation has emerged as a viable treatment option. Immunosuppression strategies and outcomes for simultaneous organ transplant recipients have been reported, but often involve limited populations. Transplanting dual organs poses challenges in terms of balancing immunosuppression with immunologic risk and allograft damage from surgical complications. Furthermore, transplanting certain organs can impose considerations on the management of immunosuppression. For example, liver allografts may confer immunologic privilege and lower rates of rejection of other allografts. This review article evaluates immunosuppression strategies for simultaneous kidney-pancreas, liver-kidney, heart-kidney, heart-liver, heart-lung, lung-liver, and lung-kidney transplants. To date, no comprehensive review exists to address immunosuppressive strategies in simultaneous organ transplant populations. Our review summarizes the available literature and provides evidence-based recommendations regarding immunosuppression strategies in simultaneous organ transplant recipients.
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Affiliation(s)
- Danielle Kovac
- Department of Pharmacy, NewYork-Presbyterian Columbia University Irving Medical Center, New York, New York, USA
| | - Jason Choe
- Department of Pharmacy, NewYork-Presbyterian Columbia University Irving Medical Center, New York, New York, USA
| | - Esther Liu
- Department of Pharmacy, NewYork-Presbyterian Weill Cornell Medical Center, New York, New York, USA
| | - Jenna Scheffert
- Department of Pharmacy, NewYork-Presbyterian Columbia University Irving Medical Center, New York, New York, USA
| | - Jessica Hedvat
- Department of Pharmacy, NewYork-Presbyterian Columbia University Irving Medical Center, New York, New York, USA
| | - Anastasia Anamisis
- Department of Pharmacy, NewYork-Presbyterian Columbia University Irving Medical Center, New York, New York, USA
| | - David Salerno
- Department of Pharmacy, NewYork-Presbyterian Weill Cornell Medical Center, New York, New York, USA
| | - Nicholas Lange
- Department of Pharmacy, NewYork-Presbyterian Columbia University Irving Medical Center, New York, New York, USA
| | - Douglas L Jennings
- Department of Pharmacy, NewYork-Presbyterian Columbia University Irving Medical Center, New York, New York, USA.,Division of Pharmacy Practice, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, New York, New York, USA
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9
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Antigen presentation, autoantibody production, and therapeutic targets in autoimmune liver disease. Cell Mol Immunol 2020; 18:92-111. [PMID: 33110250 PMCID: PMC7852534 DOI: 10.1038/s41423-020-00568-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 09/24/2020] [Indexed: 02/07/2023] Open
Abstract
The liver is an important immunological organ that controls systemic tolerance. The liver harbors professional and unconventional antigen-presenting cells that are crucial for tolerance induction and maintenance. Orchestrating the immune response in homeostasis depends on a healthy and well-toned immunological liver microenvironment, which is maintained by the crosstalk of liver-resident antigen-presenting cells and intrahepatic and liver-infiltrating leukocytes. In response to pathogens or autoantigens, tolerance is disrupted by unknown mechanisms. Intrahepatic parenchymal and nonparenchymal cells exhibit unique antigen-presenting properties. The presentation of microbial and endogenous lipid-, metabolite- and peptide-derived antigens from the gut via conventional and nonconventional mechanisms can educate intrahepatic immune cells and elicit effector responses or tolerance. Perturbation of this balance results in autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. Although the exact etiologies of these autoimmune liver diseases are unknown, it is thought that the disruption of tolerance towards self-antigens and microbial metabolites and lipids, as well as alterations in bile acid composition, may result in changes in effector cell activation and polarization and may reduce or impair protective anti-inflammatory regulatory T and B cell responses. Additionally, the canonical and noncanonical transmission of antigens and antigen:MHC complexes via trogocytosis or extracellular vesicles between different (non) immune cells in the liver may play a role in the induction of hepatic inflammation and tolerance. Here, we summarize emerging aspects of antigen presentation, autoantibody production, and the application of novel therapeutic approaches in the characterization and treatment of autoimmune liver diseases.
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10
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Donor-specific antibodies in liver transplantation: challenges in diagnosis and determining clinical impact. Curr Opin Organ Transplant 2020; 25:549-554. [PMID: 33105198 DOI: 10.1097/mot.0000000000000825] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Our understanding of the clinical impact of donor-specific antibodies in liver transplant recipients has evolved in recent years as outcomes for liver allografts have improved and advances in diagnostic testing have made recognition of antibody mediated rejection in transplant patients more sensitive. RECENT FINDINGS Two main types of donor-specific antibodies - preformed and de novo - have been reported in the literature to have a negative impact on graft survival, and researchers have been able to further identify subclasses of class II donor-specific antibodies as being the most clinically impactful. Furthermore, there is evidence that donor-specific antibody formation can augment cellular rejection in liver grafts and lead to worsened clinical outcomes. Recent data have shown a higher prevalence of donor-specific antibody formation than previously reported. SUMMARY This review explores the most recent literature regarding the clinical impact of both preformed and de-novo donor-specific antibodies and potential management guidelines for patients undergoing liver transplantation. The best practice guidelines for undergoing monitoring for donor-specific antibody formation and protocol biopsies in sensitized patients will depend on further multiinstitutional studies.
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11
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Hann A, Osei-Bordom DC, Neil DAH, Ronca V, Warner S, Perera MTPR. The Human Immune Response to Cadaveric and Living Donor Liver Allografts. Front Immunol 2020; 11:1227. [PMID: 32655558 PMCID: PMC7323572 DOI: 10.3389/fimmu.2020.01227] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 05/15/2020] [Indexed: 12/13/2022] Open
Abstract
The liver is an important contributor to the human immune system and it plays a pivotal role in the creation of both immunoreactive and tolerogenic conditions. Liver transplantation provides the best chance of survival for both children and adults with liver failure or cancer. With current demand exceeding the number of transplantable livers from donors following brain death, improved knowledge, technical advances and the desire to prevent avoidable deaths has led to the transplantation of organs from living, ABO incompatible (ABOi), cardiac death donors and machine based organ preservation with acceptable results. The liver graft is the most well-tolerated, from an immunological perspective, of all solid organ transplants. Evidence suggests successful cessation of immunosuppression is possible in ~20–40% of liver transplant recipients without immune mediated graft injury, a state known as “operational tolerance.” An immunosuppression free future following liver transplantation is an ambitious but perhaps not unachievable goal. The initial immune response following transplantation is a sterile inflammatory process mediated by the innate system and the mechanisms relate to the preservation-reperfusion process. The severity of this injury is influenced by graft factors and can have significant consequences. There are minimal experimental studies that delineate the differences in the adaptive immune response to the various forms of liver allograft. Apart from ABOi transplants, antibody mediated hyperacute rejection is rare following liver transplant. T-cell mediated rejection is common following liver transplantation and its incidence does not differ between living or deceased donor grafts. Transplantation in the first year of life results in a higher rate of operational tolerance, possibly due to a bias toward Th2 cytokines (IL4, IL10) during this period. This review further describes the current understanding of the immunological response toward liver allografts and highlight the areas of this topic yet to be fully understood.
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Affiliation(s)
- Angus Hann
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | | | - Desley A H Neil
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Department of Cellular Pathology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Vincenzo Ronca
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Suz Warner
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,The Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom
| | - M Thamara P R Perera
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom.,The Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom
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12
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Jiang Y, Que W, Zhu P, Li XK. The Role of Diverse Liver Cells in Liver Transplantation Tolerance. Front Immunol 2020; 11:1203. [PMID: 32595648 PMCID: PMC7304488 DOI: 10.3389/fimmu.2020.01203] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 05/14/2020] [Indexed: 12/11/2022] Open
Abstract
Liver transplantation is the ideal treatment approach for a variety of end-stage liver diseases. However, life-long, systemic immunosuppressive treatment after transplantation is required to prevent rejection and graft loss, which is associated with severe side effects, although liver allograft is considered more tolerogenic. Therefore, understanding the mechanism underlying the unique immunologically privileged liver organ is valuable for transplantation management and autoimmune disease treatment. The unique hepatic acinus anatomy and a complex cellular network constitute the immunosuppressive hepatic microenvironment, which are responsible for the tolerogenic properties of the liver. The hepatic microenvironment contains a variety of hepatic-resident immobile non-professional antigen-presenting cells, including hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, that are insufficient to optimally prime T cells locally and lead to the removal of alloreactive T cells due to the low expression of major histocompatibility complex (MHC) molecules, costimulatory molecules and proinflammatory cytokines but a rather high expression of coinhibitory molecules and anti-inflammatory cytokines. Hepatic dendritic cells (DCs) are generally immature and less immunogenic than splenic DCs and are also ineffective in priming naïve allogeneic T cells via the direct recognition pathway in recipient secondary lymphoid organs. Although natural killer cells and natural killer T cells are reportedly associated with liver tolerance, their roles in liver transplantation are multifaceted and need to be further clarified. Under these circumstances, T cells are prone to clonal deletion, clonal anergy and exhaustion, eventually leading to tolerance. Other proposed liver tolerance mechanisms, such as soluble donor MHC class I molecules, passenger leukocytes theory and a high-load antigen effect, have also been addressed. We herein comprehensively review the current evidence implicating the tolerogenic properties of diverse liver cells in liver transplantation tolerance.
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Affiliation(s)
- Yanzhi Jiang
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.,Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Weitao Que
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Ping Zhu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xiao-Kang Li
- Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
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13
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Piñeiro GJ, Rovira J, Montagud-Marrahí E, Torregrosa JV, Ríos J, Cucchiari D, Ugalde-Altamirano J, Ventura-Aguiar P, Gelpi R, Palou E, Colmenero J, Navasa M, Diekmann F, Esforzado N. Kidney Graft Outcomes in High Immunological Risk Simultaneous Liver-Kidney Transplants. Liver Transpl 2020; 26:517-527. [PMID: 32011089 DOI: 10.1002/lt.25726] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 01/12/2020] [Indexed: 02/07/2023]
Abstract
Recipients of simultaneous liver-kidney transplantations (SLKTs) have a lower risk of rejection compared with recipients of kidney transplants alone. However, there is disagreement about the impact of pretransplant anti-human leukocyte antigen sensitization on patient and kidney graft survival in the long term. The aim of the study was to evaluate the impact of the recipient immunological risk and comorbidities in renal graft outcomes on SLKT. We reviewed the SLKTs performed in our center from May 1993 until September 2017. Patient and graft survival were analyzed according to the immunological risk, comorbidities, liver and kidney rejection episodes, immunosuppression, and infections. A total of 20 recipients of SLKT were considered in the high immunological risk (HIR) group, and 68 recipients were included in the low immunological risk (LIR) control group. The prevalence of hepatitis C virus infection, second renal transplant, and time on dialysis prior to transplantation were significantly higher in the HIR group. The incidence of acute kidney rejection was higher in the HIR group (P<0.01). However, death-censored kidney graft survival as well as the estimated glomerular filtration rate at follow-up were not different between the 2 groups. Comorbidities, but not the immunological risk, impact negatively on patient survival. Despite the higher incidence of rejection in the HIR SLKT group, longterm renal function and graft survival were similar to the LIR group.
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Affiliation(s)
- Gastón J Piñeiro
- Department of Nephrology and Renal Transplantation, Instituto Clínic de Nefrologia y Urologia, Hospital Clinic de Barcelona, Barcelona, Spain.,Laboratori Experimental de Nefrologia i Trasplantament, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Jordi Rovira
- Laboratori Experimental de Nefrologia i Trasplantament, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Red de Investigación Renal, Madrid, Spain
| | - Enrique Montagud-Marrahí
- Department of Nephrology and Renal Transplantation, Instituto Clínic de Nefrologia y Urologia, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Jose V Torregrosa
- Department of Nephrology and Renal Transplantation, Instituto Clínic de Nefrologia y Urologia, Hospital Clinic de Barcelona, Barcelona, Spain
| | - José Ríos
- Medical Statistics Core Facility, IDIBAPS, Barcelona, Spain.,Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - David Cucchiari
- Department of Nephrology and Renal Transplantation, Instituto Clínic de Nefrologia y Urologia, Hospital Clinic de Barcelona, Barcelona, Spain.,Laboratori Experimental de Nefrologia i Trasplantament, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Jessica Ugalde-Altamirano
- Department of Nephrology and Renal Transplantation, Instituto Clínic de Nefrologia y Urologia, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Pedro Ventura-Aguiar
- Department of Nephrology and Renal Transplantation, Instituto Clínic de Nefrologia y Urologia, Hospital Clinic de Barcelona, Barcelona, Spain.,Laboratori Experimental de Nefrologia i Trasplantament, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Rosana Gelpi
- Department of Nephrology and Renal Transplantation, Instituto Clínic de Nefrologia y Urologia, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Eduard Palou
- Department of Immunology, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Jordi Colmenero
- Liver Transplant Unit, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedes Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain
| | - Miquel Navasa
- Liver Transplant Unit, Liver Unit, Hospital Clínic de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedes Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain
| | - Fritz Diekmann
- Department of Nephrology and Renal Transplantation, Instituto Clínic de Nefrologia y Urologia, Hospital Clinic de Barcelona, Barcelona, Spain.,Laboratori Experimental de Nefrologia i Trasplantament, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Red de Investigación Renal, Madrid, Spain
| | - Nuria Esforzado
- Department of Nephrology and Renal Transplantation, Instituto Clínic de Nefrologia y Urologia, Hospital Clinic de Barcelona, Barcelona, Spain
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14
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Vionnet J, Sempoux C, Pascual M, Sánchez-Fueyo A, Colmenero J. Donor-specific antibodies in liver transplantation. GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 43:34-45. [DOI: 10.1016/j.gastrohep.2019.09.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/18/2019] [Accepted: 09/30/2019] [Indexed: 12/22/2022]
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15
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Abrol N, Jadlowiec CC, Taner T. Revisiting the liver's role in transplant alloimmunity. World J Gastroenterol 2019; 25:3123-3135. [PMID: 31333306 PMCID: PMC6626728 DOI: 10.3748/wjg.v25.i25.3123] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/25/2019] [Accepted: 05/18/2019] [Indexed: 02/06/2023] Open
Abstract
The transplanted liver can modulate the recipient immune system to induce tolerance after transplantation. This phenomenon was observed nearly five decades ago. Subsequently, the liver's role in multivisceral transplantation was recognized, as it has a protective role in preventing rejection of simultaneously transplanted solid organs such as kidney and heart. The liver has a unique architecture and is home to many cells involved in immunity and inflammation. After transplantation, these cells migrate from the liver into the recipient. Early studies identified chimerism as an important mechanism by which the liver modulates the human immune system. Recent studies on human T-cell subtypes, cytokine expression, and gene expression in the allograft have expanded our knowledge on the potential mechanisms underlying immunomodulation. In this article, we discuss the privileged state of liver transplantation compared to other solid organ transplantation, the liver allograft's role in multivisceral transplantation, various cells in the liver involved in immune responses, and the potential mechanisms underlying immunomodulation of host alloresponses.
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Affiliation(s)
- Nitin Abrol
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Massyo Clinic, Rochester, MN 55905, United States
| | | | - Timucin Taner
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Massyo Clinic, Rochester, MN 55905, United States
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16
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Superior Outcomes and Reduced Wait Times in Pediatric Recipients of Living Donor Liver Transplantation. Transplant Direct 2019; 5:e430. [PMID: 30882035 PMCID: PMC6411221 DOI: 10.1097/txd.0000000000000865] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 12/21/2018] [Accepted: 12/22/2018] [Indexed: 01/10/2023] Open
Abstract
Background Living donor liver transplantation (LDLT) is increasingly used to bridge the gap between the current supply and demand imbalance for deceased donor organs to provide lifesaving liver transplantation. Methods Outcomes of 135 children who underwent LDLT were compared with 158 recipients of deceased donor liver transplantation (DDLT) at the largest pediatric liver transplant program in Canada. Results Recipients of LDLT were significantly younger than deceased donor recipients (P ≤ 0.001), less likely to require dialysis pretransplant (P < 0.002) and had shorter wait time duration when the primary indication was cholestatic liver disease (P = 0.003). The LDLT donors were either related genetically or emotionally (79%), or unrelated (21%) to the pediatric recipients. One-, 5-, and 10-year patient survival rates were significantly higher in LDLT (97%, 94%, and 94%) compared with DDLT (92%, 87%, and 80%; log-rank P = 0.02) recipients, as were graft survival rates (96%, 93%, and 93% for LDLT versus 89%, 81.4%, and 70%, respectively, for DDLT; log-rank P = 0.001). Medical and surgical complications were not statistically different between groups. Graft failure was higher in recipients of DDLT (odds ratio, 2.60; 95% confidence interval, 1.02, 6.58) than in the LDLT group after adjustment for clinical characteristics and propensity score. Conclusions Living donor liver transplantation provides superior outcomes for children and is an excellent and effective strategy to increase the chances of receiving a liver transplant.
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17
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Simultaneous Versus Sequential Heart-liver Transplantation: Ideal Strategies for Organ Allocation. Transplant Direct 2018; 5:e415. [PMID: 30656213 PMCID: PMC6324910 DOI: 10.1097/txd.0000000000000854] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 10/24/2018] [Accepted: 11/09/2018] [Indexed: 12/04/2022] Open
Abstract
Background Simultaneous heart-liver (SHL) transplantation is an efficacious therapeutic modality for patients with combined heart and liver failure. However, the extent to which heart transplantation followed by sequential liver transplantation (LAH) can match the benefit of simultaneous transplantation has not previously been examined. Our objective was to determine if LAH offers comparable survival to SHL. Methods The Organ Procurement and Transplantation Network/United Network for Organ Sharing Standard Transplant Analysis and Research file was queried for adult recipients waitlisted for both heart and liver transplantation. The United Network for Organ Sharing thoracic and liver databases were linked to facilitate examination of waitlist and transplant characteristics for simultaneously listed patients. Univariate survival analysis was used to determine overall survival. Results Of the 236 patients meeting inclusion criteria, 200 underwent SHL, 7 sequentially underwent LAH, and 29 received heart transplantation only (isolated orthotopic heart transplantation [iOHT]). Recipients of SHL were less likely to have an episode of acute rejection before discharge (LAH, 14.2%; SHL, 2.4%; iOHT, 3.6%; P = .019) or be treated for acute rejection within 1 year after transplantation (LAH, 14.3%; SHL, 2.5%; iOHT, 13.8%; P = .007). Otherwise, postoperative hospital length of stay, stroke, need for dialysis, and need for pacemaker placement were comparable across groups. Ten-year survival similarly favored both LAH and SHL over iOHT (LAH: 100%, 71.4%, 53.6%; SHL: 87.1%, 80.4%, 52.1%, iOHT: 70.1%, 51.6%, 27.5% for 1-, 5-, and 10-year survivals, respectively, P = .003). However, median time between heart and liver transplant was 302 days in patients undergoing sequential transplantation. Conclusions Although transplantation in a simultaneous or sequential fashion yields equivalent outcomes, a high fraction of patients undergoing initial heart transplant alone fail to proceed to subsequent liver transplantation. Therefore, in patients with combined heart and liver failure with a projected need for 2 allografts, simultaneous transplantation is associated with maximum benefit.
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18
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Kitajima K, Ogawa Y, Miki K, Kai K, Sannomiya A, Iwadoh K, Murakami T, Koyama I, Nakajima I, Fuchinoue S. Longterm renal allograft survival after sequential liver-kidney transplantation from a single living donor. Liver Transpl 2017; 23:315-323. [PMID: 27862900 DOI: 10.1002/lt.24676] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 11/03/2016] [Indexed: 12/31/2022]
Abstract
Combined liver-kidney transplantation (CLKT) is well established as a definitive therapy with the potential to provide complete recovery for certain liver-kidney diseases, although the results might be contingent on the cause of transplantation. The purposes of the present study were to review the longterm outcome of renal allografts in CLKT patients from single living donors and to investigate the beneficial factors, compared with solitary renal transplantation. Thirteen patients underwent sequential liver transplantation (LT) and kidney transplantation (KT) from single living donors. The indications for KT were oxaluria (n = 7), autosomal recessive polycystic disease (n = 3), and others (n = 3). The same immunosuppressive regimen used after LT was also used after KT. KT was performed between 1.7 and 47.0 months after the LT. The overall patient survival rate was 92.3% at 10 years. In 12 of the 13 surviving patients, the renal allografts were found to be functioning in 11 patients after a mean follow-up period of 103.6 months. The death-censored renal allograft survival rate at 10 years was 100%, which was better than that of KT alone (84.9%) in Japan. Immunological protection conferred by the preceding liver allograft may have contributed to the longterm outcomes of the renal allografts. In addition, the donation of double organs from a single living and related donor may have a favorable impact on the graft survival rate. In the future, investigations of factors affecting the longterm outcome of renal allografts, including details of the involvement of de novo donor-specific antibody, will be needed. Liver Transplantation 23 315-323 2017 AASLD.
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Affiliation(s)
- Kumiko Kitajima
- Department of Surgery, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Yuichi Ogawa
- Department of Surgery, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Katsuyuki Miki
- Department of Surgery, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Kotaro Kai
- Department of Surgery, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Akihito Sannomiya
- Department of Surgery, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Kazuhiro Iwadoh
- Department of Surgery, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Toru Murakami
- Department of Surgery, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Ichiro Koyama
- Department of Surgery, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Ichiro Nakajima
- Department of Surgery, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Shohei Fuchinoue
- Department of Surgery, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan
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19
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The Role of Humoral Alloreactivity in Liver Transplantation: Lessons Learned and New Perspectives. J Immunol Res 2017; 2017:3234906. [PMID: 28164136 PMCID: PMC5253491 DOI: 10.1155/2017/3234906] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 12/19/2016] [Indexed: 12/13/2022] Open
Abstract
More than ten years after the initial description of the humoral theory of transplantation by Dr. Paul I. Terasaki, the significance of humoral alloimmunity in liver transplantation has yet to be clearly defined. The liver allograft has an inherent tolerogenic capacity which confers its resistance to cell-mediated as well as antibody-mediated rejection. Nevertheless, the protection against alloimmunity is not complete, and antibody-mediated tissue injury can occur in the liver graft under specific circumstances. In this article the evidence on the clinicopathologic effects of donor-specific alloantibodies in liver transplantation will be examined and interpreted in parallel with lessons learned from renal transplantation. The unique anatomic and immunologic features of the liver will be reviewed to gain new insights into the complex interactions between humoral immune system and the liver allograft.
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20
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Wong TW, Gandhi MJ, Daly RC, Kushwaha SS, Pereira NL, Rosen CB, Stegall MD, Heimbach JK, Taner T. Liver Allograft Provides Immunoprotection for the Cardiac Allograft in Combined Heart-Liver Transplantation. Am J Transplant 2016; 16:3522-3531. [PMID: 27184686 DOI: 10.1111/ajt.13870] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 05/03/2016] [Accepted: 05/12/2016] [Indexed: 01/25/2023]
Abstract
When transplanted simultaneously, the liver allograft has been thought to have an immunoprotective role on other organs; however, detailed analyses in simultaneous heart-liver transplantation (SHLT) have not been done to date. We analyzed patient outcomes and incidence of immune-mediated injury in 22 consecutive SHLT versus 223 isolated heart transplantation (IHT) recipients between January 2004 and December 2013, by reviewing 3912 protocol- and indication-specific cardiac allograft biopsy specimens. Overall survival was similar (86.4%, 86.4%, and 69.1% for SHLT and 93.3%, 84.7%, and 70.0% for IHT at 1, 5, and 10 years; p = 0.83). Despite similar immunosuppression, the incidence of T cell-mediated rejection (TCMR) was lower in SHLT (31.8%) than in IHT (84.8%) (p < 0.0001). Although more SHLT patients had preexisting donor-specific HLA antibody (22.7% versus 8.1%; p = 0.04), the incidence of antibody-mediated rejection was not different in SHLT compared with IHT (4.5% versus 14.8%, p = 0.33). While the left ventricular ejection fraction was comparable in both groups at 5 years, the incidence and severity of cardiac allograft vasculopathy were reduced in the SHLT recipients (42.9% versus 66.8%, p = 0.03). Simultaneously transplanted liver allograft was associated with reduced risk of TCMR (odds ratio [OR] 0.003, 95% confidence interval [CI] 0-0.02; p < 0.0001), antibody-mediated rejection (OR 0.04, 95% CI 0-0.46; p = 0.004), and cardiac allograft vasculopathy (OR 0.26, 95% CI 0.07-0.84; p = 0.02), after adjusting for other risk factors. These data suggest that the incidence of alloimmune injury in the heart allograft is reduced in SHLT recipients.
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Affiliation(s)
- T W Wong
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN
| | - M J Gandhi
- Division of Transfusion Medicine, Mayo Clinic, Rochester, MN
| | - R C Daly
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN
| | - S S Kushwaha
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN
| | - N L Pereira
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN
| | - C B Rosen
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN
| | - M D Stegall
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN
| | - J K Heimbach
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN
| | - T Taner
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN
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21
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Ahmad SB, Miller M, Hanish S, Bartlett ST, Hutson W, Barth RN, LaMattina JC. Sequential kidney-liver transplantation from the same living donor for lecithin cholesterol acyl transferase deficiency. Clin Transplant 2016; 30:1370-1374. [PMID: 27490864 DOI: 10.1111/ctr.12826] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/22/2016] [Indexed: 01/11/2023]
Abstract
BACKGROUND Lecithin cholesterol acyl transferase (LCAT) deficiency is a rare autosomal recessive disorder of lipoprotein metabolism that results in end-stage renal disease (ESRD) necessitating transplantation. As LCAT is produced in the liver, combined kidney and liver transplantation was proposed to cure the clinical syndrome of LCAT deficiency. METHODS A 29-year-old male with ESRD secondary to LCAT deficiency underwent a sequential kidney-liver transplantation from the same living donor (LD). One year following the kidney transplant, auxiliary partial orthotopic liver transplant (APOLT) of a left lateral segment from the same donor was performed. RESULTS At 5 years follow-up, there have been no major complications, readmissions, or rejection episodes. Serum lipid abnormalities recurred within the first year, but liver and kidney allograft function remains intact. CONCLUSION Few cases of sequential transplantation from the same LD have been performed in adults. This is the first APOLT and multi-organ transplant performed for LCAT deficiency. Sequential organ transplant from the same LD for ESRD secondary to a metabolic disorder of the liver is feasible in adults and should be further investigated.
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Affiliation(s)
- Sarwat B Ahmad
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Michael Miller
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Steven Hanish
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Stephen T Bartlett
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - William Hutson
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Rolf N Barth
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - John C LaMattina
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
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22
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Del Bello A, Congy-Jolivet N, Danjoux M, Muscari F, Kamar N. Donor-specific antibodies and liver transplantation. Hum Immunol 2016; 77:1063-1070. [PMID: 26916836 DOI: 10.1016/j.humimm.2016.02.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 02/14/2016] [Accepted: 02/18/2016] [Indexed: 01/02/2023]
Abstract
In contrast to other types of organ transplantation, liver-transplant recipients used to be considered highly resistant to donor-specific antibodies (DSAs). Consequently, most transplant programs did not consider the presence of DSAs at transplantation or during the follow-up. However, since the early 1990s, antibody-mediated pathological lesions have been recognized in ABO-incompatible liver-transplant recipients. Recent data confirm the detrimental effect of preformed and de novo DSAs in ABO-compatible liver transplantation, with inferior clinical outcomes in patients presenting with circulating antibodies. Acute antibody-mediated rejection (AMR), plasma-cell hepatitis, biliary stricture, but also long-term complications, such as chronic rejection, liver ductopenia, and graft fibrosis, are now recognized to be associated with DSAs. Moreover, some non-HLA DSAs are suspected to induce graft dysfunction. Clinical, biological, and histological patterns within AMR need to be clarified. Treatment of these complications has yet to be defined. This article summarizes recent advances concerning the impact of preformed and de novo DSAs in liver transplantation, it defines the complications associated with DSAs, and discusses the potential strategies to manage patients with such complications.
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Affiliation(s)
- Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France; Université Paul Sabatier, Toulouse, France.
| | - Nicolas Congy-Jolivet
- Université Paul Sabatier, Toulouse, France; Molecular Immunogenetics Laboratory, EA 3034, Faculté de Médecine Purpan, IFR150 (INSERM), France; Department of Immunology, Hôpital de Rangueil, CHU de Toulouse, France
| | - Marie Danjoux
- Department of Pathology, CHU Purpan, Toulouse, France
| | - Fabrice Muscari
- Université Paul Sabatier, Toulouse, France; Department of Surgery and Liver Transplantation, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France; Université Paul Sabatier, Toulouse, France; INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France
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23
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Burghuber C, Roberts T, Knechtle S. The clinical relevance of alloantibody in liver transplantation. Transplant Rev (Orlando) 2015; 29:16-22. [DOI: 10.1016/j.trre.2014.06.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Accepted: 06/11/2014] [Indexed: 12/13/2022]
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24
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Shin M, Song S, Moon H, Lee S, Kim T, Kim J, Park J, Kwon C, Kim SJ, Lee SK, Joh JW. Characteristics of Recipients Who Achieved Spontaneous Operational Tolerance in Adult Liver Transplantation. Transplant Proc 2013; 45:3024-7. [DOI: 10.1016/j.transproceed.2013.08.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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25
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Combined heart and liver transplant attenuates cardiac allograft vasculopathy compared with isolated heart transplantation. Transplantation 2013; 95:859-65. [PMID: 23364484 DOI: 10.1097/tp.0b013e31827eef7e] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND We evaluated whether combined heart and liver transplant (H+LTx) can protect the heart graft from the development of cardiac allograft vasculopathy using coronary three-dimensional (3D) volumetric intravascular ultrasound (IVUS). METHODS From 2004 to 2009, we identified 24 isolated heart transplant (HTx) and 10 H+LTx recipients in whom two coronary 3D IVUS studies were performed 1 year apart. Baseline 3D IVUS was performed at 0.22 (0.17-1.16) years after transplantation, with follow-up 3D IVUS exams performed after baseline exam (0.96 [0.83-1.08]). RESULTS Rate of plaque volume and plaque index (plaque volume/vessel volume) progression was attenuated in the H+LTx group (0.3±1.1 vs. 1.5±2.9 mm/mm; P=0.08 and 0.01±0.03 vs. 0.1±0.1; P=0.004, respectively). Rejection burden was much lower in the H+LTx patients. Outcome analysis in 66 consecutive patients (56 HTx and 10 H+LTx) was performed irrespective of performance of second coronary IVUS. H+LTx was associated with reduced rate of cardiac events (P=0.04), which remained significant when adjusted for the difference in the primary etiology for heart disease (P=0.05). CONCLUSIONS Our preliminary serial 3D coronary IVUS data show that H+LTx attenuates cardiac allograft vasculopathy by decreasing the rate of plaque volume and plaque index progression and improves coronary-related outcomes. Because of the small numbers and the differences in etiology of heart disease, our data should be interpreted cautiously, and larger clinical trials would be required to recommend H+LTx for improved coronary remodeling.
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26
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Nelson LM, Penninga L, Sander K, Hansen PB, Villadsen GE, Rasmussen A, Gustafsson F. Long-term outcome in patients treated with combined heart and liver transplantation for familial amyloidotic cardiomyopathy. Clin Transplant 2012; 27:203-9. [DOI: 10.1111/ctr.12053] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2012] [Indexed: 11/28/2022]
Affiliation(s)
| | - Luit Penninga
- Department of Surgical Gastroenterology; Rigshospitalet; Copenhagen; Denmark
| | - Kaare Sander
- The Heart Centre; Rigshospitalet; Copenhagen; Denmark
| | | | | | - Allan Rasmussen
- Department of Surgical Gastroenterology; Rigshospitalet; Copenhagen; Denmark
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27
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Cannon RM, Hughes MG, Jones CM, Eng M, Marvin MR. A review of the United States experience with combined heart-liver transplantation. Transpl Int 2012; 25:1223-8. [PMID: 22937819 DOI: 10.1111/j.1432-2277.2012.01551.x] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Since first described by Starzl, combined heart and liver transplantation (CHLT) has been a relatively rare event, although utilization has increased in the past decade. This study was undertaken to review the United States experience with this procedure; UNOS data on CHLT was reviewed. CHLT was compared with liver transplantation alone and heart transplantation alone in terms of acute rejection within 12 months, graft survival, and patient survival. Survival was calculated according to Kaplan-Meier and Cox proportional hazards. Continuous variables were compared using Student's t-test and categorical variables with chi-squared. Between 1987 and 2010, there were 97 reported cases of CHLT in the United States. Amyloidosis was the most common indication for both heart (n = 26, 26.8%) and liver (n = 27, 27.8%) transplantation in this cohort. Liver graft survival in the CHLT cohort at 1, 5, and 10 years was 83.4%, 72.8%, and 71.0%, whereas survival of the cardiac allograft was 83.5%, 73.2%, and 71.5%. This was similar to graft survival in liver alone transplantation (79.4%, 71.0%, 65.1%; P = 0.894) and heart transplantation alone (82.6%, 71.9%, 63.2%; P = 0.341). CHLT is a safe and effective procedure, with graft survival rates similar to isolated heart and isolated liver transplantation.
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Affiliation(s)
- Robert M Cannon
- Division of Transplantation, Department of Surgery, University of Louisville, Louisville, KY 40202, USA
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Ali S, Ormsby A, Shah V, Segovia MC, Kantz KL, Skorupski S, Eisenbrey AB, Mahan M, Huang MAY. Significance of complement split product C4d in ABO-compatible liver allograft: diagnosing utility in acute antibody mediated rejection. Transpl Immunol 2011; 26:62-9. [PMID: 21907804 DOI: 10.1016/j.trim.2011.08.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Revised: 08/10/2011] [Accepted: 08/21/2011] [Indexed: 12/11/2022]
Abstract
Diagnosis of liver allograft antibody-mediated rejection (AMR) is difficult and requires a constellation of clinical, laboratory and histologic features that support the disease and exclude other causes. Histologic features of AMR may intermix with those of biliary obstruction, preservation/reperfusion injury, and graft ischemia. Tissue examination for complement degradation product 4d (C4d) has been proved to support this diagnosis in other allografts. For this reason, we conducted a retrospective review of all ABO compatible/identical re-transplanted liver patients with primary focus on identifying AMR as a possible cause of graft failure and to investigate the utility of C4d in liver allograft specimens. We reviewed 193 liver samples obtained from 53 consecutive ABO-compatible re-transplant patients. 142 specimens were stained with C4d. Anti-donor antibody screening and identification was determined by Luminex100 flow cytometry. For the study analysis, patients were stratified into 3 groups according to time to graft failure: group A, patients with graft failure within 0-7 days (n=7), group B within 8-90 days (n=13) and C >90 days (n=33). Two patients (3.7%) met the diagnostic criteria of acute AMR. Both patients experienced rapid decline of graft function with presence of donor specific antibodies (DSA), morphologic evidence of humoral rejection and C4d deposition in liver specimens. C4d-positive staining was identified in different medical liver conditions i.e., acute cellular rejection (52%), chronic ductopenic rejection (50%), recurrent liver disease (48%), preservation injury (18%), and hepatic necrosis (54%). Univariate analysis showed no significant difference of C4d-positive staining among the 3 patients groups, or patients with DSA (P>.05). In conclusion, AMR after ABO-compatible liver transplantation is an uncommon cause of graft failure. Unlike other solid organ allografts, C4d-positive staining is not a rugged indicator of humoral rejection, thus, interpretation should be done with caution to avoid diagnostic dilemmas.
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Zhao J, Guo Y, Yan Z, Zhang J, Bushkin Y, Liang P. Soluble MHC I and soluble MIC molecules: potential therapeutic targets for cancer. Int Rev Immunol 2011; 30:35-43. [PMID: 21235324 DOI: 10.3109/08830185.2010.543711] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
It has become clear that soluble MHC I (sMHC I) and soluble MIC (sMIC), which are highly elevated in sera of cancer patients, can be viewed to be tolerogenic, and that metalloproteinases are involved in their generation process. In this review, an overview is provided of the recent progress made in the sMHC I and sMIC fields, with emphasis on their structure, formation, and function, and the key-questions that still await answers are addressed. Understanding better their formation mechanism, it will become more feasible to modulate the immune responses in cancer patients by targeting molecules involved in their generation process.
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Affiliation(s)
- Jinrong Zhao
- State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, Fourth Military Medical University, Xi'an, China
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Key T, Watson CJ, Clatworthy MR, O'Rourke CM, Goodman RS, Taylor CJ, Butler AJ. The kinetics of donor HLA class I-specific antibody absorption following a combined split liver and kidney transplant. NDT Plus 2010; 3:579-81. [PMID: 25949473 PMCID: PMC4421431 DOI: 10.1093/ndtplus/sfq160] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2009] [Revised: 06/17/2010] [Accepted: 08/19/2010] [Indexed: 12/25/2022] Open
Abstract
Hyperacute rejection of a transplanted liver is rare even when the recipient has circulating donor-specific alloantibodies (DSA). There is also evidence that a transplanted liver may provide immunological protection for other organs transplanted from the same donor. We monitored the kinetics of circulating DSA in a highly sensitized recipient of a combined split liver and kidney transplant and demonstrated a reduction in antibody titres immediately after liver perfusion. The absorption of DSA was not compromised by the smaller liver mass transplanted. DSA titres remained low at 3 months post-transplant, and the recipient did not experience antibody-mediated rejection.
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Affiliation(s)
| | | | - Menna R Clatworthy
- Division of Renal Medicine , Cambridge University Hospitals NHS Foundation Trust , Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ UK
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de la Cerda F, Jimenez WA, Gjertson DW, Venick R, Tsai E, Ettenger R. Renal graft outcome after combined liver and kidney transplantation in children: UCLA and UNOS experience. Pediatr Transplant 2010; 14:459-64. [PMID: 20070563 DOI: 10.1111/j.1399-3046.2009.01264.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Although it has been described in adults that renal grafts in the context of CLKT have a lower number of AR episodes and improved renal allograft survival, this has never been examined in pediatrics. We performed a single center retrospective case-control study examining 10 patients aged 10+/-6 yr with a CLKT that survived the post-surgery period of six months, and compared outcomes to a group of 20 KO transplants matched for age, era, and immunosuppression. We observed a significant reduction in the incidence of AR episodes in the CLKT group. To evaluate whether or not this experience was reproducible nationally, we performed an analysis of the 1995-2005 UNOS database. As of March 2007, 111 CLKT and 3798 KO transplants were identified from the OPTN/UNOS data. There was a significant improvement in the late kidney graft survival at five yr post-transplant in the CLKT group. These findings support the concept that liver transplantation is immunologically protective of the kidney allograft in CLKT.
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Affiliation(s)
- Francisco de la Cerda
- Department of Pediatrics, Division of Pediatric Nephrology, Mattel Children's Hospital at UCLA, Los Angeles, CA 90095-1752, USA
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Abstract
BACKGROUND Simultaneous combined orthotopic heart and liver transplantation (CHLTx) remains a lifesaving procedure for the patients suffering from coincident end-stage heart and liver disease and several metabolic disorders. We analyze the long-term outcome of the patients undergoing CHLTx. METHODS Between January 1992 and May 2007, 15 CHLTx were attempted at the Mayo Clinic including two combined heart, liver, and kidney transplantations and one combined heart, lung, and liver transplantations. Pretransplant cardiac diagnoses were familial amyloidosis (11), hemochromatosis (1), restrictive cardiomyopathy and cardiac cirrhosis (1), previously operated congenital heart disease and cardiac cirrhosis (1), and primary pulmonary hypertension with primary biliary cirrhosis (1). RESULTS Heart and liver transplantation were performed as a single combined procedure in 13 (93%) hemodynamically stable patients, and there was no perioperative mortality. Survival rates for the CHLTx recipients at 1 year, 5 years, and 10 years were 100%, 75%, and 60%, respectively, and did not differ from survival after isolated heart transplantation (93%, 83%, and 65%, respectively, P=0.39). Freedom from cardiac allograft rejection (ISHLT > or =grade 2) for CHLTx was 83% at 1 month, did not change with time, and was lower than after isolated heart transplantation (P=0.02). At the mean follow-up of 61.6+/-53.6 months, normal left ventricular ejection fraction and good liver allograft function were demonstrated. Three patients developed end-stage renal failure secondary to calcineurin nephrotoxicity. CONCLUSION Simultaneous heart and liver transplantation is feasible and achieved excellent results for selected patients.
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Renal After Cardiothoracic Transplant: The Effect of Repeat Mismatches on Outcome. Transplantation 2009; 87:1727-32. [DOI: 10.1097/tp.0b013e3181a60c51] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Okazaki S, Hisha H, Mizokami T, Takaki T, Wang X, Song C, Li Q, Kato J, Kamiyama Y, Ikehara S. Successful acceptance of adult liver allografts by intra-bone marrow-bone marrow transplantation. Stem Cells Dev 2008; 17:629-39. [PMID: 18537462 DOI: 10.1089/scd.2007.0218] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Previously, we have shown that liver allografts obtained from the fetus or young mice are accepted when bone marrow cells (BMCs) from adult mice of the same strain are co-grafted. However, for practical clinical use, it is more convenient to obtain both BMCs and liver from the same adult donors. C57BL/6 mice were irradiated with a single high-dose irradiation or two low-dose irradiations and injected with donor BALB/c (8 weeks old) BMCs intravenously (IV-BMT) or directly into the recipient BM cavity (IBM-BMT). Liver tissues taken from the same donor were, on the same day, engrafted under the kidney capsules. Higher survival rates and more complete reconstitution of donor cells were achieved in the IBM-BMT group than in the IV-BMT group, and this was the case in both irradiation protocols. The acceptance of donor liver tissue was seen in all mice in which hematolymphoid cells were replaced by donor-type cells. The liver grafts of the reconstituted mice showed normal morphology and stained positively with anti-albumin antibody and Periodic Acid Schiff (PAs) staining, indicating that the grafted livers were accepted, had grown, and were functioning. These results demonstrate that the acceptance of allogeneic liver can be achieved by cografting donor BMCs via the IBM route.
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Affiliation(s)
- Satoshi Okazaki
- 1st Department of Pathology, Kansai Medical University, Moriguchi City, Osaka, Japan
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Lin YC, Chen CL, Nakano T, Goto S, Kao YH, Hsu LW, Lai CY, Jawan B, Cheng YF, Tateno C, Yoshizato K. Immunological role of indoleamine 2,3-dioxygenase in rat liver allograft rejection and tolerance. J Gastroenterol Hepatol 2008; 23:e243-50. [PMID: 17645734 DOI: 10.1111/j.1440-1746.2007.05036.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Indoleamine 2,3-dioxygenase (IDO) is expressed in the placenta and plays an essential role in maternal tolerance. Recent data showed that giving IDO inhibitor blocked liver allograft tolerance. However, the immunological role of IDO in rat liver allograft models has not been characterized. In the present study, the time-course of IDO expression and the localization of IDO were analyzed to address the role of IDO in the induction of tolerance. METHODS Rat orthotopic liver transplantations (OLT) were performed and IDO gene expression of OLT livers was analyzed. Immunohistochemistry was used to evaluate the localization of IDO-expressed cells in the liver. RESULTS The IDO gene was detected in the allogeneic liver graft at the acute phase but the signal could not be detected when these OLT rats were treated with cyclosporinee A. The time-course of IDO gene expression in liver grafts of the spontaneous tolerant OLT model revealed that the IDO mRNA was expressed in both the rejection phase and the induction phase of tolerance, but the signal was gradually lowered during the maintenance phase of tolerance. Immunohistochemistry confirmed that the IDO protein was detected in antigen-presenting cells but not in hepatocytes. CONCLUSION Our results demonstrated that IDO is induced in antigen-presenting cells of rat liver allografts under drug-free status, suggesting that indirect or direct recognition of donor antigen and further T-cell activation may be inhibited. IDO may act as a local immunosuppressive molecule to protect transplanted cells, tissues and organs from immune attack.
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MESH Headings
- Animals
- Antigen-Presenting Cells/enzymology
- Antigen-Presenting Cells/immunology
- Blotting, Western
- Cells, Cultured
- Cyclosporine/pharmacology
- Disease Models, Animal
- Gene Expression Regulation, Enzymologic
- Graft Rejection/enzymology
- Graft Rejection/genetics
- Graft Rejection/immunology
- Graft Rejection/prevention & control
- Immune Tolerance/drug effects
- Immunohistochemistry
- Immunosuppressive Agents/pharmacology
- Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics
- Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
- Liver/drug effects
- Liver/enzymology
- Liver/immunology
- Liver/surgery
- Liver Transplantation
- Male
- RNA, Messenger/metabolism
- Rats
- Rats, Inbred Lew
- T-Lymphocytes/immunology
- Time Factors
- Transplantation, Homologous
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Affiliation(s)
- Yu-Chun Lin
- Department of Biological Science, Developmental Biology Laboratory, Graduate School of Science, Hiroshima University, Hiroshima, Japan.
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High PD-L1/CD86 ratio on plasmacytoid dendritic cells correlates with elevated T-regulatory cells in liver transplant tolerance. Transplantation 2008; 85:369-77. [PMID: 18301333 DOI: 10.1097/tp.0b013e3181612ded] [Citation(s) in RCA: 128] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Both dendritic cells (DC) and T-regulatory cells (Treg) have been implicated in regulation of alloimmune responses and transplant tolerance. METHODS We analyzed B7 coregulatory molecule expression on circulating DC subset precursors, together with CD4+CD25(hi) Foxp3+ Treg by rare event, flow cytometric analysis in operationally tolerant pediatric liver transplant recipients (TOL), those undergoing prospective immunosuppressive drug weaning (PW) or maintenance immunosuppression (MI), and normal healthy individuals (controls). RESULTS Use of DC subset-specific monoclonal antibodies confirmed elevated precursor plasmacytoid DC/myeloid DC ratios in TOL and PW compared with MI. In addition, Treg frequencies were higher in TOL than in PW and MI, but not controls. While there was no difference in levels of costimulatory and coinhibitory molecules on precursor myeloid DC between the groups, the programmed death ligand-1 (PD-L1=B7-H1):CD86 (B7-2) ratio on precursor plasmacytoid DC was significantly higher in TOL than MI and correlated with the Treg frequency. There was no relation between prednisone or tacrolimus dose or tacrolimus trough level and either the PD-L1/CD86 ratio on plasmacytoid DC or the Treg frequency. Moreover, clinically relevant concentrations of dexamethasone or tacrolimus did not affect these values in short-term culture. CONCLUSION These novel findings suggest a possible functional relationship between the enhanced incidence of precursor plasmacytoid DC, their comparatively high relative expression of the coinhibitory molecule PD-L1, and the elevated frequency of Treg in operational liver transplant tolerance.
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Schumann A, Fiedler M, Dahmen U, Grosse-Wilde H, Roggendorf M, Lindemann M. Cellular and humoral immune response to a third generation hepatitis B vaccine. J Viral Hepat 2007; 14:592-8. [PMID: 17650294 DOI: 10.1111/j.1365-2893.2007.00848.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Liver transplantation is often the ultimate option of therapy for chronically hepatitis B virus (HBV) infected patients. Adoptive transfer of HBV immunity with the liver after vaccination of living liver donors (LLD) could be a new approach to prevent reinfection in the recipients. The time to achieve HBV immunity in LLD is usually short (1-2 months). Therefore, we established a short time immunization protocol (four injections in 2 weeks intervals) using Hepimmune, a recombinant vaccine that contains the L, M and S proteins of HBV. We examined cellular and humoral immune responses after immunization with Hepimmune and compared its immunogenicity to that of a standard HBV vaccine containing only the S protein (HBVAXPRO). Cellular immunity was measured by interferon (IFN)-gamma ELISpot and proliferation assay. HBV-specific T cells were detectable in the Hepimmune group after the second and in the standard group after the third vaccination. IFN-gamma production of T cells was significantly higher (P < 0.001) after the third vaccination with Hepimmune. Proliferative responses were also significantly (P < 0.01) higher in the Hepimmune group after the second to fourth vaccination. The humoral immune response could already be detected after the first immunization in nine of 15 Hepimmune vaccinated test persons while it was only observed in one of 15 probands of the later group. Titres differed significantly (P < 0.01) following all four vaccinations. Thus, Hepimmune appears to be a good candidate for short time immunization protocols.
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Affiliation(s)
- A Schumann
- Institut für Virologie, and Institut für Immunologie, Universitätsklinikum Essen, Essen, Germany.
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Minagar A, Adamashvili I, Kelley RE, Gonzalez-Toledo E, McLarty J, Smith SJ. Saliva soluble HLA as a potential marker of response to interferon-beta 1a in multiple sclerosis: a preliminary study. J Neuroinflammation 2007; 4:16. [PMID: 17601341 PMCID: PMC1939839 DOI: 10.1186/1742-2094-4-16] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2007] [Accepted: 07/01/2007] [Indexed: 11/11/2022] Open
Abstract
Objective Potential surrogate markers of disease activity, including response to therapy, are particularly important in a neurological disorder such as multiple sclerosis (MS) which often has a fluctuating course. Based upon previous studies in our laboratory, we hypothesized that measurement of soluble HLA (sHLA) molecules class II in saliva of MS patients can serve as marker of therapeutic response to high dose interferon beta-1a. Methods We measured the expression patterns of sHLA-II in saliva in 17 patients with relapsing/remitting MS and compared the results to clinical course and brain MRI. For comparison purposes we also assayed the saliva sHLA-II levels in 53 normal control subjects. Solid phase ELISA was used for measurement of sHLA-I and sHLA-II concentrations at baseline and after three and six months of treatment with high dose interferon beta-1a (IFN β-1a). Results The mean saliva sHLA-ll levels in MS patients was significantly higher than normal controls (354 ± 42 unit/mL vs. 222 ± 18 unit/mL, t= 8.16, p < 0.003). Comparison of saliva sHLA-II values before and after treatment with IFN β-1a revealed a consistent increase in mean concentration. The increase in saliva sHLA-II values (354 ± 42 unit/mL at baseline versus 821 ± 86 unit/mL at 3 months and 776 ± 63 unit/mL at 6 months, in unit/mL, p < 0.001 for both comparisons) was associated with a stable clinical course and a decline of the number of contrast-enhancing lesions on brain MRI. Comparison of the volume of T2-weighted lesions and the number of black holes on T1-weighted images did not reveal any significant changes (during pre-treatment versus post-treatment month 6) or any correlations with saliva sHLA-II levels. Saliva sHLA-I levels were not detectable. Conclusion Serial measurement of saliva sHLA-II may serve as a potential marker of therapeutic response to IFN β-1a. Larger clinical studies involving more RRMS patients over longer periods of time are needed to further test the significance and value of saliva sHLA-II as an accurate marker of therapeutic response to beta-interferons.
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Affiliation(s)
- Alireza Minagar
- Department of Neurology, LSU Health Sciences Center, Shreveport, Louisiana, USA
| | - Irena Adamashvili
- Department of Neurology, LSU Health Sciences Center, Shreveport, Louisiana, USA
| | - Roger E Kelley
- Department of Neurology, LSU Health Sciences Center, Shreveport, Louisiana, USA
| | | | - Jerry McLarty
- Department of Internal Medicine, LSU Health Sciences Center, Shreveport, Louisiana, USA
| | - Stacy J Smith
- Department of Neurology, LSU Health Sciences Center, Shreveport, Louisiana, USA
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Faro A, Shepherd R, Huddleston CB, Lowell J, Gandhi S, Nadler M, Sweet SC. Lower Incidence of Bronchiolitis Obliterans in Pediatric Liver−Lung Transplant Recipients With Cystic Fibrosis. Transplantation 2007; 83:1435-9. [PMID: 17565316 DOI: 10.1097/01.tp.0000266067.44499.07] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Simultaneous liver-lung transplantation is an infrequent but technically feasible procedure in patients with end-stage lung disease and advanced liver disease. We characterize the outcomes of pediatric patients who underwent this procedure at our institution. METHODS We performed a retrospective, case-control study and reviewed the medical records of all patients referred to our transplant program from its inception. Seven patients were listed for simultaneous liver-lung transplant. The five patients who survived to transplant were matched to 13 controls who underwent isolated bilateral sequential lung transplant for underlying diagnosis, age at time of transplant, gender, and era of transplant. Outcome measures included patient and graft survival, occurrence of bronchiolitis obliterans (BO), and episodes of rejection. RESULTS Of the five study patients who underwent liver-lung transplant, one died of multiorgan failure 11 days after transplant compared with 9 of 13 controls who died. The median survival for the study patients was 89 months (range, 0-112 months) compared with the controls, who had a median survival of 34 months (range, 0-118 months). The remaining four patients had bronchiolitis obliterans syndrome scores of 0 compared with 5 of 13 control patients (P=0.02). The rate of acute rejection per 100 patient days was 0.012 for the study patients compared with 0.11 for the controls (P=0.025). CONCLUSIONS Simultaneous liver-lung transplantation is a technically feasible procedure with excellent long-term outcomes. The surviving study subjects remain free from bronchiolitis obliterans syndrome. These results suggest that the transplanted liver may bestow immunologic privilege to the lung allograft.
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Affiliation(s)
- Albert Faro
- Department of Pediatrics, Washington University in St. Louis, St. Louis, MO 63110, USA.
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Curry AJ, Pettigrew GJ, Negus MC, Easterfield AJ, Young JL, Bolton EM, Bradley JA. Dendritic cells internalise and re-present conformationally intact soluble MHC class I alloantigen for generation of alloantibody. Eur J Immunol 2007; 37:696-705. [PMID: 17266175 DOI: 10.1002/eji.200636543] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Following organ transplantation soluble MHC class I is released from the graft and may contribute to alloimmunity. We determined in a well-established rat model whether DC are able to internalise soluble MHC class I alloantigen and then re-present intact alloantigen to B cells and T cells for generation of an alloantibody or CD8 T cell response. PVG.RT1(u) BM-derived DC internalised (via an active process) and retained intact a recombinant soluble form of RT1-A(a) (sRT1-A(a)). When PVG.RT1(u) rats were immunised with sRT1-A(a)-pulsed syngeneic DC, they developed a strong anti-sRT1-A(a) alloantibody response and showed accelerated rejection of RT1-A(a)-disparate PVG.R8 heart grafts. Alloantibody production and accelerated heart graft rejection were both dependent on immunisation with viable sRT1-A(a)-pulsed DC. The alloantibody response to sRT1-A(a)-pulsed DC was directed exclusively against conformational epitopes expressed by sRT1-A(a) and not epitopes expressed, for example, by non-conformational sRT1-A(a) heavy chain. Immunisation with sRT1-A(a)-pulsed syngeneic DC did not stimulate a CD8 T cell response. Our findings suggest a novel alloantigen recognition pathway whereby soluble MHC class I alloantigen released from an allograft may be taken up by recipient DC and presented in an intact unprocessed form to B cells for the generation of an alloantibody response.
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Affiliation(s)
- Allison J Curry
- Department of Surgery, School of Clinical Medicine, University of Cambridge, Cambridge, UK
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Simpson N, Cho YW, Cicciarelli JC, Selby RR, Fong TL. Comparison of renal allograft outcomes in combined liver-kidney transplantation versus subsequent kidney transplantation in liver transplant recipients: Analysis of UNOS Database. Transplantation 2007; 82:1298-303. [PMID: 17130778 DOI: 10.1097/01.tp.0000241104.58576.e6] [Citation(s) in RCA: 140] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND There may be an allograft-enhancing effect by the liver on the renal allograft in the setting of simultaneous combined liver-kidney transplantation (CLKT) from the same donor. This study was performed to investigate whether an existing liver allograft could protect a kidney allograft from immunologic injury due to histoincompatibility in liver transplant recipients who received sequential kidney transplantation (KALT). METHODS Using the United Network for Organ Sharing database covering January 1996 to December 2003, outcomes of 352 KALT were compared to 1,136 CLKT. Incidence of acute and chronic rejection and rejection-free renal graft survival was compared between two groups. RESULTS Renal half-life of KALT allografts was shorter than CLKT group (6.6+/-0.9 vs. 11.7+/-1.3 years, P < 0.001). Incidence of chronic rejection in KALT group was higher than CLKT group (4.6 vs. 1.2%, P < 0.001). One and three-year rejection-free renal graft survival of KALT and CLKT groups were different (77% and 67% KALT vs. 85% and 78% CLKT, respectively; P < 0.001). Among human leukocyte antigen mismatched and sensitized patients, rejection-free renal graft survival of KALT group was inferior to the CLKT group (75% at 1 year and 61% 3 years vs. 86% at 1 year and 79% 3 years, P < 0.001). CONCLUSION Liver allograft provided renal graft immunoprotection if both organs are transplanted simultaneously (immunogenetic identity), but not for kidneys transplanted subsequently.
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Affiliation(s)
- Nicole Simpson
- Abdominal Transplantation Program, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
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Steger U, Kingsley CI, Karim M, Bushell AR, Wood KJ. CD25+CD4+ Regulatory T Cells Develop in Mice Not Only During Spontaneous Acceptance of Liver Allografts but Also After Acute Allograft Rejection. Transplantation 2006; 82:1202-9. [PMID: 17102772 DOI: 10.1097/01.tp.0000235913.58337.b4] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Liver grafts transplanted across a major histocompatibility barrier are accepted spontaneously and induce donor specific tolerance in some species. Here, we investigated whether liver allograft acceptance is characterized by, and depends upon, the presence of donor reactive CD25CD4 regulatory T cells. METHODS CD25 and CD25CD4 T cells, isolated from CBA. Ca (H2) recipients of C57BL/10 (B10; H2) liver and heart allografts 10 days after transplantation, were transferred into CBA. Rag1 mice to investigate their influence on skin allograft rejection mediated by CD45RBCD4 effector T Cells. RESULTS Fully allogeneic B10 liver allografts were spontaneously accepted by naive CBA.Ca recipient mice, whereas B10 cardiac allografts were acutely rejected (mean survival time=7 days). Strikingly, however, CD25CD4 T cells isolated from both liver and cardiac allograft recipients were able to prevent skin allograft rejection in this adoptive transfer model. Interestingly, CD25CD4 T cells isolated from liver graft recipients also showed suppressive potency upon adoptive transfer. Furthermore, depletion of CD25CD4 T cells in primary liver allograft recipients did not prevent the acceptance of a secondary donor-specific skin graft. CONCLUSIONS Our data provide evidence that the presence of CD25CD4 regulatory T cells is not a unique feature of allograft acceptance and is more likely the result of sustained exposure to donor alloantigens in vivo.
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Affiliation(s)
- Ulrich Steger
- Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
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Bangia N, Ferrone S. Antigen presentation machinery (APM) modulation and soluble HLA molecules in the tumor microenvironment: do they provide tumor cells with escape mechanisms from recognition by cytotoxic T lymphocytes? Immunol Invest 2006; 35:485-503. [PMID: 16916763 DOI: 10.1080/08820130600808246] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Naveen Bangia
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
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Jugie M, Canioni D, Le Bihan C, Sarnacki S, Revillon Y, Jan D, Lacaille F, Cerf-Bensussan N, Goulet O, Brousse N, Damotte D. Study of the impact of liver transplantation on the outcome of intestinal grafts in children. Transplantation 2006; 81:992-7. [PMID: 16612274 DOI: 10.1097/01.tp.0000195899.32734.83] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Successful small bowel transplantation remains a challenge due to the septic and immune content of the gut. The possible beneficial role of the liver was assessed in pediatric recipients of isolated intestinal and liver intestinal combined transplantation, receiving the same immunosuppressive therapy. METHODS Fifteen children who underwent small bowel transplantation (seven SbTx) or combined liver-small bowel transplantation (eight LSbTx) at a single center between 1994 and 1998 were retrospectively reviewed and compared with fifteen controls (eight normal and seven appendicitis as inflammatory control). Transplant and patient survival, acute rejection episodes were analyzed and compared. Epithelial apoptotic body counts (ABC) and NF-kB (p65), Caspase-3 and Bax intestinal immunostaining from days 0 to 20 after transplantation were assessed. RESULTS Graft and patient survivals at 5 years were respectively 75% and 75% in LSbTx; 43% and 57% in SbTx (NS). Histological analysis showed higher ABC in LSbTx intestinal mucosa (P = 0.05 on day 5, P < 0.01 thereafter). Immunostaining of biopsies on day 0 after reperfusion showed different expression of NF-kB, Caspase-3 and Bax on endothelial (P < 0.05 for NF-kB and Bax), mononuclear (P < 0.05 for Bax) and epithelial cells in LSbTx and SbTx. CONCLUSIONS Our results suggest a protective role of the liver toward intestinal transplantation even in absence of significative difference, probably due to the small number of children. Early changes in NF-kB immunostaining in the biopsies sampled on day 0, pointed to a possible beneficial effect of the liver in the very early phase following transplantation, perhaps through the differential control of ischemia-reperfusion.
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Affiliation(s)
- Myriam Jugie
- Pediatrics Department, Saint-Vincent-de-Paul Hospital, Necker-Enfants Malades Hospital, Paris, France
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Sen SK, Lowe JB, Brenner MJ, Hunter DA, Mackinnon SE. Assessment of the immune response to dose of nerve allografts. Plast Reconstr Surg 2005; 115:823-30. [PMID: 15731684 DOI: 10.1097/01.prs.0000153032.68405.da] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Nerve allotransplantation provides a limitless source of nerve graft material for the reconstruction of large neural defects. It does require systemic immunosuppression or induction of immune unresponsiveness to prevent allograft rejection. It is unknown whether a greater volume of nerve graft material will increase the risk of rejection or the need for more intensive immunosuppression. This study assessed the relationship between the quantity of nerve tissue transplanted and the magnitude of the resulting immune response. Forty female (BALB/c) mice were randomly assigned to two groups that received either nerve isografts (BALB/c) or nerve allografts (C57BL/6). Each group was then subdivided into two groups that received either one or 10 sciatic nerve graft inlays. Histological and immunological assessments were performed at 10 days after engraftment. Histologic analysis demonstrated greater cellular infiltration in the allograft than the isograft groups but no appreciable difference in infiltration related to quantity of transplanted nerve tissue. In vitro assessments of the immune response using mixed lymphocyte assays and limiting dilution analysis similarly demonstrated a robust immune response to allografts but no effect on quantity of transplanted nerve tissue. These data suggest that larger peripheral nerve allografts may not be subject to increased risk for rejection.
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Affiliation(s)
- Subhro K Sen
- Division of Plastic and Reconstructive Surgery and the Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, Mo 63110, USA
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Matinlauri IH, Nurminen MM, Höckerstedt KA, Isoniemi HM. Risk factors predicting survival of liver transplantation. Transplant Proc 2005; 37:1155-60. [PMID: 15848655 DOI: 10.1016/j.transproceed.2004.12.078] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Prognostic models were developed for analyzing graft survival in a single-center study consisting of all 388 adult liver transplantations performed during 20 years. Proportional hazard models and generalized linear models were used to assess which risk factors, related to donor and recipient characteristics as well as graft preservation and operation, had an effect on graft survival. The prognostic modeling evidenced favorable trends in graft survival time during the successive quinquennials 1982-1987, 1988-1992, and 1993-1997, in comparison to the referent time period 1998-2002. Significant predictors of graft survival time were donor's age, recipient-donor gender compatibility, recipient's blood group, intraoperative blood transfusion, size of the transplanted organ, and indication for transplantation. Conventional histocompatibility matching did not correlate with graft outcome.
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Affiliation(s)
- I H Matinlauri
- Department of Tissue Typing, Finnish Red Cross, Blood Service, Helsinki, Finland
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Adamashvili I, Kelley RE, Pressly T, McDonald JC. Soluble HLA: patterns of expression in normal subjects, autoimmune diseases, and transplant recipients. Rheumatol Int 2005; 25:491-500. [PMID: 15986087 DOI: 10.1007/s00296-005-0585-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2004] [Accepted: 10/11/2004] [Indexed: 11/30/2022]
Affiliation(s)
- Irena Adamashvili
- Department of Neurology, Louisiana State University Medical Center, P.O. Box 33932, Shreveport, LA 71130, USA.
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Onoe T, Ohdan H, Tokita D, Hara H, Tanaka Y, Ishiyama K, Asahara T. Liver sinusoidal endothelial cells have a capacity for inducing nonresponsiveness of T cells across major histocompatibility complex barriers. Transpl Int 2005; 18:206-14. [PMID: 15691274 DOI: 10.1111/j.1432-2277.2004.00025.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Livers transplanted across major histocompatibility complex (MHC) barriers in mice are normally accepted without recipient immune suppression. To identify the cell type that contributes to induction of such a tolerance state, we established an allogeneic mixed hepatic constituent cell-lymphocyte reaction (MHLR) assay. Hepatic constituent cells were isolated from C57BL/6 (B6) and Balb/c mice as stimulators, and splenocytes were isolated from B6 mice as responders. Irradiated hepatic constituent cells were co-cultured with fluorescent dye (CFSE)-labeled B6 splenocytes. In the allogeneic MHLR using either whole hepatic constituent cells or parenchymal hepatocytes as stimulators, a lack of T-cell proliferation was observed. Only when CD105(+) cells, which are exclusively liver sinusoidal endothelial cells (LSECs), were depleted from hepatic constituent cell stimulators, the MHLR resulted in marked proliferation of both allo-reactive CD4(+) and CD8(+) T cells. These results indicate that CD105(+) LSECs have the capacity to induce nonresponsiveness of T cells across MHC barriers.
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Affiliation(s)
- Takashi Onoe
- Department of Surgery, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
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Adamashvili I, Minagar A, Gonzalez-Toledo E, Featherston L, Kelley RE. Soluble HLA measurement in saliva and cerebrospinal fluid in Caucasian patients with multiple sclerosis: a preliminary study. J Neuroinflammation 2005; 2:13. [PMID: 15932635 PMCID: PMC1180848 DOI: 10.1186/1742-2094-2-13] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2005] [Accepted: 06/02/2005] [Indexed: 11/19/2022] Open
Abstract
Background Measurement of soluble HLA in body fluids has a potential role in assessing disease activity in autoimmune disorders. Methods We applied a solid phase, enzyme-linked immunoassay to measure soluble HLA class I (sHLA-I) and class II (sHLA-II) molecules in the saliva and cerebrospinal fluid (CSF) in 13 untreated patients with relapsing-remitting form of multiple sclerosis (MS). For comparison purposes, we also studied saliva from 53 healthy subjects. Results Saliva from normal controls had detectable sHLA-I levels in 41 of 53 individuals studied, with values ranging from 9–100 ng/ml (mean = 41 ± 2.8 ng/ml). sHLA-I was undetectable in the saliva in 11 of 13 MS patients, and in none of the CSF specimens. In contrast, mean sHLA-II concentration in the saliva of MS patients was significantly increased compared to controls (386 ± 52 unit/ml vs. 222 ± 18.4 unit/ml, t = 8.68, P < 0.005). The mean CSF sHLA-II level (369 ± 16 unit/ml) was equivalent to the mean sHLA-II concentration measured in saliva (mean = 386 ± 52 unit/ml) (P = 0.7). In patients with brain magnetic resonance imaging (MRI) enhancing lesions (n = 5), reflective of more active disease, CSF sHLA-II averaged 356 ± 26 unit/ml compared to 380 ± 51 in saliva. Similarly, in patients with non-enhancing lesions (n = 8), CSF sHLA-II averaged 377 ± 18 unit/ml compared to 390 ± 77 unit/ml in saliva. Thus, the mean sHLA-II concentration in saliva and CSF was essentially equivalent for MS patients with or without enhancing plaques. Conclusion Our data suggest that the measurement of soluble HLA in saliva, specifically sHLA-II, correlates with the level found in the CSF. Therefore, if sHLA correlates with disease activity in MS, as has been proposed, saliva measurements provide a noninvasive correlate of CSF measurement.
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Affiliation(s)
- Irena Adamashvili
- Department of Neurology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130 USA
| | - Alireza Minagar
- Department of Neurology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130 USA
| | - Eduardo Gonzalez-Toledo
- Department of Radiology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130 USA
| | - Liubov Featherston
- Department of Neurology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130 USA
| | - Roger E Kelley
- Department of Neurology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130 USA
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Affiliation(s)
- Olivia M Martinez
- Stanford University School of Medicine, Stanford, CA 94305-5492, USA.
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