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Zhou L, Zhu JQ, Kou JT, Xu WL, Lyu SC, Du GS, Yang HW, Wang JF, Hu XP, Yu CZ, Yuan CH, Han DD, Sang CQ, Li B, Gao J, Qi HZ, Wang LM, Lyu L, Liu H, Wu JY, Lang R, He Q, Li XL. Chinese expert consensus on quantitatively monitoring and assessing immune cell function status and its clinical application (2024 edition). Hepatobiliary Pancreat Dis Int 2024; 23:551-558. [PMID: 39448347 DOI: 10.1016/j.hbpd.2024.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 09/27/2024] [Indexed: 10/26/2024]
Affiliation(s)
- Lin Zhou
- Department of Hepatobiliary and Pancreatic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China; Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Ji-Qiao Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China; Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Jian-Tao Kou
- Department of Hepatobiliary and Pancreatic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China; Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Wen-Li Xu
- Department of Hepatobiliary and Pancreatic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China; Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Shao-Cheng Lyu
- Department of Hepatobiliary and Pancreatic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China; Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Guo-Sheng Du
- Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China; Organ Transplantation Center, General Hospital of Northern Theater Command, Shenyang 110010, China
| | - Hong-Wei Yang
- Organ Transplantation Center, General Hospital of Northern Theater Command, Shenyang 110010, China
| | - Jian-Feng Wang
- Department of Interventional Therapy, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Xiao-Peng Hu
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Chun-Zhao Yu
- Department of General Surgery, Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
| | - Chun-Hui Yuan
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Dong-Dong Han
- Liver Transplantation Department, China-Japan Friendship Hospital, Beijing 100029, China
| | - Cui-Qin Sang
- Department of Obstetrics and Gynecology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Bo Li
- Department of Hepatobiliary Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jie Gao
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100871, China
| | - Hai-Zhi Qi
- Department of General Surgery/Organ Transplant Center, The Second Xiangya Hospital of Central South Univercity, Changsha 410011, China
| | - Li-Ming Wang
- Organ Transplant Center, The Second Affiliated Hospital of Dalian Medical University, Dalian 116027, China
| | - Ling Lyu
- Department of General Surgery, Jiangsu Provincial People's Hospital, Nanjing 210029, China
| | - Hao Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110001, China
| | - Jian-Yong Wu
- Kidney Transplant Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ren Lang
- Department of Hepatobiliary and Pancreatic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
| | - Qiang He
- Department of Hepatobiliary and Pancreatic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
| | - Xian-Liang Li
- Department of Hepatobiliary and Pancreatic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
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Kosuta I, Kelava T, Ostojic A, Sesa V, Mrzljak A, Lalic H. Immunology demystified: A guide for transplant hepatologists. World J Transplant 2024; 14:89772. [PMID: 38576757 PMCID: PMC10989464 DOI: 10.5500/wjt.v14.i1.89772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 01/24/2024] [Accepted: 02/29/2024] [Indexed: 03/15/2024] Open
Abstract
Liver transplantation has become standard practice for treating end-stage liver disease. The success of the procedure relies on effective immunosuppressive medications to control the host's immune response. Despite the liver's inherent capacity to foster tolerance, the early post-transplant period is marked by significant immune reactivity. To ensure favorable outcomes, it is imperative to identify and manage various rejection types, encompassing T-cell-mediated, antibody-mediated, and chronic rejection. However, the approach to prescribing immunosuppressants relies heavily on clinical judgment rather than evidence-based criteria. Given that the majority of patients will require lifelong immuno suppression as the mechanisms underlying operational tolerance are still being investigated, healthcare providers must possess an understanding of immune responses, rejection mechanisms, and the pathways targeted by immunosuppressive drugs. This knowledge enables customization of treatments and improved patient care, even though a consensus on an optimal immunosuppressive regimen remains elusive.
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Affiliation(s)
- Iva Kosuta
- Department of Intensive Care Medicine, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Tomislav Kelava
- Department of Physiology, School of Medicine, Univeristy of Zagreb, Zagreb 10000, Croatia
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, Zagreb 10000, Croatia
| | - Ana Ostojic
- Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Vibor Sesa
- Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, University Hospital Centre Zagreb, Zagreb 10000, Croatia
- Department of Medicine, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Hrvoje Lalic
- Department of Physiology, University of Zagreb School of Medicine, Zagreb 10000, Croatia
- Laboratory for Cell Biology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb 10000, Croatia
- Department of Laboratory Immunology, Clinical Department of Laboratory Diagnostics, University Hospital Center Zagreb, Zagreb 10000, Croatia
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Morales R, Bolarín JM, Muro M, Legaz I. Presence of KIR2DL2/S2, KIR2DL5, and KIR3DL1 Molecules in Liver Transplant Recipients with Alcoholic Cirrhosis Could Be Implicated in Death by Graft Failure. Diagnostics (Basel) 2023; 13:diagnostics13071217. [PMID: 37046435 PMCID: PMC10093628 DOI: 10.3390/diagnostics13071217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/15/2023] [Accepted: 03/21/2023] [Indexed: 03/29/2023] Open
Abstract
Background: The second-most frequent diagnosis among patients receiving liver transplants (LTs) is alcoholic liver disease. The multifactorial pathophysiology of alcoholic liver disease depends on the innate immune system and the inflammatory cascade. According to recent studies on these receptors, killer-cell immunoglobulin-like receptors (KIRs) may be involved in sepsis, liver rejection, and virus relapse. We aimed to investigate the impact of preclinical issues like ascites and encephalopathy and KIR genetic traits on death from sepsis, multiorgan failure (MF), and graft failure (GF) in AC patients undergoing LTs. Methods: We retrospectively reviewed 164 consecutive and deceased Caucasian AC patients who underwent LTs. Pre-transplant complications, cause of death, and patient survival were analyzed. Genomic DNA was taken from peripheral blood, and PCR-SSO was used for genotyping KIR. Results: Compared to GF patients, there was a statistically significant increase in the frequency of KIR2DL2+ (75.8% vs. 51.2%; p = 0.047). Another increase in frequency was also observed in KIR2DS2+ in sepsis compared to the GF group (51.2% vs. 43.7%; p = 0.018). In patients who passed away from MF, a decrease in KIR2DL5+ was observed in AC patients with and without encephalopathy (p = 0.018). The frequency of KIR3DL1+ in the AC patients significantly increased the mortality from sepsis (p = 0.045), which was confirmed by multivariate logistic regression. The frequency of KIR3DL1+ in the AC patients significantly increased the mortality from sepsis (p = 0.012) and was confirmed by multivariate logistic regression. KIR2DS1+ and KIR2DS4+ showed increased mortality due to GF compared to patients without these genes (p = 0.011 and 0.012, respectively). However, this fact was confirmed only for KIR2DS1+ by multivariate logistic Cox regression. Conclusions: The presence of the KIR2DL2/S2+, KIR2DL5+, and KIR3DL1+ genes increases the frequency of death from multiple organ failure or graft failure. Our findings highlight the AC patient’s vulnerability to a LT during hospitalization. Following the transplant and outside of it, we adopt essential preventive measures to create a routine healthcare screening to enhance and modify treatments to increase survival.
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Affiliation(s)
- Raquel Morales
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain
| | - José Miguel Bolarín
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain
| | - Manuel Muro
- Immunology Service, Instituto Murciano de Investigación Biosanitaria (IMIB), Hospital Clínico Universitario Virgen de la Arrixaca (HCUVA), 30120 Murcia, Spain
- Correspondence: (M.M.); (I.L.); Tel.: +34-968-369-599 (M.M.); +34-868-883-957 (I.L.); Fax: +34-968-349-678 (M.M.); +34-868-834-307 (I.L.)
| | - Isabel Legaz
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain
- Correspondence: (M.M.); (I.L.); Tel.: +34-968-369-599 (M.M.); +34-868-883-957 (I.L.); Fax: +34-968-349-678 (M.M.); +34-868-834-307 (I.L.)
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Nodular Regenerative Hyperplasia Is Not a Rare Condition After Liver Transplantation: Incidence, Predictive Factors, and Impact on Survival. Transplantation 2023; 107:410-419. [PMID: 36117256 DOI: 10.1097/tp.0000000000004303] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND The objectives of this study were to evaluate incidence and to identify the risk factors of occurrence and the predictive factors of symptomatic forms of nodular regenerative hyperplasia (NRH) after liver transplantation (LT). METHODS To identify risk factors of NRH following LT, we included 1648 patients transplanted from 2004 to 2018 and compared the patients developing NRH after LT to those who did not. To identify predictive factors of symptomatic NRH, we selected 115 biopsies displaying NRH and compared symptomatic to asymptomatic forms. Symptomatic NRH was defined as the presence of ascites, esophageal varices, hepatic encephalopathy, portal thrombosis, retransplantation, or death related to NRH. RESULTS The incidence of NRH following LT was 5.1%. In multivariate analysis, the independent factor of developing NRH after LT was the donor's age (odds ratio [OR] = 1.02; confidence interval, 1.01-1.03; P = 0.02). Symptomatic forms occurred in 29 (25.2%) patients: 19 (16.5%) patients presented with ascites, 13 (11.3%) with esophageal varices, 4 (3.5%) with hepatic encephalopathy, and 8 (7%) with portal thrombosis. The median period before the onset of symptoms was 8.4 (1.5-11.3) y after LT. The spleen size at diagnosis/before LT ratio (OR = 12.5; 114.17-1.37; P = 0.0252) and thrombectomy during transplantation (OR = 11.17; 1.48-84.11; P = 0.0192) were associated with symptomatic NRH in multivariate analysis. CONCLUSIONS NRH following LT is frequent (5.1%) and leads to symptomatic portal hypertension in 25.2% of patients. Using older grafts increases the risk of developing NRH after LT. Clinicians should screen for signs of portal hypertension, particularly in measuring spleen size.
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Harrington C, Krishnan S, Mack CL, Cravedi P, Assis DN, Levitsky J. Noninvasive biomarkers for the diagnosis and management of autoimmune hepatitis. Hepatology 2022; 76:1862-1879. [PMID: 35611859 PMCID: PMC9796683 DOI: 10.1002/hep.32591] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 01/07/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare disease of unclear etiology characterized by loss of self-tolerance that can lead to liver injury, cirrhosis, and acute liver failure. First-line treatment consists of systemic corticosteroids, or budesonide, and azathioprine, to which most patients are initially responsive, although predictors of response are lacking. Relapses are very common, correlate with histological activity despite normal serum transaminases, and increase hepatic fibrosis. Furthermore, current regimens lead to adverse effects and reduced quality of life, whereas medication titration is imprecise. Biomarkers that can predict the clinical course of disease, identify patients at elevated risk for relapse, and improve monitoring and medication dosing beyond current practice would have high clinical value. Herein, we review novel candidate biomarkers in adult and pediatric AIH based on prespecified criteria, including gene expression profiles, proteins, metabolites, and immune cell phenotypes in different stages of AIH. We also discuss biomarkers relevant to AIH from other immune diseases. We conclude with proposed future directions in which biomarker implementation into clinical practice could lead to advances in personalized therapeutic management of AIH.
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Affiliation(s)
- Claire Harrington
- Division of Gastroenterology & HepatologyNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
| | - Swathi Krishnan
- Medicine DepartmentYale School of MedicineNew HavenConnecticutUSA
| | - Cara L. Mack
- Section of Pediatric Gastroenterology, Hepatology & Nutrition, Children's Hospital ColoradoUniversity of Colorado School of MedicineAuroraColoradoUSA
| | - Paolo Cravedi
- Division of NephrologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - David N. Assis
- Section of Digestive DiseasesYale School of MedicineNew HavenConnecticutUSA
| | - Josh Levitsky
- Division of Gastroenterology & HepatologyNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
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Lin SH, Wu KT, Wang CC, Huang KT, Chen KD, Hsu LW, Eng HL, Chiu KW. Liver Graft MicroRNAs Expression in Different Etiology of Acute Jaundice after Living Donor Liver Transplantation. BIOLOGY 2022; 11:biology11081228. [PMID: 36009855 PMCID: PMC9404977 DOI: 10.3390/biology11081228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/14/2022] [Accepted: 08/15/2022] [Indexed: 01/11/2023]
Abstract
Background: Acute jaundice remains a critical problem following liver transplantation. MicroRNAs (miRNAs) are involved in regulating gene expression related to various disease phenotypes and statuses. Aims: To differentiate acute jaundice etiology after living donor liver transplantation (LDLT), we examined the hepatic miRNA expression patterns in several liver graft pathologies. Methods: Eighty liver transplant recipients undergoing post-LDLT graft biopsy for the evaluation of acute jaundice were enrolled in this 1-year prospective study. Using a real-time quantitative reverse transcription-polymerase chain reaction profiling assay, we identified hepatic miRNA (miRNA-122, miRNA-301, miRNA-133a, and miRNA-21) signatures in various allografts pathologies. Results: Pathologic findings of the 80 recipients were as follows: acute cholangitis (AC), 37 (46%); acute rejection (AR), 20 (25%); recurrent hepatitis (RH), 12 (15%); non-specific pathological change, 6 (8%); and fatty change (FC), 5 (6%). None of these identified hepatic miRNAs expression pattern was significantly correlated with serum parameters, including neutrophil-lymphocyte ratio. In AC, hepatic miRNA-122, miRNA-301, miRNA-133a, and miRNA-21 expression was significantly downregulated (p < 0.05). MicroRNA-122 expression was elevated in cases of AR and RH (p < 0.05); miRNA-301 and miRNA-21 expression was higher in RH than in AC (p < 0.05); and miRNA-133a expression was higher in FC than in AR (p < 0.05). Conclusions: Our study suggests that specific hepatic miRNA expression patterns as a checklist may be useful for differential diagnosis of acute jaundice following liver transplantation.
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Affiliation(s)
- Shu-Hsien Lin
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Liver Transplantation Program, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Kun-Ta Wu
- Division of General Surgery, Department of Surgery, E-Da Hospital, Kaohsiung 83301, Taiwan
| | - Chih-Chi Wang
- Liver Transplantation Program, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Division of General Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Kuang-Tzu Huang
- Liver Transplantation Program, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Kuang-Den Chen
- Liver Transplantation Program, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Li-Wen Hsu
- Liver Transplantation Program, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Hock-Liew Eng
- Liver Transplantation Program, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - King-Wah Chiu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- Liver Transplantation Program, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Correspondence: ; Tel.: +886-7-731-7123 (ext. 8190); Fax: +886-7-733-6856
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Chiang HJ, Chou MC, Chuang YH, Li CW, Lin CC, Eng HL, Chen CL, Cheng YF. Use of blood oxygen level-dependent magnetic resonance imaging to detect acute cellular rejection post-liver transplantation. Eur Radiol 2022; 32:4547-4554. [PMID: 35247088 DOI: 10.1007/s00330-022-08574-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/04/2022] [Accepted: 01/07/2022] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Acute cellular rejection (ACR) is a major immune occurrence post-liver transplant that can cause abnormal liver function. Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) can be used to evaluate liver disease, but it has not been utilized in the diagnosis of ACR post-liver transplant. Therefore, the purpose of this study is to evaluate the diagnostic performance of BOLD MRI and to monitor treatment response in recipients with ACR. METHODS This prospective study was approved by the local institutional review board. Fifty-five recipients with highly suspected ACR were enrolled in this study. Each patient underwent hepatic BOLD MRI, blood biochemistry, and biopsy before treatment. Of 55 patients, 19 recipients with ACR received a follow-up MRI after treatment. After obtaining the R2* maps, five regions-of-interest were placed on liver parenchyma to estimate the mean R2* values for statistical analysis. Receiver operating characteristic curve (ROC) analysis was performed to assess the diagnostic performance of R2* values in detecting patients with ACR. RESULTS The histopathologic results showed that 27 recipients had ACR (14 mild, 11 moderate, and 2 severe) and their hepatic R2* values were significantly lower than those of patients without ACR. ROC analysis revealed that the sensitivity and specificity of the R2* values for detection of ACR were 82.1% and 89.9%, respectively. Moreover, the R2* values and liver function in patients with ACR significantly increased after immunosuppressive treatment. CONCLUSION The non-invasive BOLD MRI technique may be useful for assessment of hepatic ACR and monitoring of treatment response after immunosuppressive therapy. KEY POINTS • Patients with acute cellular rejection post-liver transplant exhibited significantly decreased R2* values in liver parenchyma. • R2* values and liver function were significantly increased after immunosuppressive therapy. • R2* values were constructive indicators in detecting acute cellular rejection due to their high sensitivity and specificity.
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Affiliation(s)
- Hsien-Jen Chiang
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Chung Chou
- Department of Medical Imaging and Radiological Sciences, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Center for Big Data Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Hsuan Chuang
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chun-Wei Li
- Department of Medical Imaging and Radiological Sciences, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chih-Che Lin
- Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hock-Liew Eng
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Long Chen
- Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yu-Fan Cheng
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao-Sung, Kaohsiung, 833, Taiwan.
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Patients with moderate to severe COVID-19 have an impaired cytokine response with an exhausted and senescent immune phenotype. Immunobiology 2022; 227:152185. [PMID: 35134628 PMCID: PMC8813783 DOI: 10.1016/j.imbio.2022.152185] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 12/29/2021] [Accepted: 01/29/2022] [Indexed: 12/24/2022]
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Vieira DSC, Wopereis S, Walter LO, de Oliveira Silva L, Ribeiro AAB, Wilkens RS, Fernandes BL, Reis ML, Golfetto L, Santos-Silva MC. Analysis of Ki-67 expression in women with breast cancer: Comparative evaluation of two different methodologies by immunophenotyping. Pathol Res Pract 2021; 230:153750. [PMID: 34971844 DOI: 10.1016/j.prp.2021.153750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/17/2021] [Accepted: 12/21/2021] [Indexed: 10/19/2022]
Abstract
The Ki-67 antigen is a nuclear protein with proven prognostic value in different neoplasms and recognizes the predictive value in breast cancer (BC). No consensus exists on the ideal cutoff point. In this study, Ki-67 expression was evaluated in samples of BC by flow cytometry (FC) and compared with immunohistochemical (IHC) examination. For this, the BC tissue samples were sectioned, macerated, filtered, and marked with anti-Ki-67 FITC and anti-CD45 V500 antibodies. We selected the neoplastic cells according to CD45 expression and size and internal complexity (FSC × SSC) using the Infinicity 1.7 software. Lymphocytes were negative control. We compared the results with IHC analyses carried out in parallel and independently. The expression of Ki-67 was evaluated in both methodologies through Bland-Altman analysis. Among the 44 samples analyzed, only three showed bias higher than the established confidence interval (mean bias 2.1%, p = 0.62), with no significant difference for the perfect mean bias (0%). Therefore, one can state that FC provides results equivalent to IHC analysis and possibly analyzes more cells simultaneously. The results obtained in this study show the absence of observational bias through software analysis in a larger number of tumor cell populations. We can conclude that FC may be a promising alternative method for investigating Ki-67 in solid tumours.
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Affiliation(s)
- Daniella Serafin Couto Vieira
- Experimental Oncology and Hemopathies Laboratory, Postgraduate Program in Pharmacy, Health Sciences Center, Federal University of Santa Catarina, Florianópolis, Brazil; University Hospital Polydoro Ernani de São Thiago, Federal University of Santa Catarina, Florianópolis, Brazil; Federal University of Santa Catarina, Department of Pathology, Health Sciences Center, Federal University of Santa Catarina, Florianópolis, Brazil
| | - Sandro Wopereis
- University Hospital Polydoro Ernani de São Thiago, Federal University of Santa Catarina, Florianópolis, Brazil
| | - Laura Otto Walter
- Experimental Oncology and Hemopathies Laboratory, Postgraduate Program in Pharmacy, Health Sciences Center, Federal University of Santa Catarina, Florianópolis, Brazil
| | - Lisandra de Oliveira Silva
- Experimental Oncology and Hemopathies Laboratory, Postgraduate Program in Pharmacy, Health Sciences Center, Federal University of Santa Catarina, Florianópolis, Brazil
| | - Amanda Abdalla Biasi Ribeiro
- Experimental Oncology and Hemopathies Laboratory, Postgraduate Program in Pharmacy, Health Sciences Center, Federal University of Santa Catarina, Florianópolis, Brazil
| | - Renato Salerno Wilkens
- University Hospital Polydoro Ernani de São Thiago, Federal University of Santa Catarina, Florianópolis, Brazil
| | - Bráulio Leal Fernandes
- University Hospital Polydoro Ernani de São Thiago, Federal University of Santa Catarina, Florianópolis, Brazil
| | - Manoela Lira Reis
- University Hospital Polydoro Ernani de São Thiago, Federal University of Santa Catarina, Florianópolis, Brazil; Federal University of Santa Catarina, Department of Pathology, Health Sciences Center, Federal University of Santa Catarina, Florianópolis, Brazil
| | - Lisléia Golfetto
- University Hospital Polydoro Ernani de São Thiago, Federal University of Santa Catarina, Florianópolis, Brazil
| | - Maria Cláudia Santos-Silva
- Experimental Oncology and Hemopathies Laboratory, Postgraduate Program in Pharmacy, Health Sciences Center, Federal University of Santa Catarina, Florianópolis, Brazil.
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Monforte V, Ussetti P, Castejón R, Sintes H, Pérez VL, Laporta R, Sole A, Cifrián JM, Marcos PJ, Redel J, Arcos IL, Berastegui C, Alonso R, Rosado S, Escriva J, Iturbe D, Ovalle JP, Vaquero JM, López-Meseguer M, Mendoza A, Gómez-Ollés S. Predictive Value of Immune Cell Functional Assay for Non-Cytomegalovirus Infection in Lung Transplant Recipients: A Multicenter Prospective Observational Study. Arch Bronconeumol 2021; 57:690-696. [PMID: 35699006 DOI: 10.1016/j.arbr.2020.12.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 12/14/2020] [Indexed: 06/15/2023]
Abstract
INTRODUCTION Immune cell functional assay (ImmuKnow®) is a non-invasive method that measures the state of cellular immunity in immunosuppressed patients. We studied the prognostic value of the assay for predicting non-cytomegalovirus (CMV) infections in lung transplant recipients. METHODS A multicenter prospective observational study of 92 patients followed up from 6 to 12 months after transplantation was performed. Immune cell functional assay was carried out at 6, 8, 10, and 12 months. RESULTS Twenty-three patients (25%) developed 29 non-CMV infections between 6 and 12 months post-transplant. At 6 months, the immune response was moderate (ATP 225-525ng/mL) in 14 (15.2%) patients and low (ATP<225ng/mL) in 78 (84.8%); no patients had a strong response (ATP≥525ng/mL). Only 1 of 14 (7.1%) patients with a moderate response developed non-CMV infection in the following 6 months compared with 22 of 78 (28.2%) patients with low response, indicating sensitivity of 95.7%, specificity of 18.8%, positive predictive value (PPV) of 28.2%, and negative predictive value (NPV) of 92.9% (AUC 0.64; p=0.043). Similar acute rejection rates were recorded in patients with mean ATP≥225 vs. <225ng/mL during the study period (7.1% vs. 9.1%, p=0.81). CONCLUSION Although ImmuKnow® does not seem useful to predict non-CMV infection, it could identify patients with a very low risk and help us define a target for an optimal immunosuppression.
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Affiliation(s)
- Víctor Monforte
- Servicio de Neumología, Hospital Universitario Vall d'Hebron, Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain.
| | - Piedad Ussetti
- Servicio de Neumología, Hospital Universitario Puerta de Hierro, Madrid, Spain
| | - Raquel Castejón
- Laboratorio de Medicina Interna, Instituto de Investigación Sanitaria Puerta de Hierro, Madrid, Spain
| | - Helena Sintes
- Servicio de Neumología, Hospital Universitario Vall d'Hebron, Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Virginia Luz Pérez
- Servicio de Neumología, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Rosalía Laporta
- Servicio de Neumología, Hospital Universitario Puerta de Hierro, Madrid, Spain
| | - Amparo Sole
- Unidad de Trasplante Pulmonar, Hospital Universitario y Politécnico la Fe, Valencia, Spain
| | - José Manuel Cifrián
- Servicio de Neumología, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Pedro J Marcos
- Dirección de Procesos Asistenciales, Servicio de Neumología y Cirugía Torácica, Área Sanitaria de A Coruña y CEE, A Coruña, Spain
| | - Javier Redel
- Servicio de Neumología, Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Ibai Los Arcos
- Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; Servicio de Enfermedades Infecciosas, Hospital Universitario Vall d'Hebron, Barcelona, Spain
| | - Cristina Berastegui
- Servicio de Neumología, Hospital Universitario Vall d'Hebron, Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Rodrigo Alonso
- Servicio de Neumología, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Silvia Rosado
- Laboratorio de Medicina Interna, Instituto de Investigación Sanitaria Puerta de Hierro, Madrid, Spain
| | - Juan Escriva
- Unidad de Trasplante Pulmonar, Hospital Universitario y Politécnico la Fe, Valencia, Spain
| | - David Iturbe
- Servicio de Neumología, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Juan Pablo Ovalle
- Dirección de Procesos Asistenciales, Servicio de Neumología y Cirugía Torácica, Área Sanitaria de A Coruña y CEE, A Coruña, Spain
| | | | - Manuel López-Meseguer
- Servicio de Neumología, Hospital Universitario Vall d'Hebron, Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Alberto Mendoza
- Servicio de Neumología, Hospital Universitario Vall d'Hebron, Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Susana Gómez-Ollés
- Servicio de Neumología, Hospital Universitario Vall d'Hebron, Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
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11
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Maciel NB, Schwambach KH, Blatt CR. LIVER TRANSPLANTATION: TACROLIMUS BLOOD LEVELS VARIATION AND SURVIVAL, REJECTION AND DEATH OUTCOMES. ARQUIVOS DE GASTROENTEROLOGIA 2021; 58:370-376. [PMID: 34705973 DOI: 10.1590/s0004-2803.202100000-62] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 04/12/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Immunosuppressive drugs have important role in transplant of solid grafts, it aim avoid episodes of acute and chronic rejection and improving graft survival and patient survival. In Brazil, in 2016, liver transplantation was the third most frequent, with 1,880 transplants performed, of which 150 in Rio Grande do Sul. Several studies evaluated the association between variability in blood levels of immunosuppressive tacrolimus and late acute cellular graft rejection. OBJECTIVE To investigate the association of tacrolimus blood levels with clinical outcomes late acute cellular rejection, death, patient survival and graft survival in patients undergoing liver transplantation. METHODS This is a retrospective longitudinal study including patients submitted to adult liver transplantation by the Liver Transplantation Group in the Santa Casa de Misericórdia Hospital of Porto Alegre, from January 2006 to January 2013, and who used tacrolimus as immunosuppressive therapy. RESULTS Of the 127 patients included in the study, the majority were male (70.1%), 52-60 years old (33.9%) at the transplant. The most frequent causes of liver transplantation in this series were hepatitis C virus and hepatocellular carcinoma (24.4%) and alcohol (15.7%). Thirteen patients had late acute cellular rejection (10.2%); of these, three had two episodes. Regarding severity classification, seven patients had mild late acute cellular rejection. The mean time of rejection after liver transplantation was 14 months (ranging from 8 to 33 months). Overall survival was 8.98 years. Regarding tacrolimus blood levels, 52 patients with a variation ≥2 standard deviations were identified. Of these patients, eight had rejection; however, the association was not significant (P=0.146). A significant association was found between variation ≥2 standard deviations in tacrolimus blood levels and death (P=0.023) and survival (P=0.019). Regarding 5-year follow-up of graft survival, being two standard deviations above increases by 2.26 times the risk of transplanted graft loss, and for each unit of increase of standard deviation of tacrolimus blood levels there is a two-fold increase in the risk of graft loss in 5 years. CONCLUSION Increased risk of graft loss associated with increased standard deviations of tacrolimus blood levels may indicate the need for more rigorous and prospective monitoring of tacrolimus blood levels.
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Affiliation(s)
- Nicole Bianchin Maciel
- Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Hepatologia, Porto Alegre, RS, Brasil
| | - Karin Hepp Schwambach
- Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Hepatologia, Porto Alegre, RS, Brasil
| | - Carine Raquel Blatt
- Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Hepatologia, Porto Alegre, RS, Brasil
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12
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Assadiasl S, Mooney N, Nicknam MH. Cytokines in Liver Transplantation. Cytokine 2021; 148:155705. [PMID: 34564024 DOI: 10.1016/j.cyto.2021.155705] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 08/17/2021] [Accepted: 09/10/2021] [Indexed: 02/08/2023]
Abstract
Cytokines, soluble mediators of the immune system, play a critical role in the pathogenesis of autoimmune, allergic and infectious diseases. They are also implicated in the initiation and development of allograft rejection. During recent years, there have been considerable advances in generating novel anti-cytokine agents with promoted efficacy and safety, which could be administrated for managing dysregulated cytokine secretion; besides, gene therapy for overexpression of immunomodulatory cytokines has shown substantial improvements. Liver transplantation has been established as a life-saving treatment for end-stage hepatic diseases but the growing number of recipients urge for improved post-transplant care including tolerance induction, infection control and resolving immunosuppressant drugs adverse effects. Cytokines with a wide range of proinflammatory and regulatory properties might be considered as potential therapeutic targets for selective suppression or enhancement of the immune responses in recipients. In the present review, we aimed to summarize the positive and negative effects of cytokines on liver allograft in addition to their prognostic and therapeutic values.
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Affiliation(s)
- Sara Assadiasl
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nuala Mooney
- Human Immunology and Immunopathology, Inserm UMR 976, Paris, France; Université de Paris, Paris, France
| | - Mohammad Hossein Nicknam
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, Medical School, Tehran University of Medical Sciences, Tehran, Iran.
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Harrington CR, Yang GY, Levitsky J. Advances in Rejection Management: Prevention and Treatment. Clin Liver Dis 2021; 25:53-72. [PMID: 33978583 DOI: 10.1016/j.cld.2020.08.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Extended survival of liver transplant recipients has brought rejection management to the forefront of liver transplant research. This article discusses T-cell-mediated rejection, antibody-mediated rejection, and chronic rejection. We focus on the prevention and then discuss treatment options. Future directions of rejection management include biomarkers of rejection, which may allow for monitoring of patients who are considered high risk for rejection and detection of rejection before there is any clinical evidence to improve graft and patient survival. With improved graft life and survival of liver transplant recipients, the new frontier of rejection management focuses on immunosuppression minimization, withdrawal, and personalization.
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Affiliation(s)
- Claire R Harrington
- Department of Medicine, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 2330, Chicago, IL 60611, USA
| | - Guang-Yu Yang
- Department of Pathology, Northwestern University Feinberg School of Medicine, 251 E Huron St. Chicago, IL 60611, USA
| | - Josh Levitsky
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 1400, Chicago, IL 60611, USA; Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 1900, Chicago, IL 60611, USA.
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Ruetsch C, Brglez V, Crémoni M, Zorzi K, Fernandez C, Boyer-Suavet S, Benzaken S, Demonchy E, Risso K, Courjon J, Cua E, Ichai C, Dellamonica J, Passeron T, Seitz-Polski B. Functional Exhaustion of Type I and II Interferons Production in Severe COVID-19 Patients. Front Med (Lausanne) 2021; 7:603961. [PMID: 33585507 PMCID: PMC7873370 DOI: 10.3389/fmed.2020.603961] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 12/18/2020] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged in Wuhan in December 2019 and has since spread across the world. Even though the majority of patients remain completely asymptomatic, some develop severe systemic complications. In this prospective study we compared the immunological profile of 101 COVID-19 patients with either mild, moderate or severe form of the disease according to the WHO classification, as well as of 50 healthy subjects, in order to identify functional immune factors independently associated with severe forms of COVID-19. Plasma cytokine levels, and cytokine levels upon in vitro non-specific stimulation of innate and adaptive immune cells, were measured at several time points during the course of the disease. As described previously, inflammatory cytokines IL1β, IL6, IL8, and TNFα associated with cytokine storm were significantly increased in the plasma of moderate and severe COVID-19 patients (p < 0.0001 for all cytokines). During follow-up, plasma IL6 levels decreased between the moment of admission to the hospital and at the last observation carried forward for patients with favorable outcome (p = 0.02148). After in vitro stimulation of immune cells from COVID-19 patients, reduced levels of both type I and type II interferons (IFNs) upon in vitro stimulation were correlated with increased disease severity [type I IFN (IFNα): p > 0.0001 mild vs. moderate and severe; type II IFN (IFNγ): p = 0.0002 mild vs. moderate and p < 0.0001 mild vs. severe] suggesting a functional exhaustion of IFNs production. Stimulated IFNα levels lower than 2.1 pg/ml and IFNγ levels lower than 15 IU/mL at admission to the hospital were associated with more complications during hospitalization (p = 0.0098 and p =0.0002, respectively). A low IFNγ level was also confirmed by multivariable analysis [p = 0.0349 OR = 0.98 (0.962; 0.999)] as an independent factor of complications. In vitro treatment with type IFNα restored type IFNγ secretion in COVID-19 patients while the secretion of pro-inflammatory cytokines IL6 and IL1β remained stable or decreased, respectively. These results (a) demonstrate a functional exhaustion of both innate and adaptive immune response in severe forms of COVID-19; (b) identify IFNα and IFNγ as new potential biomarkers of severity; and (c) highlight the importance of targeting IFNs when considering COVID-19 treatment in order to re-establish a normal balance between inflammatory and Th1 effector cytokines.
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Affiliation(s)
- Caroline Ruetsch
- Laboratoire d'Immunologie, Centre Hospitalier Universitaire (CHU) de Nice, Université Côte d'Azur, Nice, France
- Centre Méditerranéen de Médecine Moléculaire (C3M), INSERM U1065, Université Côte d'Azur, Nice, France
| | - Vesna Brglez
- Unité de Recherche Clinique de la Côte d'Azur (UR2CA), Université Côte d'Azur, Nice, France
| | - Marion Crémoni
- Unité de Recherche Clinique de la Côte d'Azur (UR2CA), Université Côte d'Azur, Nice, France
| | - Kévin Zorzi
- Unité de Recherche Clinique de la Côte d'Azur (UR2CA), Université Côte d'Azur, Nice, France
| | - Céline Fernandez
- Unité de Recherche Clinique de la Côte d'Azur (UR2CA), Université Côte d'Azur, Nice, France
| | - Sonia Boyer-Suavet
- Unité de Recherche Clinique de la Côte d'Azur (UR2CA), Université Côte d'Azur, Nice, France
| | - Sylvia Benzaken
- Laboratoire d'Immunologie, Centre Hospitalier Universitaire (CHU) de Nice, Université Côte d'Azur, Nice, France
| | - Elisa Demonchy
- Service d'Infectiologie, Centre Hospitalier Universitaire (CHU) de Nice, Université Côte d'Azur, Nice, France
| | - Karine Risso
- Service d'Infectiologie, Centre Hospitalier Universitaire (CHU) de Nice, Université Côte d'Azur, Nice, France
| | - Johan Courjon
- Service d'Infectiologie, Centre Hospitalier Universitaire (CHU) de Nice, Université Côte d'Azur, Nice, France
| | - Eric Cua
- Service d'Infectiologie, Centre Hospitalier Universitaire (CHU) de Nice, Université Côte d'Azur, Nice, France
| | - Carole Ichai
- Service de réanimation, Centre Hospitalier Universitaire (CHU) de Nice, Université Côte d'Azur, Nice, France
| | - Jean Dellamonica
- Unité de Recherche Clinique de la Côte d'Azur (UR2CA), Université Côte d'Azur, Nice, France
- Service de réanimation, Centre Hospitalier Universitaire (CHU) de Nice, Université Côte d'Azur, Nice, France
| | - Thierry Passeron
- Centre Méditerranéen de Médecine Moléculaire (C3M), INSERM U1065, Université Côte d'Azur, Nice, France
- Service de dermatologie, Centre Hospitalier Universitaire (CHU) de Nice, Université Côte d'Azur, Nice, France
| | - Barbara Seitz-Polski
- Laboratoire d'Immunologie, Centre Hospitalier Universitaire (CHU) de Nice, Université Côte d'Azur, Nice, France
- Unité de Recherche Clinique de la Côte d'Azur (UR2CA), Université Côte d'Azur, Nice, France
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Monforte V, Ussetti P, Castejón R, Sintes H, Pérez VL, Laporta R, Sole A, Cifrián JM, Marcos PJ, Redel J, Arcos IL, Berastegui C, Alonso R, Rosado S, Escriva J, Iturbe D, Ovalle JP, Vaquero JM, López-Meseguer M, Mendoza A, Gómez-Ollés S. Predictive Value of Immune Cell Functional Assay for Non-Cytomegalovirus Infection in Lung Transplant Recipients: A Multicenter Prospective Observational Study. Arch Bronconeumol 2021; 57:S0300-2896(21)00003-X. [PMID: 33551278 DOI: 10.1016/j.arbres.2020.12.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 12/14/2020] [Accepted: 12/14/2020] [Indexed: 10/22/2022]
Abstract
INTRODUCTION Immune cell functional assay (ImmuKnow®) is a non-invasive method that measures the state of cellular immunity in immunosuppressed patients. We studied the prognostic value of the assay for predicting non-cytomegalovirus (CMV) infections in lung transplant recipients. METHODS A multicenter prospective observational study of 92 patients followed up from 6 to 12 months after transplantation was performed. Immune cell functional assay was carried out at 6, 8, 10, and 12 months. RESULTS Twenty-three patients (25%) developed 29 non-CMV infections between 6 and 12 months post-transplant. At 6 months, the immune response was moderate (ATP 225-525ng/mL) in 14 (15.2%) patients and low (ATP<225ng/mL) in 78 (84.8%); no patients had a strong response (ATP≥525ng/mL). Only 1 of 14 (7.1%) patients with a moderate response developed non-CMV infection in the following 6 months compared with 22 of 78 (28.2%) patients with low response, indicating sensitivity of 95.7%, specificity of 18.8%, positive predictive value (PPV) of 28.2%, and negative predictive value (NPV) of 92.9% (AUC 0.64; p=0.043). Similar acute rejection rates were recorded in patients with mean ATP≥225 vs. <225ng/mL during the study period (7.1% vs. 9.1%, p=0.81). CONCLUSION Although ImmuKnow® does not seem useful to predict non-CMV infection, it could identify patients with a very low risk and help us define a target for an optimal immunosuppression.
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Affiliation(s)
- Víctor Monforte
- Servicio de Neumología, Hospital Universitario Vall d'Hebron, Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain.
| | - Piedad Ussetti
- Servicio de Neumología, Hospital Universitario Puerta de Hierro, Madrid, Spain
| | - Raquel Castejón
- Laboratorio de Medicina Interna, Instituto de Investigación Sanitaria Puerta de Hierro, Madrid, Spain
| | - Helena Sintes
- Servicio de Neumología, Hospital Universitario Vall d'Hebron, Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Virginia Luz Pérez
- Servicio de Neumología, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Rosalía Laporta
- Servicio de Neumología, Hospital Universitario Puerta de Hierro, Madrid, Spain
| | - Amparo Sole
- Unidad de Trasplante Pulmonar, Hospital Universitario y Politécnico la Fe, Valencia, Spain
| | - José Manuel Cifrián
- Servicio de Neumología, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Pedro J Marcos
- Dirección de Procesos Asistenciales, Servicio de Neumología y Cirugía Torácica, Área Sanitaria de A Coruña y CEE, A Coruña, Spain
| | - Javier Redel
- Servicio de Neumología, Hospital Universitario Reina Sofía, Córdoba, Spain
| | - Ibai Los Arcos
- Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; Servicio de Enfermedades Infecciosas, Hospital Universitario Vall d'Hebron, Barcelona, Spain
| | - Cristina Berastegui
- Servicio de Neumología, Hospital Universitario Vall d'Hebron, Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Rodrigo Alonso
- Servicio de Neumología, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Silvia Rosado
- Laboratorio de Medicina Interna, Instituto de Investigación Sanitaria Puerta de Hierro, Madrid, Spain
| | - Juan Escriva
- Unidad de Trasplante Pulmonar, Hospital Universitario y Politécnico la Fe, Valencia, Spain
| | - David Iturbe
- Servicio de Neumología, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Juan Pablo Ovalle
- Dirección de Procesos Asistenciales, Servicio de Neumología y Cirugía Torácica, Área Sanitaria de A Coruña y CEE, A Coruña, Spain
| | | | - Manuel López-Meseguer
- Servicio de Neumología, Hospital Universitario Vall d'Hebron, Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Alberto Mendoza
- Servicio de Neumología, Hospital Universitario Vall d'Hebron, Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Susana Gómez-Ollés
- Servicio de Neumología, Hospital Universitario Vall d'Hebron, Barcelona, Spain; Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
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16
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Perry WA, Paulus JK, Price LL, Snydman DR, Chow JK. Association between lymphopenia at one month post-transplant and infectious outcomes or death in heart transplant recipients. Clin Infect Dis 2020; 73:e3797-e3803. [PMID: 33279963 DOI: 10.1093/cid/ciaa1800] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 12/04/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Cell-mediated immunity is a specific target of several medications used to prevent or treat rejection in orthotopic heart transplantation. Low absolute lymphocyte count (ALC) has potential to be a useful and accessible clinical indicator of overall infection risk. Though some studies have demonstrated this association in other transplant populations, it has not been assessed in heart transplant recipients. METHODS A single-center retrospective cohort study examined adult heart transplant recipients transplanted between 2000 and 2018. The exposure of interest was ALC less than 0.75 x10 3cells/µL at one month post-transplant and the primary endpoint was a composite outcome of infection (including cytomegalovirus [CMV], herpes simplex I/II or varicella zoster virus [HSV/VZV], blood stream infection [BSI], invasive fungal infection [IFI]) or death occurring after one month and before one year post-transplant. A multivariable Cox proportional hazards model was created to control for confounders identified using clinical judgment and statistical criteria. RESULTS Of 375 subjects analyzed, 101 (27%) developed the composite outcome (61 CMV, 3 HSV/VZV, 19 BSI, 10 IFI, 8 deaths). Lymphopenia (ALC<0.75 x10 3cells/µL) at one month was associated with a greater than two fold higher rate of the composite outcome (hazard ratio 2.26, 95% confidence interval 1.47-3.46, p-value <0.001) compared to patients without lymphopenia at one month. After adjustment for confounding variables, the presence of lymphopenia remained statistically significantly associated with the composite outcome (HR 1.72 95% CI 1.08-2.75, p=0.02). Conclusion: ALC measured at one month post-heart transplant is associated with an increased risk of infectious outcomes or death in the ensuing 11months. This is a simple, accessible laboratory measure.
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Affiliation(s)
- Whitney A Perry
- Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, USA
| | - Jessica K Paulus
- Predictive Analytics and Comparative Effectiveness (PACE) Center, Tufts Medical Center/Tufts University School of Medicine, Boston, MA, USA.,The Institute for Clinical and Health Research Policy Studies (ICRHPS), Tufts Medical Center, Boston, MA, USA
| | - Lori Lyn Price
- The Institute for Clinical and Health Research Policy Studies (ICRHPS), Tufts Medical Center, Boston, MA, USA.,Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA, USA
| | - David R Snydman
- Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, USA
| | - Jennifer K Chow
- Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, USA
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McClure T, Goh SK, Cox D, Muralidharan V, Dobrovic A, Testro AG. Donor-specific cell-free DNA as a biomarker in liver transplantation: A review. World J Transplant 2020; 10:307-319. [PMID: 33312892 PMCID: PMC7708879 DOI: 10.5500/wjt.v10.i11.307] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 10/09/2020] [Accepted: 10/30/2020] [Indexed: 02/05/2023] Open
Abstract
Due to advances in modern medicine, liver transplantation has revolutionised the prognosis of many previously incurable liver diseases. This progress has largely been due to advances in immunosuppressant therapy. However, despite the judicious use of immunosuppression, many liver transplant recipients still experience complications such as rejection, which necessitates diagnosis via invasive liver biopsy. There is a clear need for novel, minimally-invasive tests to optimise immunosuppression and improve patient outcomes. An emerging biomarker in this ''precision medicine'' liver transplantation field is that of donor-specific cell free DNA. In this review, we detail the background and methods of detecting this biomarker, examine its utility in liver transplantation and discuss future research directions that may be most impactful.
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Affiliation(s)
- Tess McClure
- Liver Transplant Unit, Austin Health, Heidelberg 3084, VIC, Australia
| | - Su Kah Goh
- Department of Surgery, Austin Health, Heidelberg 3084, VIC, Australia
| | - Daniel Cox
- Department of Surgery, Austin Health, Heidelberg 3084, VIC, Australia
| | | | - Alexander Dobrovic
- Department of Surgery, The University of Melbourne, Heidelberg 3084, VIC, Australia
| | - Adam G Testro
- Liver Transplant Unit, Austin Health, Heidelberg 3084, VIC, Australia
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Diagnosis of Acute Rejection of Liver Grafts in Young Children Using Acoustic Radiation Force Impulse Imaging. AJR Am J Roentgenol 2020; 215:1229-1237. [PMID: 32877250 DOI: 10.2214/ajr.19.22057] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE. Frequency of acute rejection (AR) after pediatric liver transplant remains high despite progress in immunosuppression. Liver biopsy (LB) is the reference standard for the diagnosis of AR despite its potential for morbidity. The purpose of our study was to evaluate the ability of acoustic radiation force impulse (ARFI) imaging to distinguish AR from other causes of short- and medium-term liver dysfunction and to identify liver transplant cases with normal liver function. MATERIALS AND METHODS. ARFI imaging was used to evaluate shear wave velocity (SWV) after liver transplant in young children. All pediatric liver grafts that had LB and ARFI examination between January 2014 and December 2017 were included in this retrospective study. Results of LB were compared with those of SWV. Collected data included age at biopsy and transplant, sex, weight, height, body mass index, interval between liver transplant and shear wave elastography and LB, kind of graft, type of donor, and diagnosis at transplant. ROC curve analysis was performed to assess the diagnostic performance of SWV. Optimal cutoff of SWV using ARFI imaging in predicting AR was identified using the Youden index. RESULTS. Statistical analysis was performed on 54 children; six of the original 60 were excluded because of confounding alterations or changes in outcome. Median SWV was higher in patients with AR (2.03 m/s; interquartile range [IQR], 1.80-2.45 m/s) compared with those with idiopathic hepatitis (1.33 m/s; IQR, 1.12-1.53 m/s), portal hypertension (1.42 m/s; IQR, 1.32-1.72 m/s), cholangitis (1.56 m/s; IQR, 1.07-1.62 m/s) or normal liver function (1.23 m/s; IQR 1.12-1.29 m/s) at protocol biopsies (all comparisons, p < 0.01). SWV higher than 1.73 m/s was predictive for AR (AUC, 0.966). SWV also showed good diagnostic accuracy in normal liver function (AUC, 0.791). ARFI imaging was not predictive for hepatitis (AUC, 0.402), portal hypertension (AUC, 0.556), or cholangitis (AUC, 0.420). CONCLUSION. ARFI imaging could be routinely used in place of LB in pediatric patients with liver dysfunction after liver transplant, restricting indication and risks of biopsy to selected cases.
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Marx S, Adam C, Mihm J, Weyrich M, Sester U, Sester M. A Polyclonal Immune Function Assay Allows Dose-Dependent Characterization of Immunosuppressive Drug Effects but Has Limited Clinical Utility for Predicting Infection on an Individual Basis. Front Immunol 2020; 11:916. [PMID: 32499781 PMCID: PMC7243819 DOI: 10.3389/fimmu.2020.00916] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 04/20/2020] [Indexed: 12/19/2022] Open
Abstract
Dosage of immunosuppressive drugs after transplantation critically determines rejection and infection episodes. In this study, a global immune function assay was characterized among controls, dialysis-patients, and transplant-recipients to evaluate its utility for pharmacodynamic monitoring of immunosuppressive drugs and for predicting infections. Whole-blood samples were stimulated with anti-CD3/toll-like-receptor (TLR7/8)-agonist in the presence or absence of drugs and IFN-γ secretion was measured by ELISA. Additional stimulation-induced cytokines were characterized among T-, B-, and NK-cells using flow-cytometry. Cytokine-secretion was dominated by IFN-γ, and mainly observed in CD4, CD8, and NK-cells. Intra-assay variability was low (CV = 10.4 ± 6.2%), whereas variability over time was high, even in the absence of clinical events (CV = 65.0 ± 35.7%). Cyclosporine A, tacrolimus and steroids dose-dependently inhibited IFN-γ secretion, and reactivity was further reduced when calcineurin inhibitors were combined with steroids. Moreover, IFN-γ levels significantly differed between controls, dialysis-patients, and transplant-recipients, with lowest IFN-γ levels early after transplantation (p < 0.001). However, a single test had limited ability to predict infectious episodes. In conclusion, the assay may have potential for basic pharmacodynamic characterization of immunosuppressive drugs and their combinations, and for assessing loss of global immunocompetence after transplantation, but its application to guide drug-dosing and to predict infectious on an individual basis is limited.
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Affiliation(s)
- Stefanie Marx
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | - Claudia Adam
- Department of Internal Medicine IV, Saarland University, Homburg, Germany
| | - Janine Mihm
- Department of Internal Medicine IV, Saarland University, Homburg, Germany
| | - Michael Weyrich
- Department of Internal Medicine IV, Saarland University, Homburg, Germany
| | - Urban Sester
- Department of Internal Medicine IV, Saarland University, Homburg, Germany
| | - Martina Sester
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
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20
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Drabe CH, Sørensen SS, Rasmussen A, Perch M, Gustafsson F, Rezahosseini O, Lundgren JD, Ostrowski SR, Nielsen SD. Immune function as predictor of infectious complications and clinical outcome in patients undergoing solid organ transplantation (the ImmuneMo:SOT study): a prospective non-interventional observational trial. BMC Infect Dis 2019; 19:573. [PMID: 31269923 PMCID: PMC6609391 DOI: 10.1186/s12879-019-4207-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 06/19/2019] [Indexed: 12/22/2022] Open
Abstract
Background Solid organ transplantation (SOT) is a well-established and life-saving treatment for patients with end-stage organ failure. Organ rejection and infections are among the main complications to SOT and largely determines the clinical outcome. The correct level of immunosuppression is of major importance to prevent these complications. However, it is a consistent observation that in recipients on the same immunosuppressive regimens the clinical outcome varies, and no reliable marker exists to monitor immune function. Methods In a prospective, observational study, we plan to enroll 630 adult patients with a planned organ transplantation at Rigshospitalet, University of Copenhagen, Denmark. Prior to and on different time points up to two years after transplantation we will perform a complete immunological profile on the recipients. This profile will consist of classical descriptive immune phenotyping (flow cytometry and circulating biomarkers) and the functional assay TruCulture®. In TruCulture® whole blood is incubated ex vivo with stimulants imitating bacterial, viral and fungal infections, where after a panel of selected cytokines is quantified. Clinical data from electronic health records will be obtained from the PERSIMUNE (Centre of Excellence for Personalized Medicine of Infections Complications in Immune Deficiency at Rigshospitalet, Copenhagen) data repository, a warehouse of data generated as part of routine care including vital signs, biochemistry, microbiology, pathology as well as medication, demographics, diagnoses, hospital contacts, surgical procedures and mortality. Discussion This will be the first large scale study to determine several aspects of immune function and perform a complete immunological profiling in SOT recipients. It is expected that knowledge generated will provide information to generate prediction models identifying patients at increased risk of infection and/or rejection. If the study is successful, we will subsequently use the generated prediction models to propose personalized immunosuppressive regimens to be tested in future randomized controlled trials. Trial registration This study has been approved by the Regional ethical committee (H-17024315), the Danish Data Protection Agency (RH-2016-47, RH-2015-04, I-Suite 03605) and the Danish National board of Health (3–3013-1060/1). The trial is retrospectively registered at clinicaltrials.gov (NCT03847285) the 20th February 2019.
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Affiliation(s)
- Camilla Heldbjerg Drabe
- Viro-immunology Research Unit, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | | | - Allan Rasmussen
- Department of Surgical Gastroenterology and Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Michael Perch
- Department of Cardiology, Section for Lung Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Finn Gustafsson
- Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Omid Rezahosseini
- Viro-immunology Research Unit, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Jens D Lundgren
- Department of Infectious Diseases and CHIP, Centre of Excellence for Health, Immunity and Infections and PERSIMUNE, Centre of Excellence for Personalized Medicine of Infectious Complications in Immune Deficiency, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Sisse Rye Ostrowski
- Department of Clinical Immunology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Susanne Dam Nielsen
- Viro-immunology Research Unit, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
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21
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Goh SK, Do H, Testro A, Pavlovic J, Vago A, Lokan J, Jones RM, Christophi C, Dobrovic A, Muralidharan V. The Measurement of Donor-Specific Cell-Free DNA Identifies Recipients With Biopsy-Proven Acute Rejection Requiring Treatment After Liver Transplantation. Transplant Direct 2019; 5:e462. [PMID: 31334336 PMCID: PMC6616138 DOI: 10.1097/txd.0000000000000902] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 03/15/2019] [Accepted: 03/28/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Assessment of donor-specific cell-free DNA (dscfDNA) in the recipient is emerging as a noninvasive biomarker of organ rejection after transplantation. We previously developed a digital polymerase chain reaction (PCR)-based approach that readily measures dscfDNA within clinically relevant turnaround times. Using this approach, we characterized the dynamics and evaluated the clinical utility of dscfDNA after liver transplantation (LT). METHODS Deletion/insertion polymorphisms were used to distinguish donor-specific DNA from recipient-specific DNA. Posttransplant dscfDNA was measured in the plasma of the recipients. In the longitudinal cohort, dscfDNA was serially measured at days 3, 7, 14, 28, and 42 in 20 recipients. In the cross-sectional cohort, dscfDNA was measured in 4 clinically stable recipients (>1-y posttransplant) and 16 recipients (>1-mo posttransplant) who were undergoing liver biopsies. RESULTS Recipients who underwent LT without complications demonstrated an exponential decline in dscfDNA. Median levels at days 3, 7, 14, 28, and 42 were 1936, 1015, 247, 90, and 66 copies/mL, respectively. dscfDNA was higher in recipients with treated biopsy-proven acute rejection (tBPAR) when compared to those without. The area under the receiver operator characteristic curve of dscfDNA was higher than that of routine liver function tests for tBPAR (dscfDNA: 98.8% with 95% confidence interval, 95.8%-100%; alanine aminotransferase: 85.7%; alkaline phosphatase: 66.4%; gamma-glutamyl transferase: 80.1%; and bilirubin: 35.4%). CONCLUSIONS dscfDNA as measured by probe-free droplet digital PCR methodology was reflective of organ health after LT. Our findings demonstrate the potential utility of dscfDNA as a diagnostic tool of tBPAR.
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Affiliation(s)
- Su Kah Goh
- Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia
- Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
| | - Hongdo Do
- Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
- School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia
- Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia
| | - Adam Testro
- Liver Transplant Unit, Austin Health, Heidelberg, VIC, Australia
- Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia
| | - Julie Pavlovic
- Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia
| | - Angela Vago
- Liver Transplant Unit, Austin Health, Heidelberg, VIC, Australia
| | - Julie Lokan
- Department of Anatomical Pathology, Austin Health, Heidelberg, VIC, Australia
| | - Robert M. Jones
- Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia
- Liver Transplant Unit, Austin Health, Heidelberg, VIC, Australia
- Hepato-Pancreato-Biliary & Transplant Surgery Unit, Austin Health, Heidelberg, VIC, Australia
| | - Christopher Christophi
- Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia
- Liver Transplant Unit, Austin Health, Heidelberg, VIC, Australia
- Hepato-Pancreato-Biliary & Transplant Surgery Unit, Austin Health, Heidelberg, VIC, Australia
| | - Alexander Dobrovic
- Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia
- Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
- School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia
- Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia
| | - Vijayaragavan Muralidharan
- Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, VIC, Australia
- Liver Transplant Unit, Austin Health, Heidelberg, VIC, Australia
- Hepato-Pancreato-Biliary & Transplant Surgery Unit, Austin Health, Heidelberg, VIC, Australia
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22
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Yucesan E, Goncu B, Ozdemir B, Idiz O, Ersoy YE, Aysan E. Importance of HLA typing, PRA and DSA tests for successful parathyroid allotransplantation. Immunobiology 2019; 224:485-489. [PMID: 31204065 DOI: 10.1016/j.imbio.2019.05.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 05/18/2019] [Accepted: 05/28/2019] [Indexed: 02/06/2023]
Abstract
Parathyroid allotransplantation is increasingly practiced for patients who have permanent hypoparathyroidsm. Parathyroid allotransplantation success is varied, and no defined criteria about immunologic monitoring for pre-/post-transplantation follow-up. This study sought to evaluate the possible role of immunological tests. Four unrelated recipients and one living donor who have chronic kidney disease were evaluated for HLA-typing, PRA, CXM tests to conduct parathyroid allotransplantation. Parathyroid glands were obtained and resected from the donor, then cells were isolated and cryopreserved. Upon histologic examination, cells were cultivated and injected into muscle of four recipients. Recipient's were followed for parathormone and calcium levels for four years. PRA screening were monitored and de novo DSA was evaluated as well. In two of the recipients, allografts continued to be functional more than four years. In one recipient, allograft remained functional for two years and another recipient lost function after one year. Two out four were negative for de novo DSA and three out of four of the recipients remained negative for PRA. Neither HLA-matching nor de novo DSA positivity and PRA screenings seems significant for successfull parathyroid allotransplantation. This study has considerable potential for immunological monitoring of parathyroid allotransplantation.
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Affiliation(s)
- Emrah Yucesan
- Bezmialem Vakif University, Institute of Life Sciences and Biotechnology, Istanbul, Turkey.
| | - Beyza Goncu
- Bezmialem Vakif University, Experimental Research Center, Istanbul, Turkey
| | - Burcu Ozdemir
- Bezmialem Vakif University, Experimental Research Center, Istanbul, Turkey
| | - Oguz Idiz
- Istanbul Teaching and Research Hospital, General Surgery Clinic, Istanbul, Turkey
| | - Yeliz Emine Ersoy
- Bezmialem Vakif University, Faculty of Medicine, Department of General Surgery, Istanbul, Turkey
| | - Erhan Aysan
- Bezmialem Vakif University, Faculty of Medicine, Department of General Surgery, Istanbul, Turkey
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23
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The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation 2019; 102:900-931. [PMID: 29596116 DOI: 10.1097/tp.0000000000002191] [Citation(s) in RCA: 790] [Impact Index Per Article: 131.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Despite recent advances, cytomegalovirus (CMV) infections remain one of the most common complications affecting solid organ transplant recipients, conveying higher risks of complications, graft loss, morbidity, and mortality. Research in the field and development of prior consensus guidelines supported by The Transplantation Society has allowed a more standardized approach to CMV management. An international multidisciplinary panel of experts was convened to expand and revise evidence and expert opinion-based consensus guidelines on CMV management including prevention, treatment, diagnostics, immunology, drug resistance, and pediatric issues. Highlights include advances in molecular and immunologic diagnostics, improved understanding of diagnostic thresholds, optimized methods of prevention, advances in the use of novel antiviral therapies and certain immunosuppressive agents, and more savvy approaches to treatment resistant/refractory disease. The following report summarizes the updated recommendations.
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24
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Iovino L, Taddei R, Bindi ML, Morganti R, Ghinolfi D, Petrini M, Biancofiore G. Clinical use of an immune monitoring panel in liver transplant recipients: A prospective, observational study. Transpl Immunol 2018; 52:45-52. [PMID: 30414446 DOI: 10.1016/j.trim.2018.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 11/05/2018] [Accepted: 11/05/2018] [Indexed: 02/07/2023]
Abstract
Immunosuppressive therapy greatly contributed to making liver transplantation the standard treatment for end-stage liver diseases. However, it remains difficult to predict and measure the efficacy of pharmacological immunosuppression. Therefore, we used a panel of standardized, commonly available, biomarkers with the aim to describe their changes in the first 3 weeks after the transplant procedure and assess if they may help therapeutic drug monitoring in better tailoring the dose of the immunosuppressive drugs. We prospectively studied 72 consecutive patients from the day of liver transplant (post-operative day #0) until the post-operative day #21. Leukocytes, neutrophils, lymphocytes (CD4+, CD8+), natural killer cells, monocytes, immunoglobulins and tacrolimus serum levels were measured on peripheral blood (at day 0, 3, 7, 14, 21 after surgery). Patients who developed infections showed significantly higher CD64+ monocytes on post operative day #7. IgG levels were lower on post operative day #3 among patients who later developed infections. We also found that a sharp decrease in IgA from post operative day #0 to 3 (-226 mg/dL in the ROC curve analysis) strongly correlates with the onset of infections among HCV- patients. No specific markers of rejection emerged from the tested panel of markers. Our results show that some early changes in peripheral blood white cells and immunoglobulins may predict the onset of infections and may be useful in modulating the immunosuppressive therapy. However, a panel of commonly available, standardized biomarkers do not support in improving therapeutic drug monitoring ability to individualize immunosuppressive drugs dosing.
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Affiliation(s)
- Lorenzo Iovino
- Hematology Division, University School of Medicine, Via Roma, 56100 Pisa, Italy; Program in Immunology, Clinical Research Division and Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle (WA), USA
| | - Riccardo Taddei
- Transplant Anesthesia and Critical Care, Azienda Ospedaliera Universitaria Pisana, University School of Medicine, Via Paradisa, 2, 56100 Pisa, Italy
| | - Maria Lucia Bindi
- Transplant Anesthesia and Critical Care, Azienda Ospedaliera Universitaria Pisana, University School of Medicine, Via Paradisa, 2, 56100 Pisa, Italy
| | - Riccardo Morganti
- Department of Clinical and Experimental Medicine, University School of Medicine, Via Roma, 56100 Pisa, Italy
| | - Davide Ghinolfi
- Liver Transplant Surgery, Azienda Ospedaliera Universitaria Pisana, University School of Medicine, Via Paradisa, 2, 56100 Pisa, Italy
| | - Mario Petrini
- Hematology Division, University School of Medicine, Via Roma, 56100 Pisa, Italy
| | - Gianni Biancofiore
- Transplant Anesthesia and Critical Care, Azienda Ospedaliera Universitaria Pisana, University School of Medicine, Via Paradisa, 2, 56100 Pisa, Italy.
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25
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Zhu A, Leto A, Shaked A, Keating B. Immunologic Monitoring to Personalize Immunosuppression After Liver Transplant. Gastroenterol Clin North Am 2018; 47:281-296. [PMID: 29735024 DOI: 10.1016/j.gtc.2018.01.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Although immunosuppressive drugs have enhanced patient outcomes in transplantation, the liver transplant community has made significant research efforts into the discovery of more accurate and precise methods of posttransplant monitoring and diagnosing. Current research in biomarkers reveals many promising approaches.
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Affiliation(s)
- Andrew Zhu
- Division of Transplantation, Department of Surgery, Penn Transplant Institute, The University of Pennsylvania, 3400 Spruce Street, Two Dulles Pavilion, Philadelphia, PA 19104, USA
| | - Alexandra Leto
- Division of Transplantation, Department of Surgery, Penn Transplant Institute, The University of Pennsylvania, 3400 Spruce Street, Two Dulles Pavilion, Philadelphia, PA 19104, USA
| | - Abraham Shaked
- Division of Transplantation, Department of Surgery, Penn Transplant Institute, The University of Pennsylvania, 3400 Spruce Street, Two Dulles Pavilion, Philadelphia, PA 19104, USA.
| | - Brendan Keating
- Division of Transplantation, Department of Surgery, Penn Transplant Institute, The University of Pennsylvania, 3400 Spruce Street, Two Dulles Pavilion, Philadelphia, PA 19104, USA
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26
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Luo Y, Ji WB, Duan WD, Shi XJ, Zhao ZM. Delayed introduction of immunosuppressive regimens in critically ill patients after liver transplantation. Hepatobiliary Pancreat Dis Int 2017; 16:487-492. [PMID: 28992880 DOI: 10.1016/s1499-3872(17)60050-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 05/25/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND The manipulation of immunosuppression therapy remains challenging in patients who develop infectious diseases or multiple organ dysfunction after liver transplantation. We evaluated the outcomes of delayed introduction of immunosuppression in the patients after liver transplantation under immune monitoring with ImmuKnow assay. METHODS From March 2009 to February 2014, 225 consecutive liver recipients in our institute were included. The delayed administration of immunosuppressive regimens was attempted in 11 liver recipients with multiple severe comorbidities. RESULTS The median duration of non-immunosuppression was 12 days (range 5-58). Due to the infectious complications, the serial ImmuKnow assay showed a significantly low ATP level of 64±35 ng/mL in the early period after transplantation. With the development of comorbidities, the ImmuKnow value significantly increased. However, the acute allograft rejection developed when a continuous distinct elevation of both ATP and glutamyltranspeptidase levels was detected. The average ATP level measured just before the development of acute rejection was 271±115 ng/mL. CONCLUSIONS The delayed introduction of immunosuppressive regimens is safe and effective in management of critically ill patients after liver transplantation. The serial ImmuKnow assay could provide a reliable depiction of the dynamics of functional immunity throughout the clinical course of a given patient.
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Affiliation(s)
- Ying Luo
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China.
| | - Wen-Bin Ji
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Wei-Dong Duan
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Xian-Jie Shi
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Zhi-Ming Zhao
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
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27
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Behnam Sani K, Sawitzki B. Immune monitoring as prerequisite for transplantation tolerance trials. Clin Exp Immunol 2017; 189:158-170. [PMID: 28518214 DOI: 10.1111/cei.12988] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2017] [Indexed: 02/06/2023] Open
Abstract
Ever since its first application in clinical medicine, scientists have been urged to induce tolerance towards foreign allogeneic transplants and thus avoid rejection by the recipient's immune system. This would circumvent chronic use of immunosuppressive drugs (IS) and thus avoid development of IS-induced side effects, which are contributing to the still unsatisfactory long-term graft and patient survival after solid organ transplantation. Although manifold strategies of tolerance induction have been described in preclinical models, only three therapeutic approaches have been utilized successfully in a still small number of patients. These approaches are based on (i) IS withdrawal in spontaneous operational tolerant (SOT) patients, (ii) induction of a mixed chimerism and (iii) adoptive transfer of regulatory cells. Results of clinical trials utilizing these approaches show that tolerance induction does not work in all patients. Thus, there is a need for reliable biomarkers, which can be used for patient selection and post-therapeutic immune monitoring of safety, success and failure. In this review, we summarize recent achievements in the identification and validation of such immunological assays and biomarkers, focusing mainly on kidney and liver transplantation. From the published findings so far, it has become clear that indicative biomarkers may vary between different therapeutic approaches applied and organs transplanted. Also, patient numbers studied so far are very small. This is the main reason why nearly all described parameters lack validation and reproducibility testing in large clinical trials, and are therefore not yet suitable for clinical practice.
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Affiliation(s)
- K Behnam Sani
- Institute of Medical Immunology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - B Sawitzki
- Institute of Medical Immunology, Charité Universitaetsmedizin Berlin, Berlin, Germany
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28
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Pretransplant CD28 Biomarker (Levels of Expression and Quantification of Molecules per Cell) in Peripheral CD4 + T Cells Predicts Acute Rejection Episodes in Liver and Kidney Recipients. Transplant Proc 2017; 48:2987-2989. [PMID: 27932126 DOI: 10.1016/j.transproceed.2016.09.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Revised: 08/18/2016] [Accepted: 09/01/2016] [Indexed: 11/23/2022]
Abstract
BACKGROUND Acute rejection (AR) remains a significant cause of graft loss. Better approaches to predict AR are being investigated. Surface CD28 protein is essential for T-cell proliferation and survival as well as cytokine production. PATIENTS AND METHODS Pretransplant CD4+CD28+ peripheral T cells were examined in 30 liver recipients (LRs) and 31 kidney recipients (KRs) by flow cytometry. RESULTS Pretransplant CD4+CD28+ T cells in LRs were significantly lower in rejectors than nonrejectors (P = .002). Furthermore, the total number of CD28 molecules per cell in LRs (P = .02) as well as KRs (P = .047) was significantly lower in rejectors than nonrejectors. The healthy group did not display differences when compared with patients with end-stage liver disease or renal failure; however, stratification analysis displayed higher levels of CD4+CD28+ when compared with rejected LRs (P = .04) but not KRs. CD28 levels <41.94% were able to discriminate LRs at high risk of AR (P = .003). Similarly, a total number of CD28 molecules ≤8359 (P = .031) in LRs and ≤7669 (P = .046) in KRs correlated with high risk of AR. CONCLUSION The preliminary results presented herein exhibit a fast and noninvasive method that assists clinicians to prevent AR by monitoring CD4+CD28+ peripheral T cells.
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29
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Abstract
Liver transplantation outcomes have significantly improved over the past few decades owing largely to the introduction of effective immunosuppression medications. Further comprehension of the unique immune microenvironment of the liver has led to the development of newer molecular targeted therapeutics. Understanding the mechanism of action and adverse effect profiles of these medications is crucial for appropriate management of posttransplant patients. In this review, the author describes the immunologic response elicited by liver transplantation, chronicles the various immunosuppressant drug classes, discusses the evidence behind their use, and evaluates the management of special subpopulations of posttransplantation patients.
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Affiliation(s)
- Renumathy Dhanasekaran
- Division of Gastroenterology and Hepatology, Stanford University, 750 Welch Road, Suite 210, Palo Alto, CA 94304, USA.
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30
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Boix F, Bolarín JM, Mrowiec A, Eguía J, Gonzalez-Martinez G, de la Peña J, Galian JA, Alfaro R, Moya-Quiles MR, Legaz I, Campillo JA, Ramírez P, García-Alonso A, Pons JA, Sánchez-Bueno F, Minguela A, Llorente S, Muro M. CD28 biomarker quantification and expression level profiles in CD4 + T-lymphocytes in solid organ transplantation. Transpl Immunol 2017; 42:9-17. [PMID: 28392336 DOI: 10.1016/j.trim.2017.04.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 04/03/2017] [Accepted: 04/03/2017] [Indexed: 02/08/2023]
Abstract
The introduction of anti-calcineurin-based therapies has led to an increase in the one-year survival as well as graft function rates in patients undergoing solid organ transplantation (SOT). Nonetheless, early cellular acute rejection (EAR) incidence still remains a major challenge that irrevocably heads to poor outcomes. The mechanisms underlying CD4 T cell activation in SOT are still under research. In this sense, CD28 co-stimulatory molecule plays a pivotal role triggering CD4 T cell activation as well as survival maintenance. Previous own studies stated the role that CD4+CD28+ circulating T lymphocytes plays before and during EAR episodes. We assessed the percentage as well as the absolute number of CD28 molecules on CD4+ T cells as predictive surrogate biomarker of EAR in a prospective cohort of liver and kidney transplant recipients. Quantitative analysis of CD28 was carried out on whole peripheral blood samples by flow cytometry. Decreased pre-transplant expression of CD28 was associated with EAR in both study groups. Furthermore, the expression of CD28 within the rejected group, experimented an up-regulation upon transplantation. These preliminary results suggest that patients undergoing liver or kidney transplant can be stratified at high risk of EAR according to their CD28 molecule expression on peripheral CD4+ T lymphocytes.
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Affiliation(s)
- Francisco Boix
- Department of Immunology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - José Miguel Bolarín
- Department of Immunology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - Anna Mrowiec
- Department of Immunology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - Jorge Eguía
- Department of Immunology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - Gema Gonzalez-Martinez
- Department of Immunology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - Jesús de la Peña
- Department of Pathology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - José A Galian
- Department of Immunology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - Rafael Alfaro
- Department of Immunology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - María R Moya-Quiles
- Department of Immunology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - Isabel Legaz
- Department of Immunology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - José A Campillo
- Department of Immunology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - Pablo Ramírez
- Department of Surgery, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - Ana García-Alonso
- Department of Immunology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - Jose A Pons
- Department of Surgery, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - Francisco Sánchez-Bueno
- Department of Surgery, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - Alfredo Minguela
- Department of Immunology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - Santiago Llorente
- Department of Nephrology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain
| | - Manuel Muro
- Department of Immunology, Clinical University Hospital 'Virgen Arrixaca' - IMIB (Murcian Institute of Biomedical Investigation), Murcia, Spain.
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31
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Sood S, Haifer C, Yu L, Pavlovic J, Churilov L, Gow PJ, Jones RM, Angus PW, Visvanathan K, Testro AG. A novel immune function biomarker identifies patients at risk of clinical events early following liver transplantation. Liver Transpl 2017; 23:487-497. [PMID: 28133934 DOI: 10.1002/lt.24730] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 11/29/2016] [Accepted: 12/13/2016] [Indexed: 01/13/2023]
Abstract
Balancing immunosuppression after liver transplant is difficult, with clinical events common. We investigate whether a novel immune biomarker based on a laboratory platform with widespread availability that measures interferon γ (IFNγ) after stimulation with a lyophilized ball containing an adaptive and innate immune stimulant can predict events following transplantation. A total of 75 adult transplant recipients were prospectively monitored in a blinded, observational study; 55/75 (73.3%) patients experienced a total of 89 clinical events. Most events occurred within the first month. Low week 1 results were significantly associated with risk of early infection (area under the receiver operating characteristic curve [AUROC], 0.74; P = 0.008). IFNγ ≤ 1.30 IU/mL (likelihood ratio positive, 1.93; sensitivity, 71.4%; specificity, 63.0%) was associated with the highest risk for infection with minimal rejection risk. Nearly half the cohort (27/60, 45.0%) expressed IFNγ ≤ 1.30 IU/mL. Moreover, an elevated week 1 result was significantly associated with the risk of rejection within the first month after transplant (AUROC, 0.77; P = 0.002), but no episodes of infection. On multivariate logistic regression, IFNγ ≥ 4.49 IU/mL (odds ratio, 4.75) may be an independent predictor of rejection (P = 0.05). In conclusion, low IFNγ suggesting oversuppression is associated with infections, whereas high IFNγ indicating undersuppression is associated with rejection. This assay offers the potential to allow individualization and optimization of immunosuppression that could fundamentally alter the way patients are managed following transplantation. Liver Transplantation 23 487-497 2017 AASLD.
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Affiliation(s)
- Siddharth Sood
- Liver Transplant Unit.,Department of Gastroenterology and Hepatology, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia.,Innate Immune Laboratory, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia
| | | | - Lijia Yu
- Innate Immune Laboratory, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia
| | | | - Leonid Churilov
- Florey Department of Neuroscience and Mental Health, Austin Health
| | | | | | | | - Kumar Visvanathan
- Innate Immune Laboratory, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, Australia
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32
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Chiereghin A, Petrisli E, Ravaioli M, Morelli MC, Turello G, Squarzoni D, Piccirilli G, Ambretti S, Gabrielli L, Pinna AD, Landini MP, Lazzarotto T. Infectious agents after liver transplant: etiology, timeline and patients' cell-mediated immunity responses. Med Microbiol Immunol 2016; 206:63-71. [PMID: 27783145 DOI: 10.1007/s00430-016-0485-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Accepted: 10/20/2016] [Indexed: 12/21/2022]
Abstract
Infections continue to be one of the leading causes of morbidity and mortality in liver transplant recipients. We retrospectively reviewed the symptomatic infectious episodes that occurred during the first year post-transplant to determine time of onset, causative pathogens and cell-mediated immunity response patterns. Ninety-eight of the 202 (48.5%) recipients enrolled developed at least one infectious episode. The total number of infectious episodes was 135: 77 (57.1%) bacterial, 45 (33.3%) viral and 13 (9.6%) fungal. The most frequently isolated bacteria were Escherichia coli (21 isolates) and Klebsiella pneumoniae (19 isolates). Overall, extended-spectrum beta lactamase-producing and methicillin-resistant organisms were responsible for 29 (29/77; 37.7%) infectious episodes. Members of the herpes virus group, in particular cytomegalovirus (34/45 viral infections, 75.5%), were detected. Candida species (9 isolates) followed by Aspergillus species (4 isolates) were isolated. The majority of infections (63%) occurred during the early post-transplant phase (<1 month), whereas only 8/135 episodes (5.9%) were detected after the sixth month (late phase). Significantly lower median ImmuKnow® intracellular ATP values in patients who developed bacterial and fungal infections compared to infection-free patients were observed (P < 0.0001 and P = 0.0016, respectively), whereas patients who developed a viral infection had a median intracellular ATP level not statistically different compared to uninfected patients (P = 0.4). Our findings confirm that bacteria are responsible for the majority of symptomatic infections and occur more frequently during the first month post-transplant. The ImmuKnow® measurements can be a useful tool for identifying patients at high risk of developing infection, particularly of fungal and bacterial etiology.
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Affiliation(s)
- Angela Chiereghin
- Operative Unit of Clinical Microbiology, St. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - Evangelia Petrisli
- Operative Unit of Clinical Microbiology, St. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy.,Italian National Transplant Centre - Italian National Institute of Health, Via Giano Della Bella 34, 00162, Rome, Italy
| | - Matteo Ravaioli
- Department of General Surgery and Transplantation, St. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - Maria Cristina Morelli
- Department of General Surgery and Transplantation, St. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - Gabriele Turello
- Operative Unit of Clinical Microbiology, St. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - Diego Squarzoni
- Operative Unit of Clinical Microbiology, St. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - Giulia Piccirilli
- Operative Unit of Clinical Microbiology, St. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - Simone Ambretti
- Operative Unit of Clinical Microbiology, St. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - Liliana Gabrielli
- Operative Unit of Clinical Microbiology, St. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - Antonio Daniele Pinna
- Department of General Surgery and Transplantation, St. Orsola-Malpighi University Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - Maria Paola Landini
- Department of Specialized, Experimental, and Diagnostic Medicine, Operative Unit of Clinical Microbiology, St. Orsola-Malpighi University Hospital, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - Tiziana Lazzarotto
- Department of Specialized, Experimental, and Diagnostic Medicine, Operative Unit of Clinical Microbiology, St. Orsola-Malpighi University Hospital, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.
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33
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Zhou M, Hara H, Dai Y, Mou L, Cooper DKC, Wu C, Cai Z. Circulating Organ-Specific MicroRNAs Serve as Biomarkers in Organ-Specific Diseases: Implications for Organ Allo- and Xeno-Transplantation. Int J Mol Sci 2016; 17:ijms17081232. [PMID: 27490531 PMCID: PMC5000630 DOI: 10.3390/ijms17081232] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 07/25/2016] [Accepted: 07/26/2016] [Indexed: 12/16/2022] Open
Abstract
Different cell types possess different miRNA expression profiles, and cell/tissue/organ-specific miRNAs (or profiles) indicate different diseases. Circulating miRNA is either actively secreted by living cells or passively released during cell death. Circulating cell/tissue/organ-specific miRNA may serve as a non-invasive biomarker for allo- or xeno-transplantation to monitor organ survival and immune rejection. In this review, we summarize the proof of concept that circulating organ-specific miRNAs serve as non-invasive biomarkers for a wide spectrum of clinical organ-specific manifestations such as liver-related disease, heart-related disease, kidney-related disease, and lung-related disease. Furthermore, we summarize how circulating organ-specific miRNAs may have advantages over conventional methods for monitoring immune rejection in organ transplantation. Finally, we discuss the implications and challenges of applying miRNA to monitor organ survival and immune rejection in allo- or xeno-transplantation.
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Affiliation(s)
- Ming Zhou
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518039, China.
- Institute of Immunology, Zhongshan School of Medicine, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Sun Yat-sen University, Guangzhou 510275, China.
| | - Hidetaka Hara
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Yifan Dai
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing 210029, China.
| | - Lisha Mou
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518039, China.
| | - David K C Cooper
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Changyou Wu
- Institute of Immunology, Zhongshan School of Medicine, Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Sun Yat-sen University, Guangzhou 510275, China.
| | - Zhiming Cai
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen 518039, China.
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34
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Rodríguez-Perálvarez M, Rico-Juri JM, Tsochatzis E, Burra P, De la Mata M, Lerut J. Biopsy-proven acute cellular rejection as an efficacy endpoint of randomized trials in liver transplantation: a systematic review and critical appraisal. Transpl Int 2016; 29:961-73. [DOI: 10.1111/tri.12737] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2015] [Revised: 09/18/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023]
Affiliation(s)
- Manuel Rodríguez-Perálvarez
- Department of Hepatology and Liver Transplantation; Reina Sofía University Hospital; IMIBIC; CIBERehd; Córdoba Spain
| | - Jose M. Rico-Juri
- Starzl Unit of Abdominal Transplantation; Cliniques Universitaires Saint Luc; Université Catholique de Louvain (UCL); Brussels Belgium
| | - Emmanuel Tsochatzis
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit; Royal Free Hospital and UCL; London UK
| | - Patrizia Burra
- Multivisceral Transplant Unit Gastroenterology; Padova University Hospital; Padova Italy
| | - Manuel De la Mata
- Department of Hepatology and Liver Transplantation; Reina Sofía University Hospital; IMIBIC; CIBERehd; Córdoba Spain
| | - Jan Lerut
- Starzl Unit of Abdominal Transplantation; Cliniques Universitaires Saint Luc; Université Catholique de Louvain (UCL); Brussels Belgium
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35
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Zhang AY, Liu YM, Gong JP. Kupffer cells and liver transplantation. Shijie Huaren Xiaohua Zazhi 2015; 23:1917-1923. [DOI: 10.11569/wcjd.v23.i12.1917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Nowadays, liver transplantation is globally considered the most effective treatment for end-stage liver diseases. Ischemia-reperfusion (I/R) injury and immune rejection response (IRR) are the two major imperfections which severely affect the recipients' prognosis and survival rate without satisfactory clinical management strategies. Therefore, exploring effective methods to improve I/R injury and IRR have important clinical significance under circumstances of shortage of donor livers. Kupffer cells (KCs) are the largest population of antigen representing cells (APCs) which settle in the liver. As the first defensive line of the live, KCs exhibit various biological effects. However, the exact mechanisms responsible for the role of KCs in I/R injury and IRR remain elusive. We hereby review the current finding about the role of KCs in I/R injury and IRR.
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