|
1
|
Tao J, Shen X, Qian H, Ding Q, Wang L. TIM proteins and microRNAs: distinct impact and promising interactions on transplantation immunity. Front Immunol 2024; 15:1500228. [PMID: 39650660 PMCID: PMC11621082 DOI: 10.3389/fimmu.2024.1500228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 11/06/2024] [Indexed: 12/11/2024] Open
Abstract
Achieving sustained activity and tolerance in of allogeneic grafts after post-transplantation remains a substantial challenge. The response of the immune system to "non-self" MHC-antigenic peptides initiates a crucial phase, wherein blocking positive co-stimulatory signals becomes imperative to ensure graft survival and tolerance. MicroRNAs (miRNAs) inhibit mRNA translation or promote mRNA degradation by complementary binding of mRNA seed sequences, which ultimately affects protein synthesis. These miRNAs exhibit substantial promise as diagnostic, prognostic, and therapeutic candidates for within the realm of solid organ transplantations. Current research has highlighted three members of the T cell immunoglobulin and mucin domain (TIM) family as a novel therapeutic avenue in transplantation medicine and alloimmunization. The interplay between miRNAs and TIM proteins has been extensively explored in viral infections, inflammatory responses, and post-transplantation ischemia-reperfusion injuries. This review aims to elucidate the distinct roles of miRNAs and TIM in transplantation immunity and delineate their interdependent relationships in terms of targeted regulation. Specifically, this investigation sought seeks to uncover the potential of miRNA interaction with TIM, aiming to induce immune tolerance and bolster allograft survival after transplantation. This innovative strategy holds substantial promise in for the future of transplantation science and practice.
Collapse
Affiliation(s)
- Jialing Tao
- Translational Medical Innovation Center, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, China
| | - Xiaoxuan Shen
- Department of Endocrinology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, China
| | - Haiqing Qian
- Department of Reproduction, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, Zhangjiagang, China
| | - Qing Ding
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Lihong Wang
- Department of Reproduction, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, Zhangjiagang, China
| |
Collapse
|
|
2
|
Millán O, Ruiz P, Julian J, Lizana A, Fundora Y, Crespo G, Colmenero J, Navasa M, Brunet M. A plasmatic score using a miRNA signature and CXCL-10 for accurate prediction and diagnosis of liver allograft rejection. Front Immunol 2023; 14:1196882. [PMID: 37325660 PMCID: PMC10265684 DOI: 10.3389/fimmu.2023.1196882] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/17/2023] [Indexed: 06/17/2023] Open
Abstract
Introduction The use of noninvasive biomarkers may avoid the need for liver biopsy (LB) and could guide immunosuppression adjustment in liver transplantation (LT). The aims of this study were: to confirm the predictive and diagnostic capacity of plasmatic expression of miR-155-5p, miR-181a-5p, miR-122-5p and CXCL-10 for assessing T-cell mediated rejection (TCMR) risk; to develop a score based on a panel of noninvasive biomarkers to predict graft rejection risk and to validate this score in a separate cohort. Methods A prospective, observational study was conducted with a cohort of 79 patients followed during the first year after LT. Plasma samples were collected at predetermined time points for the analysis of miRNAs and the CXCL-10. Patients with LFTs abnormalities were submitted to a LB to rule out rejection, assessing previous and concurrent expression of the biomarkers to evaluate their predictive and diagnostic ability. Information from 86 patients included in a previous study was collected and used as a validation cohort. Results Twenty-four rejection episodes were diagnosed in 22 patients. Plasmatic CXCL-10 concentration and the expression of the three miRNAs were significantly elevated prior to and at the moment of the diagnosis of rejection. We developed a logistic model for rejection prediction and diagnosis, which included CXCL-10, miR-155-5p and miR-181a-5p. The area under the ROC curve (AUROC) for rejection prediction was 0.975 (79.6% sensitivity, 99.1% specificity, 90,7% PPV; 97.7% NPV; 97.1% correctly classified) and 0.99 for diagnosis (87.5% sensitivity, 99.5% specificity, 91.3% PPV; 99.3% NPV; 98.9% correctly classified). In the validation cohort (n=86; 14 rejections), the same cut-off points were used obtaining AUROCs for rejection prediction and diagnosis of 0.89 and 0.92 respectively. In patients with graft dysfunction in both cohorts the score could discriminate those with rejection regarding other causes with an AUROC of 0.98 (97.3% sensitivity, 94.1%specificity). Conclusion These results suggest that the clinical implementation of the monitoring of this noninvasive plasmatic score may allow the prediction and diagnosis of rejection and identify patients with graft dysfunction due to rejection, helping with a more efficient guide for immunosuppressive therapy adjustment. This finding warrants the development of prospective biomarker-guided clinical trials.
Collapse
Affiliation(s)
- Olga Millán
- Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III (ISCII), Madrid, Spain
- Pharmacology and Toxicology, Biochemistry and Molecular Genetics, Biomedical Diagnostic Center (CDB), Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Pablo Ruiz
- Liver Unit, Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Judit Julian
- Pharmacology and Toxicology, Biochemistry and Molecular Genetics, Biomedical Diagnostic Center (CDB), Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
- Biochemistry and Molecular Genetics, Biomedical Diagnostic Center, Hospital Clínic of Barcelona, Barcelona, Spain
| | - Ana Lizana
- Pharmacology and Toxicology, Biochemistry and Molecular Genetics, Biomedical Diagnostic Center (CDB), Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Yiliam Fundora
- Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III (ISCII), Madrid, Spain
- Department of General and Digestive Surgery, Hospital Clínic Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Gonzalo Crespo
- Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III (ISCII), Madrid, Spain
- Liver Unit, Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Jordi Colmenero
- Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III (ISCII), Madrid, Spain
- Liver Unit, Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Miquel Navasa
- Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III (ISCII), Madrid, Spain
- Liver Unit, Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Mercè Brunet
- Biomedical Research Center in Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III (ISCII), Madrid, Spain
- Pharmacology and Toxicology, Biochemistry and Molecular Genetics, Biomedical Diagnostic Center (CDB), Hospital Clinic of Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| |
Collapse
|
|
3
|
Inhibition of miR-let-7i Induces DC Immature Cells and Improves Skin Graft Tolerance. DISEASE MARKERS 2022; 2022:8605621. [PMID: 35756489 PMCID: PMC9217530 DOI: 10.1155/2022/8605621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 04/07/2022] [Accepted: 04/18/2022] [Indexed: 11/18/2022]
Abstract
Dendritic cells (DC) initiate the immune response in the body. They can stimulate T cell activation, proliferation, and differentiation and ultimately participate in the immune response and the immune tolerance response. The purpose of this study was to coculture DCs and T cells and subcutaneously inject DCs transfected with miR-let-7i into rhesus monkey transplantations to verify the role of miR-let-7i in allograft immune tolerance. In vitro studies found that the expression of miR-let-7i was upregulated after inducing the maturation of DCs. The low expression of miR-let-7i inhibited the maturation of DCs, promoted the differentiation of T cells into T helper T cells 2 (Th2), and inhibited T helper T cell 1- (Th1-) driven rejection. In vivo studies also obtained similar results, and subcutaneous injection of DCs transfected with miR-let-7i inhibitor prolonged the survival time of allogeneic skin transplantation. Therefore, we conclude that inhibition of miR-let-7i inhibits DC maturation and improves the tolerance of grafted skin.
Collapse
|
|
4
|
Bozzini S, Del Fante C, Morosini M, Berezhinskiy HO, Auner S, Cattaneo E, Della Zoppa M, Pandolfi L, Cacciatore R, Perotti C, Hoetzenecker K, Jaksch P, Benazzo A, Meloni F. Mechanisms of Action of Extracorporeal Photopheresis in the Control of Bronchiolitis Obliterans Syndrome (BOS): Involvement of Circulating miRNAs. Cells 2022; 11:cells11071117. [PMID: 35406680 PMCID: PMC8997705 DOI: 10.3390/cells11071117] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/22/2022] [Accepted: 03/24/2022] [Indexed: 11/16/2022] Open
Abstract
Clinical evidence suggests an improvement or stabilization of lung function in a fraction of patients with bronchiolitis obliterans syndrome (BOS) treated by extracorporeal photopheresis (ECP); however, few studies have explored the epigenetic and molecular regulation of this therapy. The aim of present study was to evaluate whether a specific set of miRNAs were significantly regulated by ECP. Total RNA was isolated from serum of patients with established BOS grade 1–2 prior to the start and after 6 months of ECP treatment. We observed a significant downregulation of circulating hsa-miR-155-5p, hsa-miR-146a-5p and hsa-miR-31-5p in BOS patients at the start of ECP when compared to healthy subjects. In responders, increased miR-155-5p and decreased miR-23b-3p expression levels at 6 months were found. SMAD4 mRNA was found to be a common target of these two miRNAs in prediction pathways analysis, and a significant downregulation was found at 6 months in PBMCs of a subgroup of ECP-treated patients. According to previous evidence, the upregulation of miR-155 might be correlated with a pro-tolerogenic modulation of the immune system. Our analysis also suggests that SMAD4 might be a possible target for miR-155-5p. Further longitudinal studies are needed to address the possible role of miR-155 and its downstream targets.
Collapse
Affiliation(s)
- Sara Bozzini
- Laboratory of Respiratory Disease, Cell Biology Section, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.M.); (E.C.); (M.D.Z.); (L.P.)
- Correspondence: ; Tel.: +39-0382-501-001
| | - Claudia Del Fante
- Immunohaematology and Transfusion Service, Apheresis and Cell Therapy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (C.D.F.); (R.C.); (C.P.)
| | - Monica Morosini
- Laboratory of Respiratory Disease, Cell Biology Section, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.M.); (E.C.); (M.D.Z.); (L.P.)
| | - Hatice Oya Berezhinskiy
- Department of Thoracic Surgery, Medical University of Vienna, 1090 Wien, Austria; (H.O.B.); (S.A.); (K.H.); (P.J.); (A.B.)
| | - Sophia Auner
- Department of Thoracic Surgery, Medical University of Vienna, 1090 Wien, Austria; (H.O.B.); (S.A.); (K.H.); (P.J.); (A.B.)
| | - Elena Cattaneo
- Laboratory of Respiratory Disease, Cell Biology Section, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.M.); (E.C.); (M.D.Z.); (L.P.)
| | - Matteo Della Zoppa
- Laboratory of Respiratory Disease, Cell Biology Section, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.M.); (E.C.); (M.D.Z.); (L.P.)
| | - Laura Pandolfi
- Laboratory of Respiratory Disease, Cell Biology Section, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (M.M.); (E.C.); (M.D.Z.); (L.P.)
| | - Rosalia Cacciatore
- Immunohaematology and Transfusion Service, Apheresis and Cell Therapy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (C.D.F.); (R.C.); (C.P.)
| | - Cesare Perotti
- Immunohaematology and Transfusion Service, Apheresis and Cell Therapy Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (C.D.F.); (R.C.); (C.P.)
| | - Konrad Hoetzenecker
- Department of Thoracic Surgery, Medical University of Vienna, 1090 Wien, Austria; (H.O.B.); (S.A.); (K.H.); (P.J.); (A.B.)
| | - Peter Jaksch
- Department of Thoracic Surgery, Medical University of Vienna, 1090 Wien, Austria; (H.O.B.); (S.A.); (K.H.); (P.J.); (A.B.)
| | - Alberto Benazzo
- Department of Thoracic Surgery, Medical University of Vienna, 1090 Wien, Austria; (H.O.B.); (S.A.); (K.H.); (P.J.); (A.B.)
| | - Federica Meloni
- UOS Transplant Center, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| |
Collapse
|
|
5
|
Yatim KM, Azzi JR. Novel Biomarkers in Kidney Transplantation. Semin Nephrol 2022; 42:2-13. [DOI: 10.1016/j.semnephrol.2022.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
|
|
6
|
Usuelli V, Ben Nasr M, D'Addio F, Liu K, Vergani A, El Essawy B, Yang J, Assi E, Uehara M, Rossi C, Solini A, Capobianco A, Rigamonti E, Potena L, Venturini M, Sabatino M, Bottarelli L, Ammirati E, Frigerio M, Castillo‐Leon E, Maestroni A, Azzoni C, Loretelli C, Joe Seelam A, Tai AK, Pastore I, Becchi G, Corradi D, Visner GA, Zuccotti GV, Chau NB, Abdi R, Pezzolesi MG, Fiorina P. miR-21 antagonism reprograms macrophage metabolism and abrogates chronic allograft vasculopathy. Am J Transplant 2021; 21:3280-3295. [PMID: 33764625 PMCID: PMC8518036 DOI: 10.1111/ajt.16581] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 02/19/2021] [Accepted: 03/09/2021] [Indexed: 01/25/2023]
Abstract
Despite much progress in improving graft outcome during cardiac transplantation, chronic allograft vasculopathy (CAV) remains an impediment to long-term graft survival. MicroRNAs (miRNAs) emerged as regulators of the immune response. Here, we aimed to examine the miRNA network involved in CAV. miRNA profiling of heart samples obtained from a murine model of CAV and from cardiac-transplanted patients with CAV demonstrated that miR-21 was most significantly expressed and was primarily localized to macrophages. Interestingly, macrophage depletion with clodronate did not significantly prolong allograft survival in mice, while conditional deletion of miR-21 in macrophages or the use of a specific miR-21 antagomir resulted in indefinite cardiac allograft survival and abrogated CAV. The immunophenotype, secretome, ability to phagocytose, migration, and antigen presentation of macrophages were unaffected by miR-21 targeting, while macrophage metabolism was reprogrammed, with a shift toward oxidative phosphorylation in naïve macrophages and with an inhibition of glycolysis in pro-inflammatory macrophages. The aforementioned effects resulted in an increase in M2-like macrophages, which could be reverted by the addition of L-arginine. RNA-seq analysis confirmed alterations in arginase-associated pathways associated with miR-21 antagonism. In conclusion, miR-21 is overexpressed in murine and human CAV, and its targeting delays CAV onset by reprogramming macrophages metabolism.
Collapse
Affiliation(s)
- Vera Usuelli
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Moufida Ben Nasr
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly,Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Francesca D'Addio
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Kaifeng Liu
- Division of Pulmonary and Respiratory DiseasesBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Andrea Vergani
- Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Basset El Essawy
- Department of MedicineAl‐Azhar UniversityCairoEgypt,Renal DivisionTransplantation Research CenterBrigham and Women's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Jun Yang
- Institute of Organ TransplantationTongji Hospital and Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Emma Assi
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Mayuko Uehara
- Renal DivisionTransplantation Research CenterBrigham and Women's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Chiara Rossi
- Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Anna Solini
- Department of SurgicalMedical, Molecular and Critical Area PathologyUniversity of PisaPisaItaly
| | - Annalisa Capobianco
- Division of Immunology, Transplantation and Infectious DiseaseSan Raffaele Scientific InstituteMilanItaly
| | - Elena Rigamonti
- Division of Immunology, Transplantation and Infectious DiseaseSan Raffaele Scientific InstituteMilanItaly
| | - Luciano Potena
- Heart Failure and Heart Transplant ProgramS. Orsola‐Malpighi HospitalAlma‐Mater University of BolognaBolognaItaly
| | | | - Mario Sabatino
- Department of Cardiothoracic, Transplantation and Vascular SurgeryS. Orsola‐Malpighi HospitalAlma Mater‐University of BolognaBolognaItaly
| | | | - Enrico Ammirati
- De Gasperis Cardio Center and Transplant CenterNiguarda HospitalMilanItaly
| | - Maria Frigerio
- De Gasperis Cardio Center and Transplant CenterNiguarda HospitalMilanItaly
| | - Eduardo Castillo‐Leon
- Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Anna Maestroni
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Cinzia Azzoni
- Department of Medicine and SurgeryUniversity of ParmaParmaItaly
| | - Cristian Loretelli
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Andy Joe Seelam
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Albert K. Tai
- Tufts University Core Facility (TUCF) Genomics CoreTufts University School of MedicineBostonMassachusetts
| | - Ida Pastore
- Division of EndocrinologyASST Fatebenefratelli‐SaccoMilanItaly
| | | | | | - Gary A. Visner
- Division of Pulmonary and Respiratory DiseasesBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Gian V. Zuccotti
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly,Department of PediatricsBuzzi Children's HospitalMilanItaly
| | | | - Reza Abdi
- Renal DivisionTransplantation Research CenterBrigham and Women's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Marcus G. Pezzolesi
- Division of Nephrology and Hypertension, Diabetes and Metabolism CenterUniversity of UtahSalt Lake CityUtah
| | - Paolo Fiorina
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly,Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts,Division of EndocrinologyASST Fatebenefratelli‐SaccoMilanItaly
| |
Collapse
|
|
7
|
Tomasi R, Tariq M, Hübner M, Strauss G, Längin M, Zeuzem-Lampert C, Vandewiele S, Kreth S, Abicht JM. T-Cell Response in a Cardiac Xenotransplant Model. EXP CLIN TRANSPLANT 2021; 19:708-716. [PMID: 34085920 DOI: 10.6002/ect.2020.0359] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Despite the advances in preclinical cardiac xenotransplantation, the immune reactions caused by species differences are not fully understood. Hyperacute rejection can now be avoided using genetically engineered donor organs, but cellmediated rejection by the adaptive immune response has not been addressed successfully. Here we investigated the initial human pan-T-cell reaction using a pig-human blood working heart model. MATERIALS AND METHODS Porcine wild-type hearts (n = 7) were perfused with human blood in a biventricular working heart system for 3 hours. As control, blood from the same human donors was circulated without a pig heart. Pan-T cells were selectively extracted from blood taken before and at the end of the perfusion cycle. The relative mRNA expression of selected target genes (real-time quantitative polymerase chain reaction) and the expression of microRNAs were determined. RESULTS After xenogeneic organ perfusion, there was a moderate upregulation of several CD4+ marker cytokines (interleukin 2, interleukin 4, interferon γ) compared with control. We found a distinct increase in the mRNA expression of granzyme B and perforin, key markers of cytotoxic T cells. No differences in the marker genes of regulatory T cells were evident. Levels of the anti-inflammatory microRNAs miR-16 and miR-93 were significantly higher in the xenoperfused group than in the control group. CONCLUSIONS This study demonstrated that contact of human blood with pig endothelium activates cytotoxic T cells within the first few hours, indicating acute rejection processes. This is accompanied by upregulation of anti-inflammatory microRNAs, which may represent compensatory anti-inflammatory mechanisms.
Collapse
Affiliation(s)
- Roland Tomasi
- From the Department of Anesthesiology, University Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany.,From the Walter-Brendel Center of Experimental Medicine, Faculty of Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|
|
8
|
Zhuo DX, Ginder K, Hardin EA. Markers of Immune Function in Heart Transplantation: Implications for Immunosuppression and Screening for Rejection. Curr Heart Fail Rep 2021; 18:33-40. [PMID: 33400150 DOI: 10.1007/s11897-020-00499-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/22/2020] [Indexed: 10/22/2022]
Abstract
PURPOSE OF REVIEW Recent developments in high-throughput DNA and RNA sequencing technologies have facilitated the development of noninvasive assays to monitor heart transplant rejection. In this review, we summarize existing assays employed for the surveillance of allograft rejection, as well as promising future directions for such tests in the molecular biology field. RECENT FINDINGS The AlloMap genome expression profiling assay remains the only noninvasive test for rejection surveillance and is incorporated into the International Society of Heart and Lung Transplantation guidelines. Other efforts have focused on messenger RNA (mRNA), microRNA (miRNA), and donor-derived cell-free DNA (dd-cfDNA) as potential viable biomarkers. Mitochondrial pathways in allograft necroptosis and inflammation signaling may represent a novel direction for future research endeavors. Although endomyocardial biopsy remains the gold standard, several converging areas of molecular biology could soon yield successful alternative methods of heart transplant rejection monitoring, with the distinct advantage of avoiding procedural complications.
Collapse
Affiliation(s)
- David X Zhuo
- Fellow, Advanced Heart Failure and Transplant Cardiology, Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-9047, USA
| | - Katie Ginder
- Nurse Practitioner, Advanced Heart Failure, Transplant, LVAD, Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - E Ashley Hardin
- Internal Medicine, Advanced Heart Failure and Transplant Cardiology, Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, 5959 Harry Hines Boulevard, Ste #HP.8.110, Dallas, TX, 75390-9047, USA.
| |
Collapse
|
|
9
|
Zhou X, Zhang J, Liu J, Guo J, Wei Y, Li J, He P, Lan T, Peng L, Li H. MicroRNA miR-155-5p knockdown attenuates Angiostrongylus cantonensis-induced eosinophilic meningitis by downregulating MMP9 and TSLP proteins. Int J Parasitol 2020; 51:13-22. [PMID: 32966836 DOI: 10.1016/j.ijpara.2020.07.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 07/07/2020] [Accepted: 07/14/2020] [Indexed: 10/23/2022]
Abstract
Angiostrongylus cantonensis infection is a major cause of eosinophilic meningitis (EM). Severe cases or cases that involve infants and children present poor prognoses. MicroRNAs (miRNAs), which are important regulators of gene expression in many biological processes, were recently found to be regulators of the host response to infection by parasites; however, their roles in brain inflammation caused by A. cantonensis are still unclear. The current study confirmed that miR-155-5p peaked at 21 days after A. cantonensis infection, and its expression was positively correlated with the concentration of excretory and secretory products (ESPs). We found that miR-155-5p knockdown lentivirus successfully ameliorated brain injury and downregulated the expression of major basic protein (MBP) in vivo, and the number of eosinophils in CSF (and the percentage of eosinophils in peripheral blood were also decreased in the miR-155-5p knockdown group. Moreover, the expression of several eosinophilic inflammation cytokines such as CCL6/C10, ICAM-1, and MMP9, declined after the miR-155-5p knockdown. SOCS1 protein, which is an important negative regulator of inflammation activation, was identified as a direct miR-155-5p target. We further detected the effect of miR-155-5p knockdown on phosphorylated-STAT3 and phosphorylated-p65 proteins, which were found to be negatively regulated by SOCS1 and play an important role in regulating the inflammatory response. We found that miR-155-5p knockdown decreased the activity of p-STAT3 and p-p65, thereby leading to lower expression of MMP9 and TSLP proteins, which were closely related to the chemotaxis and infiltration of eosinophils. Interestingly, the inhibition of p-STAT3 or p-p65 was found to induce the downregulation of miR-155-5p in an opposite manner. These observations suggest that a positive feedback loop was formed between miR-155-5p, STAT3, and NF-κB in A. cantonensis infection and that miR-155-5p inhibition might provide a novel strategy to attenuate eosinophilic meningitis.
Collapse
Affiliation(s)
- Xumin Zhou
- Department of Pathogen Biology and Experimental Teaching Center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease, School of Public Health, Southern Medical University, Guangzhou 510515, PR China; Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, PR China
| | - Jinming Zhang
- Department of Respiration, Nanfang Hospital, Southern Medical University, Guangzhou 510515, PR China
| | - Jumei Liu
- Department of Pathogen Biology and Experimental Teaching Center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease, School of Public Health, Southern Medical University, Guangzhou 510515, PR China
| | - Jianyu Guo
- Department of Pathogen Biology and Experimental Teaching Center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease, School of Public Health, Southern Medical University, Guangzhou 510515, PR China
| | - Yong Wei
- Department of Pathogen Biology and Experimental Teaching Center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease, School of Public Health, Southern Medical University, Guangzhou 510515, PR China
| | - Jun Li
- Department of Pathogen Biology and Experimental Teaching Center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease, School of Public Health, Southern Medical University, Guangzhou 510515, PR China
| | - Peiqing He
- Department of Pathogen Biology and Experimental Teaching Center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease, School of Public Health, Southern Medical University, Guangzhou 510515, PR China
| | - Tian Lan
- Department of Pathogen Biology and Experimental Teaching Center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease, School of Public Health, Southern Medical University, Guangzhou 510515, PR China
| | - Lilan Peng
- Department of Pathogen Biology and Experimental Teaching Center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease, School of Public Health, Southern Medical University, Guangzhou 510515, PR China
| | - Hua Li
- Department of Pathogen Biology and Experimental Teaching Center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease, School of Public Health, Southern Medical University, Guangzhou 510515, PR China.
| |
Collapse
|
|
10
|
Shevchenko OP, Sharapchenko SO, Tsirulnikova OM, Pashkov IV, Gichkun OE, Velikiy DA, Shigaev EF, Oleshkevich DO, Bekov MT. MicroRNA expression levels in lung recipients: correlations with clinical and laboratory data. RUSSIAN JOURNAL OF TRANSPLANTOLOGY AND ARTIFICIAL ORGANS 2020. [DOI: 10.15825/1995-1191-2020-2-86-96] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Objective: to evaluate the expression levels of miRNA (miR-27, miR-101, miR-142, miR-339 and miR-424) and its relationship with clinical and laboratory parameters in lung transplant recipients. Materials and methods. The study included 57 lung recipients aged 10 to 74 years (35 ± 15), including six children (9%) – four boys 10, 12, 13 and 17 years and girls 13 and 14 years old – and 51 adult recipients, including 30 men (62.5%). The control group was made up of 14 healthy individuals that were not significantly different by gender and age. Expression levels of the microRNAs studied in blood plasma were determined via quantitative polymerase chain reaction (PCR). Correlations of miRNA expression levels with complete blood count and biochemical blood test indicators were analyzed. Results. Patients with end-stage chronic respiratory failure (potential lung recipients) were found to have significantly higher expression levels of miR-27, miR-101 and miR-339 in plasma than the healthy individuals (p = 0.02, p = 0.03 and p = 0.01, respectively). The expression level of miR-339 correlated with the age of potential lung recipients (p = 0.04). It was a negative correlation (r = –0.46). The expression levels of the other four miRNAs were age independent. The average expression level of miR-424 in lung recipients in the long-term period after lung transplant was higher than in waitlisted patients (p = 0.03). Analysis of the relationship between miRNA expression levels and external respiration function in the long-term post-transplant period showed that miR-142 expression level (r = 0.61; p = 0.04) positively correlates with the Tiffeneau-Pinelli index. This strong correlation, which exceeds 85%, indicates the presence of restrictive lung diseases. A year and more after transplantation, it was found that in the recipients, there were close positive correlations between miR-27, miR-142, miR-424 expression levels and blood leukocyte concentration, as well as between the miR-142 expression level and the sCD40L concentration during this period. Conclusion. A comparative study of the expression level of miRNAs (miR-27, miR-101, miR-142, miR-339 and miR-424) in the blood plasma of patients suffering from end-stage chronic lung diseases of various origin and in lung recipients enables us to conclude that further studies of the miRNA panels are needed in order to assess their effectiveness as potential molecular and genetic markers of post-transplant complications.
Collapse
Affiliation(s)
- O. P. Shevchenko
- Shumakov National Medical Research Center of Transplantology and Artificial Organs;
Sechenov University
| | - S. O. Sharapchenko
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
| | - O. M. Tsirulnikova
- Shumakov National Medical Research Center of Transplantology and Artificial Organs;
Sechenov University
| | - I. V. Pashkov
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
| | - O. E. Gichkun
- Shumakov National Medical Research Center of Transplantology and Artificial Organs;
Sechenov University
| | - D. A. Velikiy
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
| | - E. F. Shigaev
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
| | - D. O. Oleshkevich
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
| | - M. T. Bekov
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
| |
Collapse
|
|
11
|
Di Stefano AB, Pappalardo M, Moschella F, Cordova A, Toia F. MicroRNAs in solid organ and vascularized composite allotransplantation: Potential biomarkers for diagnosis and therapeutic use. Transplant Rev (Orlando) 2020; 34:100566. [PMID: 32682704 DOI: 10.1016/j.trre.2020.100566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 06/23/2020] [Accepted: 06/30/2020] [Indexed: 12/24/2022]
Abstract
Nowadays, solid organ transplantation (SOT) is an established treatment for patients with end-organ dysfunction, which dramatically improves the quality-of-life. Vascularized composite allotransplants (VCAs) including hand and face have been reported worldwide over the last 20 years. However, VCAs, differently to SOT, are life-enhancing instead of life-saving and are not routinely performed due to the risk of immune rejection and the adverse effects of immunosuppression. Over the past decade, although considerable improvements in short-term outcomes after allotransplantation have been registered, these results have not been translated into major progress in long-term allograft acceptance and patient survival. Recently active researches in the field of biomarker discovery have been conducted to develop individualized therapies for allograft recipients. MicroRNAs (miRNAs) are a small noncoding RNAs functioning as critical regulators of gene and protein expression by RNA interference. They have been connected in numerous biological processes and diseases. Due to their immunomodulatory functions, miRNAs have been amended as potential diagnostic and prognostic biomarker for the detection of rejection in allotransplantation. Due to their specific circulating expression profile, they could act as noninvasive predictive tools for rejection that may help clinicians in an early adjustment of the immunosuppression protocol during acute rejections episodes. Indeed, specific anti-sense oligonucleotides suppressing miRNAs expressed in rejection could reduce the rejection rate in allografts and decrease the use of immunosuppressants. We present a literature review of the immunomodulatory properties and characteristics of miRNAs. We will summarize the current knowledge on miRNAs as potential biomarkers for allograft rejection and possible application in allotransplantation monitoring. Finally, we will discuss the advances in preclinical miRNA-based therapies for immunosuppression.
Collapse
Affiliation(s)
- Anna Barbara Di Stefano
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
| | - Marco Pappalardo
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
| | - Francesco Moschella
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy.
| | - Adriana Cordova
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Unit, Department of Oncology, Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone", 90127 Palermo, Italy.
| | - Francesca Toia
- BIOPLAST-Laboratory of BIOlogy and Regenerative Medicine-PLASTic Surgery, Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Surgery Section, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; Plastic and Reconstructive Unit, Department of Oncology, Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone", 90127 Palermo, Italy.
| |
Collapse
|
|
12
|
MicroRNA-142-5p is Up-regulated on Allogeneic Immune Responses and Up-regulates MHC Class II Expression in Human Umbilical Vein Endothelial Cells. Transplant Proc 2020; 53:408-416. [PMID: 32616346 DOI: 10.1016/j.transproceed.2020.05.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 05/12/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE MicroRNA could be biomarker and therapeutic target for rejection. The aim of this study was to investigate the role of miR-142-5p in allogeneic immune responses using in vitro and in vivo models. MATERIALS AND METHODS Primary and immortalized human umbilical vein endothelial cells (HUVECs) were cultured with unrelated blood mononuclear cells to induce allogeneic immune responses. Syngeneic and allogeneic skin graft was performed in mice. Flow cytometry, quantitative reverse transcription-polymerase chain reaction, and Western blotting was performed to understand the underlying mechanisms. RESULTS miR-142-5p was up-regulated in primary HUVEC and a HUVEC line when allogeneic immune responses were elicited. miR-142-5p was also up-regulated in the murine allogeneic skin graft. Overexpression of miR-142-5p in HUVEC increased the expression of HLA-ABC and HLA-DR additively to allogeneic immune responses, suggesting a possible increase in alloantigen presentation. Inhibition of miR-142-5p reduced the expression of HLA-DR. ZEB1, a putative target gene of miR-142-5p, was down-regulated in HUVEC on allogeneic immune response as well as in murine allogeneic skin graft. CONCLUSION These results suggest that the up-regulation of miR-142-5p on allogeneic immune response might facilitate endothelial activation to exacerbate rejection.
Collapse
|
|
13
|
Huang S, Cheng A, Cui M, Pan Y, Wang M, Huang J, Zhu D, Chen S, Liu M, Zhao X, Wu Y, Yang Q, Zhang S, Ou X, Mao S, Yu Y, Tian B, Liu Y, Zhang L, Yin Z, Jing B, Chen X, Jia R. Duck Tembusu virus promotes the expression of suppressor of cytokine signaling 1 by downregulating miR-148a-5p to facilitate virus replication. INFECTION GENETICS AND EVOLUTION 2020; 85:104392. [PMID: 32534026 DOI: 10.1016/j.meegid.2020.104392] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 06/02/2020] [Accepted: 06/03/2020] [Indexed: 11/16/2022]
Abstract
Duck Tembusu virus (DTMUV), an emerging infectious pathogen, has caused severe disease in ducks and huge economic losses to the poultry industry in China since 2009. Despite considerable advances in understanding the effects of microRNAs on host antiviral immune responses, it remains unclear how miRNAs regulate DTMUV replication in duck embryo fibroblast (DEF) cells. This study aims to clarify the role of host microRNA-148a-5p (miR-148a-5p) in regulating DTMUV replication by targeting SOCS1. First, we found that during DTMUV infection, the expression of miR-148a-5p in DEFs was downregulated in a time-dependent and dose-dependent manner, while the expression of SOCS1 was significantly upregulated. In addition, we found that when miR-148a-5p mimics were transfected into DEFs, viral RNA copies, viral E protein expression levels and viral titres, which represent viral replication and proliferation, were significantly downregulated, while the opposite result was observed when miR-148a-5p inhibitor was transfected into DEFs. Next, we found that SOCS1 was the target gene of miR-148a-5p through software analysis. Therefore, we further confirmed that SOCS1 was the target of miR-148a-5p and that miR-148a-5p could negatively regulate the expression of SOCS1 at the mRNA and protein levels. Furthermore, our results indicated that overexpression of SOCS1 promoted DTMUV replication, while knockdown of SOCS1 inhibited DTMUV replication. Finally, we found that in DTMUV-infected DEFs, the overexpression of SOCS1 inhibited the production of IFN-α and IFN-β, while knocking down SOCS1 produced the opposite result. This indicates that during DTMUV infection, the virus promotes the expression of SOCS1 by downregulating the expression of miR-148a-5p, while the upregulation of SOCS1 suppresses the production of type I interferon and promotes virus replication. Taken together, these findings provide new insights into virus-host interactions during DTMUV infection and provide potential new antiviral treatment strategies for DTMUV infection.
Collapse
Affiliation(s)
- Shanzhi Huang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Anchun Cheng
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China.
| | - Min Cui
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Yuhong Pan
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Mingshu Wang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Juan Huang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Dekang Zhu
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Shun Chen
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Mafeng Liu
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Xinxin Zhao
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Yin Wu
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Qiao Yang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Shaqiu Zhang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Xumin Ou
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Sai Mao
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Yanling Yu
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Bin Tian
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Yunya Liu
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Ling Zhang
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Zhongqiong Yin
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Bo Jing
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Xiaoyue Chen
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China
| | - Renyong Jia
- Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Key Laboratory of Animal Disease and Human Health of Sichuan Province, Chengdu, Sichuan 611130, China.
| |
Collapse
|
|
14
|
Czaja AJ. Examining pathogenic concepts of autoimmune hepatitis for cues to future investigations and interventions. World J Gastroenterol 2019; 25:6579-6606. [PMID: 31832000 PMCID: PMC6906207 DOI: 10.3748/wjg.v25.i45.6579] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 11/25/2019] [Accepted: 11/29/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Multiple pathogenic mechanisms have been implicated in autoimmune hepatitis, but they have not fully explained susceptibility, triggering events, and maintenance or escalation of the disease. Furthermore, they have not identified a critical defect that can be targeted. The goals of this review are to examine the diverse pathogenic mechanisms that have been considered in autoimmune hepatitis, indicate investigational opportunities to validate their contribution, and suggest interventions that might evolve to modify their impact. English abstracts were identified in PubMed by multiple search terms. Full length articles were selected for review, and secondary and tertiary bibliographies were developed. Genetic and epigenetic factors can affect susceptibility by influencing the expression of immune regulatory genes. Thymic dysfunction, possibly related to deficient production of programmed cell death protein-1, can allow autoreactive T cells to escape deletion, and alterations in the intestinal microbiome may help overcome immune tolerance and affect gender bias. Environmental factors may trigger the disease or induce epigenetic changes in gene function. Molecular mimicry, epitope spread, bystander activation, neo-antigen production, lymphocytic polyspecificity, and disturbances in immune inhibitory mechanisms may maintain or escalate the disease. Interventions that modify epigenetic effects on gene expression, alter intestinal dysbiosis, eliminate deleterious environmental factors, and target critical pathogenic mechanisms are therapeutic possibilities that might reduce risk, individualize management, and improve outcome. In conclusion, diverse pathogenic mechanisms have been implicated in autoimmune hepatitis, and they may identify a critical factor or sequence that can be validated and used to direct future management and preventive strategies.
Collapse
Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, United States
| |
Collapse
|
|
15
|
Wolfson AM, Kobashigawa JA. Genetic and Genomic Approaches to Predict Cardiac Allograft Rejection. CURRENT CARDIOVASCULAR RISK REPORTS 2019. [DOI: 10.1007/s12170-019-0626-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
|
|
16
|
Hosny N, Burlak C. Xenotransplantation literature update, March/April 2019. Xenotransplantation 2019; 26:e12538. [DOI: 10.1111/xen.12538] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 05/29/2019] [Indexed: 12/17/2022]
Affiliation(s)
- Nora Hosny
- Department of Surgery University of Minnesota Medical School Minneapolis Minnesota
- Department of Medical Biochemistry and Molecular Biology Suez Canal University Faculty of Medicine Ismailia Egypt
| | - Christopher Burlak
- Department of Surgery University of Minnesota Medical School Minneapolis Minnesota
| |
Collapse
|
|
17
|
Abstract
PURPOSE OF REVIEW Micro-RNAs (miRNAs) are highly conserved small RNA molecules that have selective gene-regulatory functions. This posttranscriptional regulation by miRNAs is critical for many immunological processes. Many developments in establishing the biological role of miRNAs in solid organ transplantation have been generated in the last decade. Discoveries of immune regulation by miRNAs, resulting in graft prolongation and transplant tolerance, are rapidly advancing and are the subject of this review. RECENT FINDINGS Many elegant experimental studies have revealed intriguing associations between transplant tolerance and specific miRNA profiles. These findings have provided insight into the miRNAs critical for sustaining immune suppression, and have revealed common miRNA pathways that should be further investigated and/or targeted therapeutically. Further reports have strategized and corroborated different methods of manipulating miRNA expression for prolonging allograft survival, yielding promising preclinical evidence of the efficacy of miRNA-based therapies. SUMMARY The review covers these recent developments in miRNA research that can revolutionize how we implement diagnostics and prognostics and how we can strategize transplantation therapies.
Collapse
|
|
18
|
Roat R, Hossain MM, Christopherson J, Free C, Guay C, Regazzi R, Guo Z. Circulating miRNA-150-5p is associated with immune-mediated early β-cell loss in a humanized mouse model. Xenotransplantation 2018; 26:e12474. [PMID: 30461074 DOI: 10.1111/xen.12474] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/06/2018] [Accepted: 10/31/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Aberrant microRNA (miRNA) expression levels are associated with various graft rejections. We used our humanized mouse model with transplanted human islets to identify miRNAs in islet grafts related to xenograft rejection and circulating miRNAs associated with xenograft rejection-mediated β-cell loss. METHODS Diabetic immunodeficient NOD.scid mice were transplanted with human islets and subsequently achieved stable normoglycemia. Lymphocytes from NOD mice were then adoptively transferred to the humanized mice to induce human β-cell destruction. Islet graft and plasma were collected immediately once blood glucose reached >200 mg/dL. miRNAs in the islet grafts and in the plasma with or without adoptive lymphocyte transfer (ALT) were measured using NanoString nCounter® miRNA Expression Assay and qPCR. RESULTS A set of immune-related miRNAs was significantly increased in human islet grafts of ALT-treated mice compared to control mice. Of these miRNAs, miR-150-5p was significantly increased in the circulation of ALT-treated mice at tissue collection and the increase was a result of immune activation rather than simply the presence of lymphocytes in circulation. Furthermore, miR-150-5p was significantly increased in human islet graft and circulation prior to the development of hyperglycemia in the ALT-treated mice. CONCLUSIONS Our data demonstrated that immune-related miRNAs are associated with human islet xenograft rejection in mice. miR-150-5p is increased in human islet graft and in the circulation during islet xenograft rejection and β-cell destruction prior to hyperglycemia and may be an early biomarker for islet xenograft rejection.
Collapse
Affiliation(s)
- Regan Roat
- Sanford Research, Sioux Falls, South Dakota
| | | | | | | | - Claudiane Guay
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Romano Regazzi
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Zhiguang Guo
- Sanford Research, Sioux Falls, South Dakota.,Departments of Pediatrics and Surgery, University of South Dakota, Sioux Falls, South Dakota
| |
Collapse
|
|
19
|
Czaja AJ. Emerging therapeutic biomarkers of autoimmune hepatitis and their impact on current and future management. Expert Rev Gastroenterol Hepatol 2018. [PMID: 29540068 DOI: 10.1080/17474124.2018.1453356] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Autoimmune hepatitis lacks a quantifiable biomarker that is close to its pathogenic mechanisms and that accurately reflects inflammatory activity, correlates with treatment response, and ensures inactive disease before treatment withdrawal. Areas covered: Micro-ribonucleic acids, programmed death-1 protein and its ligands, macrophage migration inhibitory factor, soluble CD163, B cell activating factor, and metabolite patterns in blood were considered the leading candidates as therapeutic biomarkers after search of PubMed from August 1981 to August 2017 using the search words 'biomarkers of autoimmune hepatitis'. Expert commentary: Each of the candidate biomarkers is close to the putative pathogenic mechanisms of autoimmune hepatitis, and each has attributes that support its potential role as a surrogate marker of inflammatory activity that can be monitored during treatment. Future studies must demonstrate the superiority of each biomarker to conventional indices of inflammatory activity and validate their correlation with treatment response and outcome. A reliable therapeutic biomarker would facilitate the individualization of current management algorithms, ensure that pathogenic mechanisms were disrupted or eliminated prior to treatment withdrawal, and reduce the frequency of relapse or unnecessary protracted therapy. The biomarker might also prove to be a target of next-generation therapies.
Collapse
Affiliation(s)
- Albert J Czaja
- a Division of Gastroenterology and Hepatology , Mayo Clinic College of Medicine and Science , Rochester , MN , USA
| |
Collapse
|
|
20
|
Czaja AJ. Epigenetic changes and their implications in autoimmune hepatitis. Eur J Clin Invest 2018; 48. [PMID: 29383703 DOI: 10.1111/eci.12899] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 01/25/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND The genetic risk of autoimmune hepatitis is insufficient to explain the observed risk, and epigenetic changes may explain disparities in disease occurrence in different populations within and between countries. The goal of this review was to examine how epigenetic changes induced by the environment or inherited as a phenotypic trait may affect autoimmune hepatitis and be amenable to therapeutic intervention. MATERIALS AND METHODS Pertinent abstracts were identified in PubMed by multiple search terms. The number of abstracts reviewed was 1689, and the number of full-length articles reviewed exceeded 150. RESULTS Activation of pro-inflammatory genes in autoimmune disease is associated with hypomethylation of deoxyribonucleic acid and modification of histones within chromatin. Organ-specific microribonucleic acids can silence genes by marking messenger ribonucleic acids for degradation, and they can promote inflammatory activity or immunosuppression. High circulating levels of the microribonucleic acids 21 and 122 have been demonstrated in autoimmune hepatitis, and they may increase production of pro-inflammatory cytokines. Microribonucleic acids are also essential for maintaining regulatory T cells. Drugs, pollutants, infections, diet and ageing can induce inheritable epigenetic changes favouring autoimmunity. Reversal is feasible by manipulating enzymes, transcription factors, gene-silencing molecules and toxic exposures or by administering methyl donors and correcting vitamin D deficiency. Gene targets, site specificity, efficacy and consequences are uncertain. CONCLUSIONS Potentially reversible epigenetic changes may affect the occurrence and outcome of autoimmune hepatitis, and investigations are warranted to determine the nature of these changes, key genomic targets, and feasible interventions and their consequences.
Collapse
Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| |
Collapse
|
|
21
|
Kaul V, Weinberg KI, Boyd SD, Bernstein D, Esquivel CO, Martinez OM, Krams SM. Dynamics of Viral and Host Immune Cell MicroRNA Expression during Acute Infectious Mononucleosis. Front Microbiol 2018; 8:2666. [PMID: 29379474 PMCID: PMC5775229 DOI: 10.3389/fmicb.2017.02666] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 12/21/2017] [Indexed: 11/13/2022] Open
Abstract
Epstein–Barr virus (EBV) is the etiological agent of acute infectious mononucleosis (IM). Since acute IM is a self-resolving disease with most patients regaining health in 1–3 weeks there have been few studies examining molecular signatures in early acute stages of the disease. MicroRNAs (miRNAs) have been shown, however, to influence immune cell function and consequently the generation of antibody responses in IM. In this study, we performed a comprehensive analysis of differentially expressed miRNAs in early stage uncomplicated acute IM. miRNAs were profiled from patient peripheral blood obtained at the time of IM diagnosis and at subsequent time points, and pathway analysis performed to identify important immune and cell signaling pathways. We identified 215 differentially regulated miRNAs at the most acute stage of infection when the patients initially sought medical help. The number of differentially expressed miRNAs decreased to 148 and 68 at 1 and 2 months post-primary infection, with no significantly changed miRNAs identified at 7 months post-infection. Interferon signaling, T and B cell signaling and antigen presentation were the top pathways influenced by the miRNAs associated with IM. Thus, a dynamic and regulated expression profile of miRNA accompanies the early acute immune response, and resolution of infection, in IM.
Collapse
Affiliation(s)
- Vandana Kaul
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, CA, United States
| | - Kenneth I Weinberg
- Division of Stem Cell Transplantation, Department of Pediatrics, Stanford University, Stanford, CA, United States
| | - Scott D Boyd
- Department of Pathology, Stanford University, Stanford, CA, United States
| | - Daniel Bernstein
- Division of Cardiology, Department of Pediatrics, Stanford University, Stanford, CA, United States
| | - Carlos O Esquivel
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, CA, United States
| | - Olivia M Martinez
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, CA, United States.,Stanford Immunology, Stanford University School of Medicine, Stanford, CA, United States
| | - Sheri M Krams
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, CA, United States.,Stanford Immunology, Stanford University School of Medicine, Stanford, CA, United States
| |
Collapse
|
|
22
|
Sukma Dewi I, Celik S, Karlsson A, Hollander Z, Lam K, McManus JW, Tebbutt S, Ng R, Keown P, McMaster R, McManus B, Öhman J, Gidlöf O. Exosomal miR-142-3p is increased during cardiac allograft rejection and augments vascular permeability through down-regulation of endothelial RAB11FIP2 expression. Cardiovasc Res 2017; 113:440-452. [PMID: 28073833 DOI: 10.1093/cvr/cvw244] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 12/01/2016] [Indexed: 01/24/2023] Open
Abstract
Aims Exosome-mediated microRNA transfer is a recently discovered mode of cell-to-cell communication, in which microRNAs act as paracrine molecules, exerting their regulatory effects in recipient cells. T cells and endothelial cells are two main players in the mechanism of acute cellular cardiac rejection. The aim of this study was to investigate the role of exosomal microRNAs in the crosstalk between T cells and endothelial cells and its implications for the molecular mechanisms that drive acute cellular rejection in heart transplantation. Methods and results Exosomes isolated from serum samples of heart transplant patients with and without acute cardiac allograft rejection were profiled and showed enrichment of miR-142-3p, miR-92a-3p, miR-339-3p and miR-21-5p. Treatment of endothelial cells with the respected serum exosomes resulted the increased of miR-142-3p level in endothelial cells. Using T cells isolated from healthy donors and activated with either anti-CD3/CD28 antibody or IL-2/PHA, we could show that miR-142-3p is released from activated cells, is contained in exosomes and can be transferred to human vascular endothelial cells in vitro. Transcriptome analysis of endothelial cells treated with activated T cell supernatant with or without exosomes was used to identify mRNA targets of transferred miR-142-3-p. Overexpression of miR-142-3p in endothelial cells resulted in a significant down-regulation of RAB11FIP2, and interaction of miR-142-3p with its predicted target site was confirmed with a reporter assay. Moreover, treatment of endothelial cells with serum exosomes from heart transplant patients with acute cellular rejection resulted in down-regulation of RAB11FIP2 expression and increase in vascular endothelial permeability. Conclusion We have identified a novel mechanism whereby miR-142-3p, a microRNA enriched in exosomes during acute cellular rejection, is transferred to endothelial cells and compromises endothelial barrier function via down-regulation of RAB11FIP2. This study sheds new light on the interaction between host immune system and cardiac allograft endothelium during acute cellular rejection.
Collapse
Affiliation(s)
- Ihdina Sukma Dewi
- Department of Cardiology, Clinical Sciences, Skåne University Hospital, Lund University, BMC D12, S?gatan 19, 221 84, Lund, Sweden
| | - Selvi Celik
- Department of Cardiology, Clinical Sciences, Skåne University Hospital, Lund University, BMC D12, S?gatan 19, 221 84, Lund, Sweden
| | - Anna Karlsson
- Department of Cardiology, Clinical Sciences, Skåne University Hospital, Lund University, BMC D12, S?gatan 19, 221 84, Lund, Sweden
| | - Zsuzsanna Hollander
- Prevention of Organ Failure (PROOF) Centre of Excellence, 1190 Hornby Street, Vancouver, British Columbia, V6Z 2K5. Canada.,UBC James Hogg Research Centre, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada
| | - Karen Lam
- Prevention of Organ Failure (PROOF) Centre of Excellence, 1190 Hornby Street, Vancouver, British Columbia, V6Z 2K5. Canada
| | - Janet-Wilson McManus
- netCAD, Canadian Blood Services, 2150 Western Parkway, Vancouver, British Columbia V6T 1V6, Canada
| | - Scott Tebbutt
- Prevention of Organ Failure (PROOF) Centre of Excellence, 1190 Hornby Street, Vancouver, British Columbia, V6Z 2K5. Canada.,UBC James Hogg Research Centre, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.,Department of Medicine, University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.,Centre for Heart Lung Innovation, University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada
| | - Raymond Ng
- Prevention of Organ Failure (PROOF) Centre of Excellence, 1190 Hornby Street, Vancouver, British Columbia, V6Z 2K5. Canada.,Department of Computer Science, University of British Columbia, 2366 Main Mall, Vancouver, British Columbia V6T 1Z4, Canada
| | - Paul Keown
- Vancouver General Hospital, 899 West 12th Avenue, Vancouver, British Columbia V5Z 1M9, Canada
| | - Robert McMaster
- Department of Transplantation and Immunology, Vancouver Coastal Health Research Institute, 910 West 10th Avenue, Vancouver, British Columbia V5Z 1M9, Canada
| | - Bruce McManus
- Prevention of Organ Failure (PROOF) Centre of Excellence, 1190 Hornby Street, Vancouver, British Columbia, V6Z 2K5. Canada.,UBC James Hogg Research Centre, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.,Centre for Heart Lung Innovation, University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia V6T 2B5, Canada
| | - Jenny Öhman
- Department of Cardiology, Clinical Sciences, Skåne University Hospital, Lund University, BMC D12, S?gatan 19, 221 84, Lund, Sweden
| | - Olof Gidlöf
- Department of Cardiology, Clinical Sciences, Skåne University Hospital, Lund University, BMC D12, S?gatan 19, 221 84, Lund, Sweden
| |
Collapse
|
|
23
|
Role of Circulating MicroRNAs in the Immunopathogenesis of Rejection After Pediatric Lung Transplantation. Transplantation 2017; 101:2461-2468. [PMID: 27941431 DOI: 10.1097/tp.0000000000001595] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Acute rejection (AR) and development of chronic rejection, bronchiolitis obliterans syndrome (BOS) remain major limiting factors for lung transplantation (LTx). This retrospective study is to identify differentially expressed circulating microRNAs (miRNAs) that associate with development of AR and BOS in pediatric lung transplant recipients (LTxR). METHODS We determined the circulating levels of 7 selected candidate miRNAs in 14 LTxR with AR, 7 with BOS, and compared them against 13 stable pediatric LTxR at 1, 6, and 12 months after LTx. In addition, 6 AR, 7 BOS, and 8 stable pediatric LTxR, 16 AR, 17 BOS, and 16 stable adult LTxR were included for validation. RESULTS MiR-10a, -195, -133b were significantly lower in AR and miR-144, -142-5p, -155 were higher in AR compared to stable (P < 0.05). In addition, circulating levels of miR-134, -10a, -195, -133b were significantly lower and miR-144, -142-5p, -155 were higher (P < 0.05) with development of BOS. The receiver-operating characteristic demonstrated that miR-142-5p, miR-155, and miR-195 strongly discriminated patients with AR from stable LTxR (P < 0.001 for all comparisons): miR-142-5p (area under the curve [AUC], 0.854), miR-155 (AUC, 0.876), and miR-195 (AUC, 0.872). Further, miR-10a, miR-142-5p, miR-144, and miR-155 strongly discriminated BOS from stable LTxR (P < 0.001 for all comparisons). CONCLUSIONS We demonstrated that differential expression of circulating miRNAs occurs in LTxR with AR and BOS, suggesting that they can provide not only important clues to pathogenesis but also may serve as potential noninvasive biomarkers for AR and BOS after pediatric LTx.
Collapse
|
|
24
|
Zununi Vahed S, Poursadegh Zonouzi A, Ghanbarian H, Ghojazadeh M, Samadi N, Omidi Y, Ardalan M. Differential expression of circulating miR-21, miR-142-3p and miR-155 in renal transplant recipients with impaired graft function. Int Urol Nephrol 2017; 49:1681-1689. [PMID: 28455659 DOI: 10.1007/s11255-017-1602-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 04/17/2017] [Indexed: 02/05/2023]
Abstract
BACKGROUND The discovery of circulating microRNAs (miRNAs), as potential noninvasive diagnostic biomarkers, has opened new avenues of research for identifying patients with chronic failure in renal transplantation. The present study aimed to investigate the expression levels of four immune-related miRNAs (miR-21, miR-31, miR-142-3p and miR-155) in plasma samples of renal recipients. METHODS The plasma expression levels of the miRNAs were evaluated by quantitative real-time PCR (qPCR) in 53 renal recipients with long-term stable allograft function, SGF (N = 27), and with biopsy-proven interstitial fibrosis and tubular atrophy (IFTA) (N = 26) and also healthy controls (N = 15). The possible correlation between clinical parameters and the circulating miRNAs and the receiver-operating characteristic (ROC) analysis were performed. RESULTS Our results showed that expression of miR-21 (p = 0.023), miR-142-3p (p = 0.048) and miR-155 (p = 0.005) was significantly upregulated in plasma samples of recipients with IFTA in comparison with SGF and healthy control groups. Concentration of miR-21 (∆Ct value) in plasma was negatively correlated with creatinine (r = -0.432, p = 0.028) and positively correlated with eGFR (r = 0.423, p = 0.031). The multivariate ROC curve analysis indicated that miR-21, miR-142-3p and miR-155 in plasma samples could discriminate almost most of the IFTA patients (area under curve = 0.802, sensitivity = 81%, specificity = 92%). CONCLUSION Our data suggested that altered expression of miR-21, miR-142-3p and miR-155 in plasma samples may be associated with renal dysfunction and can be used for graft monitoring.
Collapse
Affiliation(s)
- Sepideh Zununi Vahed
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
| | - Ahmad Poursadegh Zonouzi
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
| | - Hossein Ghanbarian
- School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Morteza Ghojazadeh
- Liver and Gastrointestinal Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
| | - Nasser Samadi
- School of Advanced Biomedical Sciences, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
| | - Yadollah Omidi
- Research Center for Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tabriz University of Medical Science, Tabriz, Islamic Republic of Iran
| | - Mohammadreza Ardalan
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran.
| |
Collapse
|
|
25
|
Dlouhá D, Hubáček JA. Regulatory RNAs and cardiovascular disease - with a special focus on circulating microRNAs. Physiol Res 2017; 66:S21-S38. [PMID: 28379027 DOI: 10.33549/physiolres.933588] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) are a class of short non-coding regulatory RNA molecules which play an important role in intracellular communication and cell signaling and which influence cellular processes such as proliferation, differentiation, and cellular death. Over the past two decades, the crucial role of microRNAs in controlling tissue homeostasis and disease in cardiovascular systems has become widely recognized. By controlling the expression levels of their targets, several miRNAs have been shown to modulate the function of endothelial cells (miR-221/222 and -126), vascular smooth muscle cells (miR-143/145) and macrophages (miR-33, -758, and -26), thereby regulating the development and progression of atherosclerosis. The stability of miRNAs within the blood suggests that circulating miRNAs may function as important biomarkers of disease development and progression. Numerous circulating miRNAs have been found to be dysregulated in a wide variety of different disease states, including diabetes, cancer, and cardiovascular disease.
Collapse
Affiliation(s)
- D Dlouhá
- Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
| | | |
Collapse
|
|
26
|
Revilla-Nuin B, de Bejar Á, Martínez-Alarcón L, Herrero JI, Martínez-Cáceres CM, Ramírez P, Baroja-Mazo A, Pons JA. Differential profile of activated regulatory T cell subsets and microRNAs in tolerant liver transplant recipients. Liver Transpl 2017; 23:933-945. [PMID: 28006867 DOI: 10.1002/lt.24691] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Revised: 11/24/2016] [Accepted: 11/29/2016] [Indexed: 02/07/2023]
Abstract
Regulatory T cells (Tregs) play a potential role in operational tolerance in liver transplantation (LT) patients, and microRNAs (miRNAs) are known to be involved in immunological responses and tolerance. Thus, we analyzed the implication of different peripheral blood Treg subsets and miRNAs on LT tolerance in 24 tolerant (Tol) and 23 non-tolerant (non-Tol) LT recipients by cellular, genetic, and epigenetic approximation. Non-Tol patients had a lower demethylation rate of the forkhead box P3 (FOXP3) regulatory T cell-specific demethylated region (TSDR) than Tol patients that correlated with the frequency of circulating Tregs. Tol patients presented a different signature of Treg subset markers compared with non-Tol patients with increased expression of HELIOS and FOXP3 and a higher proportion of latency-associated peptide (LAP)+ Tregs and CD45RA- human leukocyte antigen D related (HLA-DR)+ activated effector-memory Tregs. The expression of miR95, miR24, miR31, miR146a, and miR155 was higher in Tol than in non-Tol patients and was positively correlated with activated Treg markers. In conclusion, these data suggest that activated effector-memory Tregs and a TSDR-demethylation state of Tregs may play a role in the complex system of regulation of LT tolerance. In addition, we describe a set of miRNAs differentially expressed in human LT Tol patients providing suggestive evidence that miRNAs are implied in the preservation of self-tolerance as mediated by Tregs. Liver Transplantation 23 933-945 2017 AASLD.
Collapse
Affiliation(s)
- Beatriz Revilla-Nuin
- Biomedical Research Institute of Murcia, University Clinical Hospital "Virgen de la Arrixaca," University of Murcia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Murcia, Spain
| | - África de Bejar
- Clinical Laboratory Unit, Hospital General Universitario Santa Lucía, Cartagena, Spain
| | - Laura Martínez-Alarcón
- Biomedical Research Institute of Murcia, University Clinical Hospital "Virgen de la Arrixaca," University of Murcia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Murcia, Spain
| | - José Ignacio Herrero
- Liver Unit, Clínica Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Pamplona, Spain
| | - Carlos Manuel Martínez-Cáceres
- Biomedical Research Institute of Murcia, University Clinical Hospital "Virgen de la Arrixaca," University of Murcia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Murcia, Spain
| | - Pablo Ramírez
- Biomedical Research Institute of Murcia, University Clinical Hospital "Virgen de la Arrixaca," University of Murcia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Murcia, Spain.,Division of Gastroenterology and Hepatology and Liver Transplant Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Alberto Baroja-Mazo
- Biomedical Research Institute of Murcia, University Clinical Hospital "Virgen de la Arrixaca," University of Murcia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Murcia, Spain
| | - José Antonio Pons
- Biomedical Research Institute of Murcia, University Clinical Hospital "Virgen de la Arrixaca," University of Murcia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Murcia, Spain.,Division of Gastroenterology and Hepatology and Liver Transplant Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain
| |
Collapse
|
|
27
|
Domenico TD, Joelsons G, Montenegro RM, Manfro RC. Upregulation of microRNA 142-3p in the peripheral blood and urinary cells of kidney transplant recipients with post-transplant graft dysfunction. ACTA ACUST UNITED AC 2017; 50:e5533. [PMID: 28380212 PMCID: PMC5423747 DOI: 10.1590/1414-431x20175533] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 01/30/2017] [Indexed: 01/01/2023]
Abstract
We analyzed microRNA (miR)-142-3p expression in leucocytes of the peripheral blood and urinary sediment cell samples obtained from kidney transplant recipients who developed graft dysfunction. Forty-one kidney transplant recipients with kidney graft dysfunction and 8 stable patients were included in the study. The groups were divided according to histological analysis into acute rejection group (n=23), acute tubular necrosis group (n=18) and stable patients group used as a control for gene expression (n=8). Percutaneous biopsies were performed and peripheral blood samples and urine samples were obtained. miR-142-3p was analyzed by real-time polymerase chain reaction. The group of patients with acute tubular necrosis presented significantly higher expressions in peripheral blood (P<0.05) and urine (P<0.001) compared to the stable patients group. Also, in the peripheral blood, miR-142-3p expression was significantly higher in the acute tubular necrosis group compared to the acute rejection group (P<0.05). Urine samples of the acute rejection group presented higher expression compared to the stable patients group (P<0.001) but the difference between acute tubular necrosis and acute rejection groups was not significant in the urinary analyzes (P=0.079). miR-142-3p expression has a distinct pattern of expression in the setting of post-operative acute tubular necrosis after kidney transplantation and may potentially be used as a non-invasive biomarker for renal graft dysfunction.
Collapse
Affiliation(s)
- T D Domenico
- Programa de Pós-Graduação em Medicina: Ciências Médicas, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - G Joelsons
- Programa de Pós-Graduação em Medicina: Ciências Médicas, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
| | - R M Montenegro
- Unidade de Transplante Renal, Serviço de Nefrologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil
| | - R C Manfro
- Programa de Pós-Graduação em Medicina: Ciências Médicas, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil.,Unidade de Transplante Renal, Serviço de Nefrologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil
| |
Collapse
|
|
28
|
Erpicum P, Hanssen O, Weekers L, Lovinfosse P, Meunier P, Tshibanda L, Krzesinski JM, Hustinx R, Jouret F. Non-invasive approaches in the diagnosis of acute rejection in kidney transplant recipients, part II: omics analyses of urine and blood samples. Clin Kidney J 2017; 10:106-115. [PMID: 28643819 PMCID: PMC5469577 DOI: 10.1093/ckj/sfw077] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 07/15/2016] [Indexed: 12/13/2022] Open
Abstract
Kidney transplantation (KTx) represents the best available treatment for patients with end-stage renal disease. Still, the full benefits of KTx are undermined by acute rejection (AR). The diagnosis of AR ultimately relies on transplant needle biopsy. However, such an invasive procedure is associated with a significant risk of complications and is limited by sampling error and interobserver variability. In the present review, we summarize the current literature about non-invasive approaches for the diagnosis of AR in kidney transplant recipients (KTRs), including in vivo imaging, gene-expression profiling and omics analyses of blood and urine samples. Most imaging techniques, such as contrast-enhanced ultrasound and magnetic resonance, exploit the fact that blood flow is significantly lowered in case of AR-induced inflammation. In addition, AR-associated recruitment of activated leucocytes may be detectable by 18F-fluorodeoxyglucose positron emission tomography. In parallel, urine biomarkers, including CXCL9/CXCL10 or a three-gene signature of CD3ε, CXCL10 and 18S RNA levels, have been identified. None of these approaches has yet been adopted in the clinical follow-up of KTRs, but standardization of analysis procedures may help assess reproducibility and comparative diagnostic yield in large, prospective, multicentre trials.
Collapse
Affiliation(s)
- Pauline Erpicum
- Division of Nephrology, University of Liège Academic Hospital (ULg CHU), B-4000 Liège, Belgium
- GIGA Cardiovascular Sciences, Université de Liège, Liège, Belgium
| | - Oriane Hanssen
- Division of Nephrology, University of Liège Academic Hospital (ULg CHU), B-4000 Liège, Belgium
| | - Laurent Weekers
- Division of Nephrology, University of Liège Academic Hospital (ULg CHU), B-4000 Liège, Belgium
| | - Pierre Lovinfosse
- Division of Nuclear Medicine, University of Liège Academic Hospital (ULg CHU), Liège, Belgium
| | - Paul Meunier
- Division of Radiology, University of Liège Academic Hospital (ULg CHU), Liège, Belgium
| | - Luaba Tshibanda
- Division of Radiology, University of Liège Academic Hospital (ULg CHU), Liège, Belgium
| | - Jean-Marie Krzesinski
- Division of Nephrology, University of Liège Academic Hospital (ULg CHU), B-4000 Liège, Belgium
- GIGA Cardiovascular Sciences, Université de Liège, Liège, Belgium
| | - Roland Hustinx
- Division of Nuclear Medicine, University of Liège Academic Hospital (ULg CHU), Liège, Belgium
| | - François Jouret
- Division of Nephrology, University of Liège Academic Hospital (ULg CHU), B-4000 Liège, Belgium
- GIGA Cardiovascular Sciences, Université de Liège, Liège, Belgium
| |
Collapse
|
|
29
|
Sukma Dewi I, Hollander Z, Lam KK, McManus JW, Tebbutt SJ, Ng RT, Keown PA, McMaster RW, McManus BM, Gidlöf O, Öhman J. Association of Serum MiR-142-3p and MiR-101-3p Levels with Acute Cellular Rejection after Heart Transplantation. PLoS One 2017; 12:e0170842. [PMID: 28125729 PMCID: PMC5268768 DOI: 10.1371/journal.pone.0170842] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 01/11/2017] [Indexed: 11/28/2022] Open
Abstract
Background Identifying non-invasive and reliable blood-derived biomarkers for early detection of acute cellular rejection in heart transplant recipients is of great importance in clinical practice. MicroRNAs are small molecules found to be stable in serum and their expression patterns reflect both physiological and underlying pathological conditions in human. Methods We compared a group of heart transplant recipients with histologically-verified acute cellular rejection (ACR, n = 26) with a control group of heart transplant recipients without allograft rejection (NR, n = 37) by assessing the levels of a select set of microRNAs in serum specimens. Results The levels of seven microRNAs, miR-142-3p, miR-101-3p, miR-424-5p, miR-27a-3p, miR-144-3p, miR-339-3p and miR-326 were significantly higher in ACR group compared to the control group and could discriminate between patients with and without allograft rejection. MiR-142-3p and miR-101-3p had the best diagnostic test performance among the microRNAs tested. Serum levels of miR-142-3p and miR-101-3p were independent of calcineurin inhibitor levels, as measured by tacrolimus and cyclosporin; kidney function, as measured by creatinine level, and general inflammation state, as measured by CRP level. Conclusion This study demonstrated two microRNAs, miR-142-3p and miR-101-3p, that could be relevant as non-invasive diagnostic tools for identifying heart transplant patients with acute cellular rejection.
Collapse
Affiliation(s)
- Ihdina Sukma Dewi
- Department of Cardiology, Skåne University Hospital, Lund University, Lund, Sweden
- * E-mail:
| | - Zsuzsanna Hollander
- Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, Canada
- UBC James Hogg Research Centre, Vancouver, Canada
| | - Karen K. Lam
- Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, Canada
| | | | - Scott J. Tebbutt
- Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, Canada
- UBC James Hogg Research Centre, Vancouver, Canada
- Department of Medicine, University of British Columbia, Vancouver, Canada
- Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada
| | - Raymond T. Ng
- Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, Canada
- Department of Computer Science, University of British Columbia, Vancouver, Canada
| | | | | | - Bruce M. McManus
- Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, Canada
- UBC James Hogg Research Centre, Vancouver, Canada
- Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
| | - Olof Gidlöf
- Department of Cardiology, Skåne University Hospital, Lund University, Lund, Sweden
| | - Jenny Öhman
- Department of Cardiology, Skåne University Hospital, Lund University, Lund, Sweden
| |
Collapse
|
|
30
|
Rekers NV, de Fijter J, Claas FH, Eikmans M. Mechanisms and risk assessment of steroid resistance in acute kidney transplant rejection. Transpl Immunol 2016; 38:3-14. [DOI: 10.1016/j.trim.2016.07.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 07/28/2016] [Indexed: 12/15/2022]
|
|
31
|
Abstract
BACKGROUND Although the liver is less immunogenic than other solid organs, most liver transplant recipients receive lifelong immunosuppression. In both experimental models and clinical transplantation, total lymphoid irradiation (TLI) has been shown to induce allograft tolerance. Our goal was to identify the microRNAs (miRNAs) expressed in tolerant liver allograft recipients in an experimental model of TLI-induced tolerance. METHODS To identify the miRNAs associated with TLI-induced tolerance, we examined syngeneic recipients (Lewis→Lewis) and allogeneic recipients (Dark Agouti→Lewis) of orthotropic liver transplants that received posttransplant TLI, allogeneic recipients that were not treated posttransplantation and experienced acute rejection, and native Dark Agouti livers. Quantitative-polymerase chain reaction miRNA array cards were used to profile liver grafts. RESULTS We identified 12 miRNAs that were specifically and significantly increased during acute rejection. In early tolerance, 33 miRNAs were altered compared with syngeneic livers, with 80% of the miRNAs increased. In established tolerance, 42 miRNAs were altered. In addition, miR-142-5p and miR-181a demonstrated increased expression in tolerant livers (both early and established tolerance) as compared with syngeneic livers. A principal component analysis of all miRNAs assayed demonstrated a profile in established tolerance that was closely related to that seen in syngeneic livers. CONCLUSIONS The miRNA profile of established tolerant allografts is very similar to syngeneic grafts, suggesting tolerance may be a return to an immunological state of quiescence.
Collapse
|
|
32
|
Iwasaki K, Yamamoto T, Inanaga Y, Hiramitsu T, Miwa Y, Murotani K, Narumi S, Watarai Y, Katayama A, Uchida K, Kobayashi T. MiR-142-5p and miR-486-5p as biomarkers for early detection of chronic antibody-mediated rejection in kidney transplantation. Biomarkers 2016; 22:45-54. [PMID: 27323802 DOI: 10.1080/1354750x.2016.1204000] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
De novo donor-specific HLA antibody (DSA) would not necessarily contribute to chronic antibody-mediated rejection (CAMR) in kidney transplantation. Here, we investigated whether PBMC miRNAs could be predictable biomarkers for CAMR. Microarray profiling of 435 mature miRNAs in pooled samples was conducted. Individual analysis revealed that miR-142-5p was significantly (p < 0.01) underexpressed in patients with DSA. After DSA production, miR-486-5p and its target PTEN/foxO3 mRNA were significantly overexpressed (p < 0.01) and underexpressed (p < 0.01), respectively, in patients with biopsy-proven CAMR, compared with non-CAMR. Our studies suggest that miRNA expression patterns may serve as noninvasive diagnostic biomarkers to evaluate immune response and kidney allograft status.
Collapse
Affiliation(s)
- Kenta Iwasaki
- a Department of Kidney Disease and Transplant Immunology , Aichi Medical University , Nagakute , Japan
| | - Takayuki Yamamoto
- b Department of Transplant Surgery , Nagoya Daini Red Cross Hospital , Nagoya , Japan
| | - Yukiko Inanaga
- c Department of Surgery II , Nagoya University School of Medicine , Nagoya , Japan
| | - Takahisa Hiramitsu
- b Department of Transplant Surgery , Nagoya Daini Red Cross Hospital , Nagoya , Japan
| | - Yuko Miwa
- c Department of Surgery II , Nagoya University School of Medicine , Nagoya , Japan
| | - Kenta Murotani
- d Department of Center for Clinical Research , Aichi Medical University , Nagakute , Japan
| | - Shuji Narumi
- b Department of Transplant Surgery , Nagoya Daini Red Cross Hospital , Nagoya , Japan
| | - Yoshihiko Watarai
- b Department of Transplant Surgery , Nagoya Daini Red Cross Hospital , Nagoya , Japan
| | - Akio Katayama
- e Department of Transplant Surgery , Masuko Memorial Hospital , Nagoya , Japan
| | - Kazuharu Uchida
- a Department of Kidney Disease and Transplant Immunology , Aichi Medical University , Nagakute , Japan.,f Department of Transplant Surgery , Aichi Medical University , Nagakute , Japan
| | - Takaaki Kobayashi
- f Department of Transplant Surgery , Aichi Medical University , Nagakute , Japan
| |
Collapse
|
|
33
|
Fujino M, Zhu P, Cai S, Nishio Y, Zhuang J, Li XK. MicroRNAs Involved in Acute Rejection and Tolerance in Murine Cardiac Allografts. EXP CLIN TRANSPLANT 2016; 14:424-30. [PMID: 27227980 DOI: 10.6002/ect.2015.0251] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Induction of immunologic tolerance is the ultimate goal of organ transplant. To investigate the involvement of microRNA in tolerance induction after organ transplant, murine cardiac allografts were performed and the expression of microRNA in the grafts was analyzed. MATERIALS AND METHODS Cardiac allografts were performed using C57BL/10 (H2-Kb) to CBA/N (H2-Kk) fully mismatched combination with or without eicosapentaenoic acid for tolerance induction. Ten microRNA, mir-146a, 15b, 223, 23a, 27a, 34a, 451, 101a, 101b, 148a, discovered in hepatic grafts were examined by quantitative reverse transcription polymerase chain reaction using RNA from the cardiac allografts. RESULTS The administration of eicosapentaenoic acid markedly prolonged the cardiac allograft survival (median survival time > 100 days) and decreased the pathological score. Quantitative reverse transcription polymerase chain reaction revealed that mir-223 was up-regulated in accordance with pathological deterioration as compared with the expression observed in the syngeneic grafts. In contrast, the other microRNA was down-regulated. Pearson product moment correlation analysis demonstrated that the expression patterns of mir-223 and mir-146a had high or moderate positive associations between the cardiac and haptic allografts in mice. CONCLUSIONS The change in the microRNA expression in the allografts suggests that microRNA plays a role in the induction and/or maintenance of tolerance after allograft transplant. Our findings suggest that mir-223 may be associated with rejection while mir-146a, -15b, -23a, -27a, -34a, -451, -101a, -101b, -148a may be involved in tolerance. A superior grasp of the mechanism for rejection and tolerance observed in the murine heart allotransplant model may provide a better curative treatment strategy to mitigate allograft rejection.
Collapse
Affiliation(s)
- Masayuki Fujino
- rom the Division of Transplantation Immunology National Research Institute for Child Health and Development; and the AIDS Research Center National Institute of Infectious Diseases Tokyo Japan
| | | | | | | | | | | |
Collapse
|
|
34
|
Ladak SS, Ward C, Ali S. The potential role of microRNAs in lung allograft rejection. J Heart Lung Transplant 2016; 35:550-9. [DOI: 10.1016/j.healun.2016.03.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 02/18/2016] [Accepted: 03/21/2016] [Indexed: 01/13/2023] Open
|
|
35
|
Mohan R, Kobashigawa J. Detecting rejection in cardiac transplantation: applications of genomic medicine. Per Med 2016; 13:257-264. [DOI: 10.2217/pme-2015-0008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The primary focus of care in heart transplant recipients is to prevent rejection. Checking serum levels of immunosuppressant drugs as well as performing biopsies to obtain tissue samples for histological analysis have been the mainstays of rejection surveillance. Novel applications of genomics have proven to be useful in adding a noninvasive alternative to the standard of care. In particular, the use of gene-expression profiling to detect upregulation of rejection-related genes, detection of donor-derived cell-free DNA as a marker of graft apoptosis and rejection, as well as mRNA and miRNA as intragraft and peripheral markers of rejection have come to the forefront of genomics as they relate to transplantation. This review focuses on the use of genomics in heart transplant recipients.
Collapse
Affiliation(s)
- Rajeev Mohan
- Cedars-Sinai Heart Institute, 127 S San Vicente Blvd, Third Floor Cardiology A3107, Los Angeles, CA 90048, USA
| | - Jon Kobashigawa
- Cedars-Sinai Heart Institute, 127 S San Vicente Blvd, Third Floor Cardiology A3107, Los Angeles, CA 90048, USA
| |
Collapse
|
|
36
|
Zhang P, Guo Z, Zhong K, Li Q, Ouyang J, Chen M, Hu A, Jiao X, Zhu X, He X. Evaluation of Immune Profiles and MicroRNA Expression Profiles in Peripheral Blood Mononuclear Cells of Long-Term Stable Liver Transplant Recipients and Recipients With Acute Rejection Episodes. Transplant Proc 2015; 47:2907-15. [PMID: 26707312 DOI: 10.1016/j.transproceed.2015.10.048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 10/20/2015] [Indexed: 12/16/2022]
Abstract
OBJECTIVE This study aimed to document the difference of immunophenotypes in peripheral blood mononuclear cells (PBMCs) between long-term stable liver transplant recipients and recipients with acute rejection. We also sought to identify whether there is any correlation between microRNA (miRNA) expression profile and the differential immunoprofile in these 2 groups to establish a specific miRNA biomarker to identify potential liver transplant recipients. METHODS PBMCs were isolated from 53 stable liver transplant recipients (STA group) and 15 liver transplant recipients with repeated biopsy-proven rejection episodes admitted to our hospital. Immunoprofiles were analyzed by means of flow cytometry. Analysis of miRNA expression in the PBMCs was performed by means of real-time polymerase chain reaction. RESULTS The immune profiling analysis showed increased frequency of peripheral natural killer cells and regulatory T cells in stable liver transplant recipients compared with the acute rejection recipients and healthy volunteers (P < .05). There was no significant difference in the immune cell levels (CD19(+) B cells, CD4(+) T cells, and CD8(+) T cells) in PBMCs among the transplant recipient groups and healthy control subjects. Three miRNAs, miR-18b, miR-340, and miR-106b, were up-regulated in the PBMCs of the STA recipients compared with recipients with acute rejection. CONCLUSIONS These results suggest that miR-18b, miR-340, and miR-106b, which regulate the expression of specific immunophenotypes, can be used as potential biomarkers to identify long-term stable liver transplant recipients from recipients with acute rejection.
Collapse
Affiliation(s)
- P Zhang
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Z Guo
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - K Zhong
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - Q Li
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - J Ouyang
- Department of Surgical Oncology, Sun Yat-sen University, Dongguan, Guangdong, People's Republic of China
| | - M Chen
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - A Hu
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - X Jiao
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
| | - X Zhu
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
| | - X He
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
| |
Collapse
|
|
37
|
Harris-Arnold A, Arnold CP, Schaffert S, Hatton O, Krams SM, Esquivel CO, Martinez OM. Epstein-Barr virus modulates host cell microRNA-194 to promote IL-10 production and B lymphoma cell survival. Am J Transplant 2015; 15:2814-24. [PMID: 26147452 DOI: 10.1111/ajt.13375] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Revised: 04/19/2015] [Accepted: 04/28/2015] [Indexed: 01/25/2023]
Abstract
Epstein-Barr virus (EBV) is a γ-herpesvirus that is linked to the development of posttransplant lymphoproliferative disorder (PTLD) in solid organ recipients. We previously demonstrated that EBV(+) B cell lymphoma cell lines isolated from patients with PTLD produce human IL-10 as an autocrine growth factor. However, little is known regarding IL-10 regulation in B cells. Here we show that EBV infection markedly alters the expression of host B cell microRNA, a class of small noncoding RNA that is an important regulator of transcriptional and posttranscriptional gene expression. Gene arrays reveal unique microRNA profiles in EBV(+) B cell lymphoma lines from patients with PTLD, compared to normal B cells or in vitro generated EBV(+) lymphoblastoid cell lines. We show that microRNA-194 expression is uniquely suppressed in EBV(+) B cell lines from PTLD patients and that the 3'untranslated region of IL-10 is targeted by microRNA-194. Overexpression of microRNA-194 attenuates IL-10 production and increases apoptosis of EBV(+) B cell lymphoma lines. Together, these data indicate that EBV co-opts the host B cell microRNA network and specifically suppresses microRNA-194 to override control of IL-10 expression. Thus, modulation of microRNA-194 may constitute a novel approach to inhibiting proliferation of EBV(+) B cell lymphomas in PTLD.
Collapse
Affiliation(s)
- A Harris-Arnold
- Department of Surgery, Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA.,Program in Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA
| | - C P Arnold
- Program in Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA
| | - S Schaffert
- Department of Surgery, Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA.,Program in Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA
| | - O Hatton
- Department of Surgery, Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA.,Program in Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA
| | - S M Krams
- Department of Surgery, Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA.,Program in Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA
| | - C O Esquivel
- Department of Surgery, Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA
| | - O M Martinez
- Department of Surgery, Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA.,Program in Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA
| |
Collapse
|
|
38
|
Serum microRNAs as new diagnostic biomarkers for pre- and post-kidney transplantation. Transplant Proc 2015; 46:3358-62. [PMID: 25498051 DOI: 10.1016/j.transproceed.2014.08.050] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 07/18/2014] [Accepted: 08/19/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND In the present study, we compared the expression levels of 3 microRNAs (miRNAs) between patients who had undergone kidney transplantation and healthy individuals in a search for a new diagnostic biomarker after kidney transplantation. METHODS We used real-time quantitative polymerase chain reaction to investigate the expression levels of miR-181a, miR-483-5p, and miR-557 in the serum of 15 kidney transplantation patients before transplantation on the first, third, and seventh days after transplantation. The study was performed in the Guilin 181st Hospital between 2010 and 2012. The results of this study may assist with early diagnosis and treatment and contribute to our understanding of the pathological parameters. Receiver operating characteristic (ROC) analysis was performed to determine the area under the curve of each equation to predict evolution to rejection. RESULTS ROC curves were performed to explore miRNAs to predict rejection occurrence after transplantation showed pre-transplantation expression levels of miR-181a to be a potential factor with a significant area under the curve (AUC = 0.985, P < .05). The expression of miR-181a before kidney transplantation was also significantly different on days 1 and 3 after kidney transplantation, the area under the curve (AUC) was, respectively, 0.980 (P < .05) and 0.830 (P < .05). Predictors on days 1, 3, and 7 show that miR-483-5p and miR-557 are also predictive factors for rejection. Predictors for miR-483-5p and miR-557 were significantly under the area ROC, respectively (AUC = 0.920, P < .05), and (AUC = 0.990, P < .005) on day 1 (AUC = 0.920, P < .05) and (AUC = 0.960, P < .005) on day 3, (AUC = 0.845, P < .05) and (AUC = 0.889, P < .05) on day 7. CONCLUSIONS This study of miRNAs was unrelated to age, sex, histological classification, and metastasis (all P > .05). Serum miR-181a, miR-483-5p, and miR-557 could serve as circulating biomarkers for the early diagnosis of active situations of before and after kidney transplantation.
Collapse
|
|
39
|
Asaoka T, Hernandez D, Tryphonopoulos P, Tekin A, Garcia J, Nishida S, Fan J, Beduschi T, Vianna R, Ruiz P. Clinical significance of intragraft miR-122 and -155 expression after liver transplantation. Hepatol Res 2015; 45:898-905. [PMID: 25220676 DOI: 10.1111/hepr.12424] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 08/21/2014] [Accepted: 09/08/2014] [Indexed: 02/08/2023]
Abstract
AIM Recurrent hepatitis C (RHC) and acute cellular rejection (AR) remain critical problems following liver transplantation (LT) in hepatitis C virus (HCV) positive recipients because of the similar clinical features. Discrimination between these conditions can be problematic, and adjunctive biomarkers would be useful to discriminate these processes. The aim of our study was to investigate the possibility of the intragraft miR-122 and -155 expression as new biomarkers after LT. METHODS A total of 29 HCV positive recipients were enrolled in this study. Intragraft expressions of miR-122 and -155 were studied between RHC predominant (n = 17) and AR predominant cases (n = 12) using quantitative reverse transcription polymerase chain reaction. Furthermore, we investigated the correlations between these expression levels and clinical serum parameters. RESULTS Intragraft miR-122 expression had a good correlation with serum alkaline phosphatase (P = 0.02), but it was not correlated with the serum HCV viral load. The expression levels of miR-122 in the AR group were significantly higher than those in the RHC group (P = 0.0006) and, inversely, the expression levels of miR-155 in the AR group were significantly lower than those in the RHC group (P = 0.01). CONCLUSION Our study emphasizes a useful pattern of miR-122 and -155 as ancillary markers to discriminate AR predominant cases from RHC in HCV positive patients after LT.
Collapse
Affiliation(s)
- Tadafumi Asaoka
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Dayami Hernandez
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | | | - Akin Tekin
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Jennifer Garcia
- Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Seigo Nishida
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Ji Fan
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Thiago Beduschi
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Rodrigo Vianna
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Phillip Ruiz
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| |
Collapse
|
|
40
|
Rascio F, Pontrelli P, Accetturo M, Oranger A, Gigante M, Castellano G, Gigante M, Zito A, Zaza G, Lupo A, Ranieri E, Stallone G, Gesualdo L, Grandaliano G. A type I interferon signature characterizes chronic antibody-mediated rejection in kidney transplantation. J Pathol 2015; 237:72-84. [DOI: 10.1002/path.4553] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Revised: 04/13/2015] [Accepted: 04/22/2015] [Indexed: 12/11/2022]
Affiliation(s)
- Federica Rascio
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences; University of Foggia; Viale L Pinto 1 Foggia Italy
| | - Paola Pontrelli
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation; University of Bari; Piazza G Cesare 11 Bari Italy
| | - Matteo Accetturo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation; University of Bari; Piazza G Cesare 11 Bari Italy
| | - Annarita Oranger
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation; University of Bari; Piazza G Cesare 11 Bari Italy
| | - Margherita Gigante
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation; University of Bari; Piazza G Cesare 11 Bari Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation; University of Bari; Piazza G Cesare 11 Bari Italy
| | - Maddalena Gigante
- Clinical Pathology, Department of Medical and Surgical Sciences; University of Foggia; Italy, Viale L Pinto 1 Foggia Italy
| | - Anna Zito
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation; University of Bari; Piazza G Cesare 11 Bari Italy
| | - Gianluigi Zaza
- Renal Unit, Department of Medicine; University of Verona; Piazzale A Stefani 1 Verona Italy
| | - Antonio Lupo
- Renal Unit, Department of Medicine; University of Verona; Piazzale A Stefani 1 Verona Italy
| | - Elena Ranieri
- Clinical Pathology, Department of Medical and Surgical Sciences; University of Foggia; Italy, Viale L Pinto 1 Foggia Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences; University of Foggia; Viale L Pinto 1 Foggia Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation; University of Bari; Piazza G Cesare 11 Bari Italy
| | - Giuseppe Grandaliano
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences; University of Foggia; Viale L Pinto 1 Foggia Italy
| |
Collapse
|
|
41
|
Xu Z, Nayak DK, Benshoff N, Hachem R, Gelman AE, Mohanakumar T. De novo-developed antibodies to donor MHC antigens lead to dysregulation of microRNAs and induction of MHC class II. THE JOURNAL OF IMMUNOLOGY 2015; 194:6133-43. [PMID: 25941328 DOI: 10.4049/jimmunol.1401848] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 04/03/2015] [Indexed: 01/09/2023]
Abstract
Immune responses to HLA and development of anti-donor HLA (DSA) were shown to play a role in chronic rejection following transplantation. We hypothesized that Abs to MHC change microRNAs (miRNAs), leading to chronic lung allograft rejection. Microarray analysis was performed in a murine model of anti-MHC-induced obliterative airway disease (OAD), a correlate of obliterative bronchiolitis. A unique profile of dysregulated miRNAs was detected in OAD mice on days 7 and 15 after Ab administration compared with control. Sixty-seven miRNAs were increased and 42 miRNAs were decreased in OAD mice on day 7. In addition, 15 miRNAs were overexpressed and 16 miRNAs were underexpressed in OAD mice on day 15. The expression of miR-16 and miR-195 was significantly decreased in lungs of OAD mice, as assessed by quantitative RT-PCR and in situ hybridization, with increases in H-2 Aa and H-2 Dma mRNA levels. Significant reductions in miR-16 and miR-195 levels were also noted in lung transplant (LTx) patients with DSA compared with LTx patients without DSA. Bioinformatic TargetScan and reporter assays identified the binding of miR-16 and miR-195 to the 3'-untranslated region of regulatory factor X 5. Quantitative PCR and immunohistochemistry indicated posttranscriptional increases in regulatory factor X 5 mRNA and protein expression in OAD mice, as well as in LTx recipients with DSA, which was associated with increased expression of HLA-DPA1, HLA-DQA1, and HLA-DRA mRNA. Therefore, our results demonstrated that miRNAs induced by alloimmunity may play important roles in chronic rejection after LTx.
Collapse
Affiliation(s)
- Zhongping Xu
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110
| | - Deepak K Nayak
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110
| | - Nicholas Benshoff
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110
| | - Ramsey Hachem
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and
| | - Andrew E Gelman
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110
| | - Thalachallour Mohanakumar
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
| |
Collapse
|
|
42
|
Li Y, Zhang Z. Computational Biology in microRNA. WILEY INTERDISCIPLINARY REVIEWS-RNA 2015; 6:435-52. [DOI: 10.1002/wrna.1286] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Revised: 03/24/2015] [Accepted: 03/25/2015] [Indexed: 01/24/2023]
Affiliation(s)
- Yue Li
- Department of Computer Science; University of Toronto; Toronto Ontario Canada
- Donnelly Centre for Cellular and Biomolecular Research; University of Toronto; Toronto Ontario Canada
| | - Zhaolei Zhang
- Donnelly Centre for Cellular and Biomolecular Research; University of Toronto; Toronto Ontario Canada
- Department of Molecular Genetics; University of Toronto; Toronto Ontario Canada
| |
Collapse
|
|
43
|
Hatton OL, Harris-Arnold A, Schaffert S, Krams SM, Martinez OM. The interplay between Epstein-Barr virus and B lymphocytes: implications for infection, immunity, and disease. Immunol Res 2015; 58:268-76. [PMID: 24619311 DOI: 10.1007/s12026-014-8496-1] [Citation(s) in RCA: 138] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Human B cells are the primary targets of Epstein-Barr virus (EBV) infection. In most cases, EBV infection is asymptomatic because of a highly effective host immune response, but some individuals develop self-limiting infectious mononucleosis, while others develop EBV-associated lymphoid or epithelial malignancies. The viral and immune factors that determine the outcome of infection are not understood. The EBV life cycle includes a lytic phase, culminating in the production of new viral particles, and a latent phase, during which the virus remains largely silent for the lifetime of the host in memory B cells. Thus, in healthy individuals, there is a tightly orchestrated interplay between EBV and the host that allows the virus to persist. To promote viral persistence, EBV has evolved a variety of strategies to modulate the host immune response including inhibition of immune cell function, blunting of apoptotic pathways, and interfering with antigen processing and presentation pathways. In this article, we focus on mechanisms by which dysregulation of the host B cell and immune modulation by the virus can contribute to development of EBV+ B cell lymphomas.
Collapse
Affiliation(s)
- Olivia L Hatton
- Program in Immunology and Department of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | | | | | | | | |
Collapse
|
|
44
|
MicroRNA-486 regulates normal erythropoiesis and enhances growth and modulates drug response in CML progenitors. Blood 2014; 125:1302-13. [PMID: 25515961 DOI: 10.1182/blood-2014-06-581926] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
MicroRNAs (miRNAs) are key regulators of hematopoietic cell differentiation and may contribute to altered growth of leukemic stem cells. Using microarray-based miRNA profiling, we found that miRNA 486 (miR-486) is significantly upregulated in chronic myeloid leukemia (CML) compared with normal CD34(+) cells, particularly in the megakaryocyte-erythroid progenitor population. miR-486-5p expression increased during erythroid differentiation of both CML and normal CD34(+) cells. Ectopic miR-486-5p expression enhanced in vitro erythroid differentiation of normal CD34(+) cells, whereas miR-486-5p inhibition suppressed normal CD34(+) cell growth in vitro and in vivo and inhibited erythroid differentiation and erythroid cell survival. The effects of miR-486-5p on hematopoietic cell growth and survival are mediated at least in part via regulation of AKT signaling and FOXO1 expression. Using gene expression and bioinformatics analysis, together with functional screening, we identified several novel miR-486-5p target genes that may modulate erythroid differentiation. We further show that increased miR-486-5p expression in CML progenitors is related to both kinase-dependent and kinase-independent mechanisms. Inhibition of miR-486-5p reduced CML progenitor growth and enhanced apoptosis following imatinib treatment. In conclusion, our studies reveal a novel role for miR-486-5p in regulating normal hematopoiesis and of BCR-ABL-induced miR-486-5p overexpression in modulating CML progenitor growth, survival, and drug sensitivity.
Collapse
|
|
45
|
Bushkin Y, Radford F, Pine R, Lardizabal A, Mangura BT, Gennaro ML, Tyagi S. Profiling T cell activation using single-molecule fluorescence in situ hybridization and flow cytometry. THE JOURNAL OF IMMUNOLOGY 2014; 194:836-41. [PMID: 25505292 DOI: 10.4049/jimmunol.1401515] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Flow cytometric characterization of Ag-specific T cells typically relies on detection of protein analytes. Shifting the analysis to detection of RNA would provide several significant advantages, which we illustrate by developing a new host immunity-based platform for detection of infections. Cytokine mRNAs synthesized in response to ex vivo stimulation with pathogen-specific Ags are detected in T cells with single-molecule fluorescence in situ hybridization followed by flow cytometry. Background from pre-existing in vivo analytes is lower for RNAs than for proteins, allowing greater sensitivity for detection of low-frequency cells. Moreover, mRNA analysis reveals kinetic differences in cytokine expression that are not apparent at the protein level but provide novel insights into gene expression programs expected to define different T cell subsets. The utility of probing immunological memory of infections is demonstrated by detecting T cells that recognize mycobacterial and viral Ags in donors exposed to the respective pathogens.
Collapse
Affiliation(s)
- Yuri Bushkin
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103; and
| | - Felix Radford
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103; and
| | - Richard Pine
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103; and
| | - Alfred Lardizabal
- Global Tuberculosis Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103
| | - Bonita T Mangura
- Global Tuberculosis Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103
| | - Maria Laura Gennaro
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103; and
| | - Sanjay Tyagi
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103; and
| |
Collapse
|
|
46
|
Wang Y, Tian Y, Ding Y, Wang J, Yan S, Zhou L, Xie H, Chen H, Li H, Zhang J, Zhao J, Zheng S. MiR-152 may silence translation of CaMK II and induce spontaneous immune tolerance in mouse liver transplantation. PLoS One 2014; 9:e105096. [PMID: 25133393 PMCID: PMC4136864 DOI: 10.1371/journal.pone.0105096] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 07/19/2014] [Indexed: 01/08/2023] Open
Abstract
Spontaneous immune tolerance in mouse liver transplantation has always been a hotspot in transplantation-immune research. Recent studies revealed that regulatory T cells (Tregs), hepatic satellite cells and Kupffer cells play a potential role in spontaneous immune tolerance, however the precise mechanism of spontaneous immune tolerance is still undefined. By using Microarray Chips, we investigated different immune regulatory factors to decipher critical mechanisms of spontaneous tolerance after mouse liver transplantation. Allogeneic (C57BL/6-C3H) and syngeneic (C3H-C3H) liver transplantation were performed by 6-8 weeks old male C57BL/6 and C3H mice. Graft samples (N = 4 each group) were collected from 8 weeks post-operation mice. 11 differentially expressed miRNAs in allogeneic grafts (Allografts) vs. syngeneic grafts (Syngrafts) were identified using Agilent Mouse miRNA Chips. It was revealed that 185 genes were modified by the 11 miRNAs, furthermore, within the 185 target genes, 11 of them were tightly correlated with immune regulation after Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Genbank data cross-comparison. Verified by real-time PCR and western blot, our results indicated that mRNA expression levels of IL-6 and TAB2 were respectively down regulated following miR-142-3p and miR-155 augment. In addition, increased miR-152 just silenced mRNA of CaMK II and down-regulated translation of CaMK II in tolerated liver grafts, which may play a critical role in immune regulation and spontaneous tolerance induction of mouse liver transplantation.
Collapse
Affiliation(s)
- Yan Wang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yang Tian
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuan Ding
- Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jingcheng Wang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Sheng Yan
- Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lin Zhou
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haiyang Xie
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hui Chen
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hui Li
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jinhua Zhang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiacong Zhao
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- * E-mail:
| |
Collapse
|
|
47
|
|
|
48
|
Sun Y, Tawara I, Zhao M, Qin ZS, Toubai T, Mathewson N, Tamaki H, Nieves E, Chinnaiyan AM, Reddy P. Allogeneic T cell responses are regulated by a specific miRNA-mRNA network. J Clin Invest 2014; 123:4739-54. [PMID: 24216511 DOI: 10.1172/jci70013] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 08/12/2013] [Indexed: 12/26/2022] Open
Abstract
Donor T cells that respond to host alloantigens following allogeneic bone marrow transplantation (BMT) induce graft-versus-host (GVH) responses, but their molecular landscape is not well understood. MicroRNAs (miRNAs) regulate gene (mRNA) expression and fine-tune the molecular responses of T cells. We stimulated naive T cells with either allogeneic or nonspecific stimuli and used argonaute cross-linked immunoprecipitation (CLIP) with subsequent ChIP microarray analyses to profile miR responses and their direct mRNA targets. We identified a unique expression pattern of miRs and mRNAs following the allostimulation of T cells and a high correlation between the expression of the identified miRs and a reduction of their mRNA targets. miRs and mRNAs that were predicted to be differentially regulated in allogeneic T cells compared with nonspecifically stimulated T cells were validated in vitro. These analyses identified wings apart-like homolog (Wapal) and synaptojanin 1 (Synj1) as potential regulators of allogeneic T cell responses. The expression of these molecular targets in vivo was confirmed in MHC-mismatched experimental BMT. Targeted silencing of either Wapal or Synj1 prevented the development of GVH response, confirming a role for these regulators in allogeneic T cell responses. Thus, this genome-wide analysis of miRNA-mRNA interactions identifies previously unrecognized molecular regulators of T cell responses.
Collapse
|
|
49
|
Xie LN, Zhou F, Liu XM, Fang Y, Yu Z, Song NX, Kong FS. Serum microRNA155 is increased in patients with acute graft-versus-host disease. Clin Transplant 2014; 28:314-23. [PMID: 24494749 DOI: 10.1111/ctr.12314] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/13/2013] [Indexed: 01/05/2023]
Affiliation(s)
- Lin-Na Xie
- Department of Hematology; The General Hospital of Jinan Military District; Jinan China
| | - Fang Zhou
- Department of Hematology; The General Hospital of Jinan Military District; Jinan China
| | - Xi-Min Liu
- Department of Hematology; The General Hospital of Jinan Military District; Jinan China
| | - Yuan Fang
- Department of Hematology; The General Hospital of Jinan Military District; Jinan China
| | - Zhe Yu
- Department of Hematology; The General Hospital of Jinan Military District; Jinan China
| | - Ning-Xia Song
- Department of Hematology; The General Hospital of Jinan Military District; Jinan China
| | - Fan-Sheng Kong
- Department of Hematology; The General Hospital of Jinan Military District; Jinan China
| |
Collapse
|
|
50
|
Huang H, He J, Teng X, Yu Y, Ye W, Hu Y, Shen Z. Combined intrathymic and intravenous injection of mesenchymal stem cells can prolong the survival of rat cardiac allograft associated with decrease in miR-155 expression. J Surg Res 2013; 185:896-903. [PMID: 23870834 DOI: 10.1016/j.jss.2013.06.015] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Revised: 05/08/2013] [Accepted: 06/06/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have the potential to improve graft outcomes and promote allograft tolerance. In this study, we examined the effects and mechanism of combined intrathymic (i.t.) and intravenous (i.v.) injection of MSCs on the survival of transplanted hearts in a rat allograft model. METHODS Recipient Sprague-Dawley rats were transplanted with hearts from Wistar rats. Wistar rat MSCs were infused via i.t. or i.v. or combined i.t. and i.v. (i.t./i.v.) injection at designated intervals. In vitro mixed lymphocyte reaction assays were performed to assess the immunosuppressive capacity of MSCs. Mesenchymal stem cell surface markers and CD4+, CD25+, and Foxp3+ T-cells in the peripheral blood were detected using flow cytometry analysis. The expression of microRNAs and cytokines in graft infiltrating lymphocytes was analyzed by real-time polymerase chain reaction. RESULTS The MSCs cultured in vitro had multipotential differentiation capacity. Mixed lymphocyte reaction assays showed that donor-derived MSCs could not stimulate a proliferative response of recipient lymphocytes and could markedly suppress T-cell responses. Survival of the allografts was significantly prolonged by administration of i.t./i.v. injection of MSCs compared with controls, with a mean survival of 32.2 versus 6.5 d, respectively. Compared with the syngeneic groups posttransplant, miR-155 expression was significantly increased in the allogeneic group, and could be restored by injection of MSCs, especially i.t./i.v. injection of MSCs. Moreover, i.t./i.v. injection of MSCs decreased the level of interleukin (IL)-2 and interferon-gamma, but increased the levels of IL-4 and IL-10 in the allogeneic group. More important, i.t./i.v. injection of MSCs was the best way to increase the percentage of CD4+, CD25+, and Foxp3+ T-cell peripheral blood. CONCLUSIONS Our results indicated that i.t./i.v. injection of MSCs can prolong the survival of rat cardiac allograft, which may be associated with down-regulating miR-155 expression, a shift in the Th1/Th2 balance, and up-regulation of Treg cells expression.
Collapse
Affiliation(s)
- Haoyue Huang
- Department of Cardiovascular Surgery, First Affiliated Hospital of Soochow University, Suzhou, China
| | | | | | | | | | | | | |
Collapse
|