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Awad SM, El Batanony EH, Elmahdy SK, Allam ET, Rizk SK, Zaid AB, Taha M, Salem RH. Interleukin 6 and interleukin 17A serum levels and gene- polymorphisms in the development of early allograft rejection in living donor liver transplant recipients. Sci Rep 2024; 14:21687. [PMID: 39289412 PMCID: PMC11408691 DOI: 10.1038/s41598-024-71102-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 08/26/2024] [Indexed: 09/19/2024] Open
Abstract
The aim of this study is to evaluate the role of serum level of Interleukin 6(IL-6) and Interleukin 17 (IL-17) in liver transplantation outcome for living recipients, Analyze the relation between the gene polymorphism and the occurrence of rejection after liver transplantation and Study the relation between the gene polymorphism and the occurrence of different infectious complications. The study was conducted in March 2023 and included 60 healthy volunteers from the National Liver Institute (NLI) blood bank at Menoufia University and 120 live donation liver recipient patients at NLI. During one month of liver transplantation, the cytokine levels (IL-17, IL-6 proteins, IL-6 G-174C, and IL-17 A rs2275913 gene polymorphism) and CD4 levels for 60 patients of 120 live donation liver recipient patients whom early reject transplanted tissue and the same parameters were measured after 6 months follow up for non-reject group. The main finding of this study was that the post-transplant rejection group and the post-transplant non-rejection and control groups differed significantly in the genotype frequency (CC, CG, and GG) or alleles of IL-6 G-174C (p = 0.011). On the other hand IL-17A rs2275913 gene polymorphism and its alleles (p = 0.71) showed no statistically significant difference. We also observed that serum IL-17 levels, with 100% specificity and 100% sensitivity threshold, will be more sensitive and specific than serum IL-6 and CD4 count in differentiating post-transplant rejection from non-rejection patients. The results showed that there was no significant relationship between the genotypes and serum levels of interleukins and the type and degree of rejection. Proinflammatory cytokines might be useful indicators for distinguishing and early identifying unfavorable outcomes after transplantation, allowing for prompt and effective treatment intervention. To evaluate these findings, prospective clinical trials are required.
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Affiliation(s)
- Samah Mohammed Awad
- Clinical Microbiology and Immunology Department, National Liver Institute, Menoufia University, Shibin Elkom, 32511, Egypt
| | - Eman Helmy El Batanony
- Clinical Microbiology and Immunology Department, National Liver Institute, Menoufia University, Shibin Elkom, 32511, Egypt
| | - Shaimaa K Elmahdy
- Gastroenterology and Hepatology Department, National Liver Institute, Menoufia University, Shibin Elkom, 32511, Egypt
| | - Esraa Tawfik Allam
- Departments of Clinical Pathology, National Liver Institute, Menoufia University, Shibin Elkom, 32511, Egypt
| | - Sara Kamal Rizk
- Biochemistry department, Faculty of Medicine, Menoufia University, Shibin Elkom, 32511, Egypt
| | - Ahmed B Zaid
- Departments of Clinical Pathology, National Liver Institute, Menoufia University, Shibin Elkom, 32511, Egypt.
| | - Mohammad Taha
- Hepatopancreatobiliary and Liver Transplant Surgery, National Liver Institute, Shibin Elkom, 32511, Egypt
| | - Radwa H Salem
- Clinical Microbiology and Immunology Department, National Liver Institute, Menoufia University, Shibin Elkom, 32511, Egypt
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Song W, Xiong X, Ge W, Zhu H. Prognostic value of protein biomarkers in liver transplantation: A systematic review. Proteomics Clin Appl 2022; 16:e2100038. [PMID: 35344271 DOI: 10.1002/prca.202100038] [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: 06/16/2021] [Revised: 01/30/2022] [Accepted: 03/22/2022] [Indexed: 12/30/2022]
Abstract
Liver transplantation is currently the preferred method for the treatment of advanced liver disease and early-stage hepatocellular carcinoma (HCC). Although advances in surgical techniques, immunosuppressive drugs and postoperative management have reduced the incidence of postoperative complications, how to effectively predict or diagnose postoperative complications earlier and reduce their incidence is still a clinical concern. We performed a comprehensive proteomics literature research to identified protein biomarkers in complications after liver transplantation. Seventeen studies met the inclusion criteria including ischemia reperfusion injury (IRI) (n = 4), acute rejection (AR) (n = 4), renal dysfunction (n = 4), HCC recurrence (n = 2), primary graft dysfunction (PGD) (n = 1), infection (n = 1), and liver fibrosis (n = 1). A total of 625 differentially expressed proteins (DEPs) have been reported between postoperative complications and controls, of which 63 have been validated by quantitative protein expression and 26 have been reported by at least two studies and showed consistently changes. The results of the bioinformation analysis show that the immune system, especially the innate immune system and cytokine signaling in immune system, is an important protein-mediated pathway that affects the prognosis of liver transplantation.
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Affiliation(s)
- Wei Song
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China
| | - Xiaofu Xiong
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China.,Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Weihong Ge
- Department of Pharmacy, Nanjing Medical Center for Clinical Pharmacy, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Huaijun Zhu
- Department of Pharmacy, Nanjing Medical Center for Clinical Pharmacy, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.,Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China
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Zhu JQ, Wang J, Li XL, Xu WL, Lv SC, Zhao X, Lang R, He Q. A combination of the percentages of IFN-γ +CD4 +T cells and granzyme B +CD19 +B cells is associated with acute hepatic rejection: a case control study. J Transl Med 2021; 19:187. [PMID: 33933100 PMCID: PMC8088570 DOI: 10.1186/s12967-021-02855-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 04/21/2021] [Indexed: 12/22/2022] Open
Abstract
Background T cells and B cells play a key role in alloimmune responses. We aimed to characterize the shift of T cell subsets and B cell subsets during acute hepatic rejection, and further determine whether they could serve as a prognostic marker. Methods Blood samples together with the clinical data from liver transplant recipients with and without acute hepatic rejection were collected and analyzed as well as from a validation cohort. Results Upon activation the expression of TGF-β and granzyme B in CD19+B cells, and the expression of IL-2 and IFN-γ in CD4+T cells were higher in acute hepatic rejection. However, only the frequencies of granzyme B+CD19+B cells and IFN-γ+CD4+T cells correlated with liver function in addition to with each other. A combination of the two cell subsets as a novel marker could classify rejection versus non-rejection (area under the curve 0.811, p = 0.001) with the cut-off value of 62.93%, which was more sensitive for worse histological changes (p = 0.027). Moreover, the occurrence rate of acute rejection was higher in the group with the novel marker > 62.93% (p = 0.000). The role of the novel marker was further confirmed in a validation cohort, which was identified to be the only significant independent risk factor for acute rejection (odds ratio: 0.923; 95% CI confidence interval: 0.885–0.964; p = 0.000). Conclusions A combination of the percentages of IFN-γ+CD4+T cells and granzyme B+CD19+B cells can distinguish rejection from non-rejection, which can be used as a potential prognostic marker for acute rejection in liver transplant recipients. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-02855-w.
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Affiliation(s)
- Ji-Qiao Zhu
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China
| | - Jing Wang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China
| | - Xian-Liang Li
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China
| | - Wen-Li Xu
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China
| | - Shao-Cheng Lv
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China
| | - Xin Zhao
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China
| | - Ren Lang
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China.
| | - Qiang He
- Department of Hepatobiliary and Pancreaticosplenic Surgery, Medical Research Center, Beijing Organ Transplant Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongtinan Road, Chaoyang District, Beijing, 100020, China.
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Thomson AW, Vionnet J, Sanchez-Fueyo A. Understanding, predicting and achieving liver transplant tolerance: from bench to bedside. Nat Rev Gastroenterol Hepatol 2020; 17:719-739. [PMID: 32759983 DOI: 10.1038/s41575-020-0334-4] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/11/2020] [Indexed: 02/07/2023]
Abstract
In the past 40 years, liver transplantation has evolved from a high-risk procedure to one that offers high success rates for reversal of liver dysfunction and excellent patient and graft survival. The liver is the most tolerogenic of transplanted organs; indeed, immunosuppressive therapy can be completely withdrawn without rejection of the graft in carefully selected, stable long-term liver recipients. However, in other recipients, chronic allograft injury, late graft failure and the adverse effects of anti-rejection therapy remain important obstacles to improved success. The liver has a unique composition of parenchymal and immune cells that regulate innate and adaptive immunity and that can promote antigen-specific tolerance. Although the mechanisms underlying liver transplant tolerance are not well understood, important insights have been gained into how the local microenvironment, hepatic immune cells and specific molecular pathways can promote donor-specific tolerance. These insights provide a basis for the identification of potential clinical biomarkers that might correlate with tolerance or rejection and for the development of novel therapeutic targets. Innovative approaches aimed at promoting immunosuppressive drug minimization or withdrawal include the adoptive transfer of donor-derived or recipient-derived regulatory immune cells to promote liver transplant tolerance. In this Review, we summarize and discuss these developments and their implications for liver transplantation.
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Affiliation(s)
- Angus W Thomson
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. .,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - Julien Vionnet
- Institute of Liver Studies, Medical Research Council (MRC) Centre for Transplantation, School of Immunology and Infectious Diseases, King's College London University, King's College Hospital, London, UK.,Transplantation Center, University Hospital of Lausanne, Lausanne, Switzerland.,Service of Gastroenterology and Hepatology, University Hospital of Lausanne, Lausanne, Switzerland
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, Medical Research Council (MRC) Centre for Transplantation, School of Immunology and Infectious Diseases, King's College London University, King's College Hospital, London, UK
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Dawood RM, Salum GM, Abd El-Meguid M, Shemis M, Abdel Aziz AO, El Awady MK. Recipient interleukin 6 gene polymorphism and expression predict HCV recurrence post liver transplantation. Gene 2020; 754:144887. [PMID: 32534059 DOI: 10.1016/j.gene.2020.144887] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 06/03/2020] [Accepted: 06/08/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Liver transplantation (LTX)is a lifesaving- effective protocol for patients suffering end stage liver disease (ESLD) and its complications post HCV infection. Recurrence of disease is a frequent clinical complication that is observed in patients undergoing LTX. Cytokines play a central role in the immunological events occurring after the surgery. METHODS Using Allelic Discrimination PCR, the allelic variation G174C of IL-6 gene was investigated. The abundance of IL6- mRNA and plasma IL6 cytokine levels were evaluated by using qRT-PCR in peripheral blood mononuclear cells (PBMCs) and enzyme-linked immunosorbent assay (ELISA) respectively in 76 liver transplant recipients recruited from Al Sahel teaching hospital, Ministry of Health and Population Cairo Egypt within the period between June 2015 and October 2017. RESULTS The frequencies of IL-6 GG genotype and the G allele were significantly detected more in LTX recipients who experienced HCV recurrence versus those who did not suffer recurrence when compared to healthy controls (P = 0.001) and (P = 0.006), respectively. On the contrary, levels of IL-6 related transcripts in PBMC's of recurrent patients were indifferent from non-recurrent patients and healthy controls (P ≥ 0.124). Interestingly, the circulating IL-6 protein in plasma was significantly elevated in recurrent as compared to the non-recurrent recipients (P = 0.002). CONCLUSION HCV recurrence post liver transplantation occur more frequently in patients with -174 G/G IL-6 genotype and elevated plasma IL-6 levels.
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Affiliation(s)
- Reham M Dawood
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth Street Dokki, Giza 12622, Egypt.
| | - Ghada M Salum
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth Street Dokki, Giza 12622, Egypt
| | - Mai Abd El-Meguid
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth Street Dokki, Giza 12622, Egypt
| | - Mohamed Shemis
- Department of Biochemistry and Molecular Biology, Theodor Bilharz Research Institute, Egypt
| | - Ashraf O Abdel Aziz
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Egypt
| | - Mostafa K El Awady
- Department of Microbial Biotechnology, Genetic Engineering Division, National Research Centre, 33 EL Bohouth Street Dokki, Giza 12622, Egypt
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Kamei H, Masuda S, Ishigami M, Nakamura T, Fujimoto Y, Takada Y, Hamajima N. Association of interleukin4 gene polymorphisms of recipients and donors with acute rejection following living donor liver transplantation. Clin Res Hepatol Gastroenterol 2016. [PMID: 26212175 DOI: 10.1016/j.clinre.2015.06.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Little is known as to whether the interleukin4 (IL4) gene polymorphisms in recipients or donors affect the incidence of acute cellular rejection (ACR) following living donor liver transplantation (LDLT). Therefore, we determined the effect of IL4 T-33C polymorphisms in recipients and donors on ACR in a large cohort of patients that underwent LDLT. METHODS We examined 155 LDLT cases treated at Nagoya University or Kyoto University, Japan, between 2004 and 2009. IL4 T-33C polymorphisms were analyzed in recipients and donors. RESULTS Forty-seven recipients (30.3%) developed early ACR. The genotype frequency of IL4 T-33C in the recipients was associated with ACR incidence (P=0.008, P<0.0125 considered significant). Patients with the IL4-33C carrier genotype (C/C or C/T) were significantly associated with a higher incidence of ACR relative to those with the T/T genotype (OR=3.27, 95% CI: 1.56-6.88, P=0.002). The genotype frequencies of IL4 T-33C in the donors were not associated with rejection incidence. In addition, there was no significant effect of IL4 T-33C genotype combinations on ACR incidence in donors and recipients. CONCLUSIONS Genotyping of IL4 T-33C in recipients might be useful to stratify the liver transplant recipients according to their risk of ACR.
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Affiliation(s)
- Hideya Kamei
- Department of Transplantation Surgery, Nagoya University, 65 Tsurumai, Showa, 466-8550 Nagoya, Japan.
| | - Satohiro Masuda
- Department of Pharmacy, Faculty of Medicine, Kyoto University, Kyoto, Japan
| | | | - Taro Nakamura
- Department of Transplantation Surgery, Nagoya University, 65 Tsurumai, Showa, 466-8550 Nagoya, Japan
| | - Yasuhiro Fujimoto
- Department of Surgery, Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Kyoto University, Kyoto, Japan
| | - Yasutsugu Takada
- Department of Surgery, Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Kyoto University, Kyoto, Japan
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Thude H, Kramer K, Peine S, Sterneck M, Nashan B, Koch M. Role of the Fyn -93A>G polymorphism (rs706895) in acute rejection after liver transplantation. Hum Immunol 2015; 76:657-62. [PMID: 26407913 DOI: 10.1016/j.humimm.2015.09.013] [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: 02/26/2015] [Revised: 09/22/2015] [Accepted: 09/22/2015] [Indexed: 10/23/2022]
Abstract
The tyrosine kinase Fyn phosphorylates tyrosine residues on key targets involved in early T-cell signal transduction. T-cell signal transduction is one essential step for acute transplant rejection. The aim of this study was to evaluate the association of Fyn -93A>G single nucleotide polymorphism (SNP) (rs706895) with the susceptibility to acute rejection episodes in liver transplantation. In total, 72 liver transplant recipients with one biopsy proven acute rejection (S-BPAR), 56 with multiple BPAR (M-BPAR), 105 without BPAR (No-BPAR), and 145 healthy controls were enrolled in this case-control study. The SNP was genotyped by polymerase chain reaction-allele specific restriction enzyme analysis (PCR-ASRA) and was analyzed for a recessive and a dominant model. The Fyn -93G allele exhibits in healthy controls a statistically significant lower frequency than in liver recipients (18% vs. 24%; p=0.046) or in liver recipients with BPAR (18% vs. 27%; p=0.017). However, the genotype and allele frequencies of the Fyn -93A>G SNP demonstrate no significant differences between recipients with acute rejection episodes (S-BPAR and M-BPAR) and No-BPAR recipients. Thus our results provide no evidence that the Fyn -93A>G SNP contributes to the susceptibility to acute liver transplant rejection in a Caucasian population.
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Affiliation(s)
- Hansjörg Thude
- University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary and Transplant Surgery, Martinistraße 52, 20246 Hamburg, Germany.
| | - Kathrin Kramer
- University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary and Transplant Surgery, Martinistraße 52, 20246 Hamburg, Germany
| | - Sven Peine
- University Medical Center Hamburg-Eppendorf, Institute for Transfusion Medicine, Martinistraße 52, 20246 Hamburg, Germany
| | - Martina Sterneck
- University Medical Center Hamburg-Eppendorf, Department of Medicine, Martinistraße 52, 20246 Hamburg, Germany
| | - Björn Nashan
- University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary and Transplant Surgery, Martinistraße 52, 20246 Hamburg, Germany
| | - Martina Koch
- University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary and Transplant Surgery, Martinistraße 52, 20246 Hamburg, Germany
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Kramer K, Thye T, Treszl A, Peine S, Koch M, Sterneck M, Nashan B, Thude H. Polymorphism in NFKBIA gene is associated with recurrent acute rejections in liver transplant recipients. ACTA ACUST UNITED AC 2014; 84:370-7. [DOI: 10.1111/tan.12411] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 06/17/2014] [Accepted: 07/07/2014] [Indexed: 01/01/2023]
Affiliation(s)
- K. Kramer
- Department of Hepatobiliary and Transplant Surgery; University Medical Center Hamburg-Eppendorf; Hamburg 20246 Germany
| | - T. Thye
- Molecular Medicine Department; Bernhard Nocht Institute for Tropical Medicine; Hamburg 20359 Germany
| | - A. Treszl
- Department of Medical Biometry and Epidemiology; University Medical Center Hamburg-Eppendorf; Hamburg 20246 Germany
| | - S. Peine
- Institute for Transfusion Medicine; University Medical Center Hamburg-Eppendorf; Hamburg 20246 Germany
| | - M. Koch
- Department of Hepatobiliary and Transplant Surgery; University Medical Center Hamburg-Eppendorf; Hamburg 20246 Germany
| | - M. Sterneck
- Department of Medicine; University Medical Center Hamburg-Eppendorf; Hamburg 20246 Germany
| | - B. Nashan
- Department of Hepatobiliary and Transplant Surgery; University Medical Center Hamburg-Eppendorf; Hamburg 20246 Germany
| | - H. Thude
- Department of Hepatobiliary and Transplant Surgery; University Medical Center Hamburg-Eppendorf; Hamburg 20246 Germany
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Mu HJ, Xie P, Chen JY, Gao F, Zou J, Zhang J, Zhang B. Association of TNF-α, TGF-β1, IL-10, IL-6, and IFN-γ gene polymorphism with acute rejection and infection in lung transplant recipients. Clin Transplant 2014; 28:1016-24. [PMID: 24974875 DOI: 10.1111/ctr.12411] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/23/2014] [Indexed: 11/28/2022]
Affiliation(s)
- Hui-jun Mu
- Department of Clinical Laboratory Science; Wuxi People's Hospital affiliated to Nanjing Medical University; Wuxi China
- Jiangsu Key laboratory of Organ Transplantation; Wuxi China
| | - Ping Xie
- Department of Clinical Laboratory Science; Wuxi People's Hospital affiliated to Nanjing Medical University; Wuxi China
- Jiangsu Key laboratory of Organ Transplantation; Wuxi China
| | - Jing-yu Chen
- Department of Thoracic Surgery; Wuxi People's Hospital affiliated to Nanjing Medical University; Wuxi China
| | - Fei Gao
- Department of Thoracic Surgery; Wuxi People's Hospital affiliated to Nanjing Medical University; Wuxi China
| | - Jian Zou
- Department of Clinical Laboratory Science; Wuxi People's Hospital affiliated to Nanjing Medical University; Wuxi China
- Jiangsu Key laboratory of Organ Transplantation; Wuxi China
| | - Ji Zhang
- Department of Thoracic Surgery; Wuxi People's Hospital affiliated to Nanjing Medical University; Wuxi China
| | - Bin Zhang
- Department of Clinical Laboratory Science; Wuxi People's Hospital affiliated to Nanjing Medical University; Wuxi China
- Jiangsu Key laboratory of Organ Transplantation; Wuxi China
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Karimi MH, Ebadi P, Pourfathollah AA. Association of cytokine/costimulatory molecule polymorphism and allograft rejection: a comparative review. Expert Rev Clin Immunol 2014; 9:1099-112. [PMID: 24168415 DOI: 10.1586/1744666x.2013.844462] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
One reason for genetic variations among human individuals is SNP which may confer diverse disease susceptibility or resistance in a population. Genetic variations in a key immunoregulatory agent can manifest various immunological responses, such as graft rejection. In fact, the outcome of organ transplantation can be impacted by several genetic causes including polymorphisms in genes encoding cytokines and costimulatory molecules in the donor or recipient. Thus, it can be helpful to contemplate the SNPs relating to these immunological determinants in order to achieve an improved transplantation therapy.
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Affiliation(s)
- Mohammad H Karimi
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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11
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Fosby B, Næss S, Hov JR, Traherne J, Boberg KM, Trowsdale J, Foss A, Line PD, Franke A, Melum E, Scott H, Karlsen TH. HLA variants related to primary sclerosing cholangitis influence rejection after liver transplantation. World J Gastroenterol 2014; 20:3986-4000. [PMID: 24744588 PMCID: PMC3983454 DOI: 10.3748/wjg.v20.i14.3986] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 02/11/2014] [Accepted: 03/10/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate influence of human leukocyte antigen (HLA) and killer immunoglobuline-like receptor (KIR) genotypes on risks of acute rejection (AR) after liver transplantation (LTX).
METHODS: In this retrospective study we included 143 adult donor-recipient pairs with a minimum of 6 mo follow-up after LTX for whom DNA was available from both donor and recipients. Clinical data, all early complications including episodes and severity of AR and graft/patient survival were registered. The diagnosis of AR was based on clinical, biochemical and histological criteria. All suspected episodes of AR were biopsy confirmed. Key classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped using Sanger sequencing. 16 KIR genes were genotyped using a novel real time PCR approach which allows for determination of the diploid copy number of each KIR gene. Immunohistochemical staining for T (CD3), B (CD20) and natural killer (NK) cells (CD56 and CD57) were performed on liver biopsies from 3 different patient groups [primary sclerosing cholangitis (PSC), primary biliary cirrhosis and non-autoimmune liver disease], 10 in each group, with similar grade of AR.
RESULTS: Fourty-four (31%) patients were transplanted on the basis of PSC, 40% of them had AR vs 24% in the non-PSC group (P = 0.04). No significant impact of donor-recipient matching for HLA and KIR genotypes was detected. In the overall recipient population an increased risk of AR was detected for HLA-B*08 (P = 0.002, OR = 2.5; 95%CI: 1.4-4.6), HLA-C*07 (P = 0.001, OR = 2.4; 95%CI: 1.4-4.0) and HLA-DRB1*03 (P = 0.03, OR = 1.9; 95%CI: 1.0-3.3) and a decreased risk for HLA-DRB1*04 (P = 0.001, OR = 0.2; 95%CI: 0.1-0.5). For HLA-B*08, HLA-C*07 and DRB1*04 the associations remained evident in a subgroup analysis of non-PSC recipients (P = 0.04, P = 0.003 and P = 0.02, respectively). In PSC recipients corresponding P values were 0.002, 0.17 and 0.01 for HLA-B*08, HLA-C*07 and DRB1*04, respectively. A dosage effect of AR prevalence according to the PSC associated HLA alleles was also notable in the total recipient population. For HLA-B*08 the frequency of AR was 56% in HLA-B*08 homozygous recipients, 39% in heterozygous recipients and 21% in recipients lacking HLA-B*08 (P = 0.02). The same was observed for the HLA-C*07 allele with AR in 57%, 27% and 18% in recipients being homozygous, heterozygous and lacking HLA-C*07 respectively (P = 0.003). Immunohistochemical analysis showed similar infiltration of T, B and NK cells in biopsies with AR in all three groups.
CONCLUSION: We found significant associations between the PSC-associated HLA-B*08, HLA-C*07, HLA-DRB1*03 and HLA-DRB1*04 alleles and risk of AR in liver transplant recipients.
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Abstract
Many of the causes of short and late morbidity following liver transplantation are associated with immunosuppression or immunosuppressive medications. Current care often involves close monitoring of liver biochemistry as well as therapeutic drug levels. However, the postoperative course following liver transplantation can often be associated with significant complications including infection and rejection, suggesting an inadequacy in current immune function monitoring. Many assays have been tested in the research setting to identify possible biomarkers that may be used to predict clinical events such as acute cellular rejection, and therefore allow modification of a patient’s immunosuppressive regimen prior to a clinical event. However, these generally require significant laboratory processing and have had difficulty becoming established in common clinical use outside the research setting. One assay, Cylex ImmuKnow has been food and drug administration approved but has had variable results. In this review we discuss the assays that have been used to assess monitoring of immune function after liver transplantation and consider possible future directions.
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Kamei H, Masuda S, Nakamura T, Ishigami M, Fujimoto Y, Ogura Y, Oike F, Takada Y, Hamajima N. Cytokine gene polymorphisms in acute cellular rejection following living donor liver transplantation: analysis of 155 donor-recipient pairs. Hepatol Int 2013. [DOI: 10.1007/s12072-013-9443-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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14
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Yao J, Feng XW, Yu XB, Xie HY, Zhu LX, Yang Z, Wei BJ, Zheng SS, Zhou L. Recipient IL-6-572C/G genotype is associated with reduced incidence of acute rejection following liver transplantation. J Int Med Res 2013; 41:356-64. [PMID: 23569034 DOI: 10.1177/0300060513477264] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE Acute rejection resulting from alloimmune responses is a major risk factor affecting patient survival following liver transplantation. Since interleukin (IL)-6 can mediate acute rejection, the association between IL-6 gene single nucleotide polymorphisms (SNPs) and incidence of acute rejection in liver transplant recipients was investigated. METHODS Patients who received liver transplant between January 2005 and December 2010 were typed for IL6-572C/G (rs1800796) polymorphisms using the snapshot technique. Association between genotype and acute rejection was analysed using the SNP Statistics website: http://bioinfo.iconcologia.net/snpstats/start.htm. Allelic and genotypic distributions for rs1800796 were compared among 335 patients with or without acute rejection within the first 6 months following liver transplant. RESULTS Incidence of acute rejection was 11.94%. A heterozygous CG genotype for IL6-572C/G was associated with a lower acute rejection rate compared with homozygous CC or GG genotypes. CONCLUSION IL6-572 CG genotype may be related to protection from acute rejection following liver transplant in Han Chinese patients.
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Affiliation(s)
- Jia Yao
- Division of Hepatobiliary and Pancreatic Surgery, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
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Kamei H, Masuda S, Nakamura T, Fujimoto Y, Oike F, Ogura Y, Takada Y, Hamajima N. Impact of glutathione S-transferase T1 gene polymorphisms on acute cellular rejection in living donor liver transplantation. Transpl Immunol 2012; 28:14-7. [PMID: 23153768 DOI: 10.1016/j.trim.2012.11.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Revised: 11/01/2012] [Accepted: 11/02/2012] [Indexed: 11/29/2022]
Abstract
It has previously been demonstrated that glutathione S-transferase T1 (GSTT1) genetic mismatch between recipient and donor is a risk factor for developing immune-mediated hepatitis following liver transplantation and for antibody-mediated rejection in renal transplantation. Little is known whether the GSTT1 gene polymorphism affects the incidence of acute cellular rejection (ACR) following living donor liver transplantation (LDLT). Patients underwent LDLT at Nagoya University or Kyoto University, Japan, between 2004 and 2009. Genotyping of GSTT1 genes (null or present genotype) was conducted in recipients and donors. A total of 155 LDLT cases were examined. Forty-seven recipients (30.3%) developed early ACR. There was no association of recipient GSTT1 genotype with ACR incidence. However, ACR incidence was significantly higher in recipients transplanted from GSTT1 present genotype donors than in those transplanted from GSTT1 null genotype donors [odds ratio (OR)=2.64, 95% confidence interval (CI)=1.12-5.83, p=0.016]. Moreover, GSTT1 recipient/donor genotype mismatch (present/null or null/present) was significantly associated with ACR development (OR=2.28, 95% CI=1.12-4.61, p=0.022). The genotyping of GSTT1 in recipients and donors might be useful to stratify the liver transplant recipients according to risk of ACR.
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Affiliation(s)
- Hideya Kamei
- Department of Transplantation Surgery, Nagoya University, Nagoya, Japan.
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16
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Brunet M. Cytokines as predictive biomarkers of alloreactivity. Clin Chim Acta 2012; 413:1354-8. [DOI: 10.1016/j.cca.2012.04.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Revised: 03/29/2012] [Accepted: 04/11/2012] [Indexed: 10/28/2022]
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17
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Liu F, Li B, Wang WT, Wei YG, Yan LN, Wen TF, Xu MQ, Yang JY. Interleukin-10-1082G/A polymorphism and acute liver graft rejection: A meta-analysis. World J Gastroenterol 2012; 18:847-54. [PMID: 22371646 PMCID: PMC3286149 DOI: 10.3748/wjg.v18.i8.847] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Revised: 09/02/2011] [Accepted: 10/28/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between interleukin (IL)-10-1082 (G/A) promoter polymorphism and acute rejection (AR) in liver transplant (LT) recipients.
METHODS: Two investigators independently searched the Medline, Embase, China National Knowledge Infrastructure, and Chinese Biomedicine Databases. Summary odds ratios (ORs) and 95% CIs for IL-10-1082 G/A polymorphism and AR were calculated in a fixed- and a random-effects model as appropriate.
RESULTS: This meta-analysis included seven case-control studies, which comprised 652 cases of LT recipients in which 241 cases developed AR and 411 cases did not develop AR. Overall, the variant A allele was not associated with AR risk when compared with the wild-type G allele (OR = 0.94, 95% CI: 0.64-1.39). Moreover, similar results were observed when the AA genotype was compared with the AG/GG genotype (OR = 1.05, 95% CI: 0.55-2.02). When stratifying for ethnicity, no significant association was observed among either Caucasians or Asians. Because only one study was performed in Asian patients, the result of subgroup analysis by ethnicity would not be reliable for Asians. Limiting the analysis to the studies with controls in the Hardy-Weinberg equilibrium, the results were persistent and robust. No publication bias was found in the present study.
CONCLUSION: This meta-analysis suggests that IL-10-1082 G/A polymorphism may be not associated with AR risk in LT recipients among Caucasians.
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18
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Fosby B, Karlsen TH, Melum E. Recurrence and rejection in liver transplantation for primary sclerosing cholangitis. World J Gastroenterol 2012; 18:1-15. [PMID: 22228965 PMCID: PMC3251800 DOI: 10.3748/wjg.v18.i1.1] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2011] [Revised: 06/15/2011] [Accepted: 06/22/2011] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic progressive inflammatory disease affecting the bile ducts, leading to fibrosis and eventually cirrhosis in most patients. Its etiology is unknown and so far no effective medical therapy is available. Liver transplantation (LTX) is the only curative treatment and at present PSC is the main indication for LTX in the Scandinavian countries. Close to half of the PSC patients experience one or more episodes of acute cellular rejection (ACR) following transplantation and approximately 1/5 of the transplanted patients develop recurrent disease in the graft. In addition, some reports indicate that ACR early after LTX for PSC can influence the risk for recurrent disease. For these important post-transplantation entities affecting PSC patients, we have reviewed the current literature on epidemiology, pathogenesis, treatment and the possible influence of rejection on the risk of recurrent disease in the allograft.
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19
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Zhang X, Wang Z, Fan J, Liu G, Peng Z. Impact of interleukin-10 gene polymorphisms on tacrolimus dosing requirements in Chinese liver transplant patients during the early posttransplantation period. Eur J Clin Pharmacol 2011; 67:803-13. [DOI: 10.1007/s00228-011-0993-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Accepted: 01/06/2011] [Indexed: 12/13/2022]
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20
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Karimi MH, Daneshmandi S, Pourfathollah AA, Geramizadeh B, Malekhosseini SA, Nikeghbalian S, Yaghobi R, Bolandparvaz S. Association of IL-6 promoter and IFN-γ gene polymorphisms with acute rejection of liver transplantation. Mol Biol Rep 2010; 38:4437-43. [PMID: 21132384 DOI: 10.1007/s11033-010-0572-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2010] [Accepted: 11/19/2010] [Indexed: 01/14/2023]
Abstract
Liver transplantation is one of the most important therapies for end-stage liver diseases and is associated with major problems including infections and acute rejection. The outcome of transplantation can be determined by immune responses as a key role in response to the graft. Inflammatory and anti-inflammatory mediators especially cytokines influence the graft microenvironment. Th1 and Th2 immune responses in contrast to regulatory responses cause acute rejection or help graft survival. In this study, we evaluated the gene polymorphisms of IL-6 G-174C, TGF-β T + 869C, IL-4 C-590T, and IFN-γ T + 874A cytokines in liver transplant patients. ARMS-PCR method was used to characterize IL-6 G-174C, TGF-β T + 869C and IFN-γ T + 874A polymorphisms and PCR-RFLP using AvaII restriction enzyme was done for IL-4 C-590T characterization in 70 liver transplant patients. Acute rejection episodes were diagnosed according to standard criteria. The analysis of the results showed that IL-6-174 GG genotype ( P = 0.009, OR = 4.333, 95% CI = 1.043-18.000), IL-6-174G allele (P = 0.011, OR = 5.273, 95% CI = 1.454-19.127) was more frequent and IFN-γ +874 TT genotype was less frequent (P = 0.043, OR = 0.143, 95% CI = 0.0118-1.190) in acute rejection than in non-rejection patients. TGF-β T + 869C and IL-4 C-590T frequencies were not significantly different (P > 0.05). According to the results, it can be conclude that IL-6 G-174C and IFN-γ T + 874A gene polymorphisms have predictive values for acute rejection after liver transplantation. High producer genotype of IL-6 is a genetic risk factor and IFN-γ is a protective factor for acute rejection development.
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21
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Azarpira N, Nikeghbalian S, Geramizadeh B, Darai M. Influence of glutathione S-transferase M1 and T1 polymorphisms with acute rejection in Iranian liver transplant recipients. Mol Biol Rep 2009; 37:21-5. [DOI: 10.1007/s11033-009-9487-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2008] [Accepted: 02/19/2009] [Indexed: 11/24/2022]
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Tredger JM, Brown NW, Dhawan A. Calcineurin inhibitor sparing in paediatric solid organ transplantation : managing the efficacy/toxicity conundrum. Drugs 2008; 68:1385-414. [PMID: 18578558 DOI: 10.2165/00003495-200868100-00004] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Despite their efficacy, the calcineurin inhibitors (CNIs) ciclosporin and tacrolimus carry a risk of debilitating adverse effects, especially nephrotoxicity, that affect the long-term outcome and survival of children who are given organ transplants. Simple reduction in dosage of CNI has little or no long-term benefit on their adverse effects, and complete withdrawal without threatening graft outcome may only be possible after liver transplantation. Until the last decade, the only option was to increase corticosteroid and/or azathioprine doses, which imposed additional long-term hazards. Considered here are the emerging generation of new agents offering an opportunity for improving long-term graft survival, minimizing CNI-related adverse events and ensuring patient well-being.A holistic, multifaceted strategy may need to be considered - initial selection and optimized use and monitoring of immunosuppressant regimens, early recognition of indicators of patient and graft dysfunction, and, where applicable, early introduction of CNI-sparing regimens facilitating CNI withdrawal. The evidence reviewed here supports these approaches but remains far from definitive in paediatric solid organ transplantation. Because de novo immunosuppression uses CNI in more than 93% of patients, reduction of CNI-related adverse effects has focused on CNI sparing or withdrawal.A recurring theme where sirolimus and mycophenolate mofetil have been used for this purpose is the importance of their early introduction to limit CNI damage and provide long-term benefit: for example, long-term renal function critically reflects that at 1 year post-transplant. While mycophenolic acid shows advantages over sirolimus in preserving renal function because the latter is associated with proteinuria, sirolimus appears the more potent immunosuppressant but also impairs early wound healing. The use of CNI-free immunosuppressant regimens with depleting or non-depleting antibodies plus sirolimus and mycophenolic acid needs much wider investigation to achieve acceptable rejection rates and conserve renal function. The adverse effects of the alternative immunosuppressants, particularly the dyslipidaemia associated with sirolimus, needs to be minimized to avoid replacing one set of adverse effects (from CNIs) with another. While we can only conjecture that judicious combinations with the second generation of novel immunosuppressants currently in development will provide these solutions, a rationale of low-dose therapy with multiple immunosuppressants acting by complementary mechanisms seems to hold the promise for efficacy with minimal toxicity until the vision of tolerance achieves reality.
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Affiliation(s)
- J Michael Tredger
- Institute of Liver Studies, King's College Hospital and King's College London School of Medicine, London, UK.
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23
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Girnita DM, Burckart G, Zeevi A. Effect of cytokine and pharmacogenomic genetic polymorphisms in transplantation. Curr Opin Immunol 2008; 20:614-25. [PMID: 18706500 PMCID: PMC2739872 DOI: 10.1016/j.coi.2008.08.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2008] [Revised: 08/01/2008] [Accepted: 08/04/2008] [Indexed: 12/13/2022]
Abstract
Consolidating the information that we have on pharmacogenetics and on cytokine genetics to produce patient-oriented individualized drug regimens is an important challenge in transplantation medicine. Using a multi-variant approach based on genetic profile and other relevant clinical factors a score system may be developed to predict the severity of rejection, infection, or other complications associated with transplantation. The ultimate goal of these studies is to improve patient outcome through individualized drug regimens.
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Affiliation(s)
- Diana M Girnita
- Department of Pathology, Thomas E Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, PA 15213
| | - Gilbert Burckart
- Office of Clinical Pharmacology, Office of Translational Science, U.S. Food and Drug Administration, Silver Spring, MD 20993
| | - Adriana Zeevi
- Department of Pathology, Thomas E Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, PA 15213
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24
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Cytokine Gene Polymorphism and Postreperfusion Syndrome During Orthotopic Liver Transplantation. Transplant Proc 2008; 40:1290-3. [DOI: 10.1016/j.transproceed.2008.01.078] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2007] [Revised: 10/08/2007] [Accepted: 01/16/2008] [Indexed: 11/18/2022]
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25
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Polymorphisms in cytokine genes and their association with acute rejection and recurrence of hepatitis B in Chinese liver transplant recipients. Arch Med Res 2008; 39:420-8. [PMID: 18375254 DOI: 10.1016/j.arcmed.2008.01.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2007] [Accepted: 01/02/2008] [Indexed: 01/14/2023]
Abstract
BACKGROUND Acute rejection (AR) and hepatitis B virus (HBV) recurrence after liver transplantation (LT) are the two major complications leading to chronic graft dysfunction. Genomic polymorphisms in interleukin (IL)-10, tumor necrosis factor (TNF)alpha and transforming growth factor (TGF)beta1 genes have been found to affect the susceptibility to certain diseases. However, the relationship between cytokine gene polymorphisms and risk of AR as well as HBV recurrence after LT in Han Chinese has not been reported. The objective of the present study was to investigate the association of polymorphisms within these cytokine genes with the risk of AR as well as HBV recurrence. METHODS One hundred eighty six Chinese LT recipients in which 41 patients developed AR and 29 patients experienced HBV recurrence were enrolled; 151 age- and gender-matched healthy individuals were selected as controls. Single-nucleotide polymorphisms (SNPs) at loci of IL-10 -1082, -819, -592, and TNFalpha -308, -238, as well as TGFbeta1 -988, -800, -509, +869, and +915 were determined by using DNA sequencing and then confirmed by restriction fragment length polymorphism (PCR-RFLP). Analyses of linkage disequilibrium and haplotype frequency were performed using Haploview program. RESULTS The -819 and -592 polymorphisms in the IL-10 gene were in complete linkage (r(2) = 1). Another linkage was found at -509 and +869 in the TGFbeta1 gene (r(2) = 0.66). A significant difference was observed in the distribution of allelic frequencies at position -819 and -592 in the IL-10 gene between ARs and non-ARs (p = 0.036, OR = 1.134, 95% CI 0.999-1.287 and p = 0.036, OR = 1.134, 95% CI 0.999-1.287, respectively). After adjustment for a Bonferroni correction, there was no significant difference between the polymorphism and AR (p >0.05). Furthermore, the overall genotype distribution between HBV recurrence patients and non-HBV recurrence patients was also not significantly different (p >0.05). CONCLUSIONS Our study suggests that gene polymorphisms of IL10, TNFalpha, and TGFbeta1 do not have a major independent role in AR and HBV recurrence after LT and may not be risk factors of AR and HBV recurrence after LT in Chinese liver transplant recipients.
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26
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Janssens ACJW, Gwinn M, Bradley LA, Oostra BA, van Duijn CM, Khoury MJ. A critical appraisal of the scientific basis of commercial genomic profiles used to assess health risks and personalize health interventions. Am J Hum Genet 2008; 82:593-9. [PMID: 18319070 PMCID: PMC2427295 DOI: 10.1016/j.ajhg.2007.12.020] [Citation(s) in RCA: 159] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2007] [Revised: 11/08/2007] [Accepted: 12/04/2007] [Indexed: 12/25/2022] Open
Abstract
Predictive genomic profiling used to produce personalized nutrition and other lifestyle health recommendations is currently offered directly to consumers. By examining previous meta-analyses and HuGE reviews, we assessed the scientific evidence supporting the purported gene-disease associations for genes included in genomic profiles offered online. We identified seven companies that offer predictive genomic profiling. We searched PubMed for meta-analyses and HuGE reviews of studies of gene-disease associations published from 2000 through June 2007 in which the genotypes of people with a disease were compared with those of a healthy or general-population control group. The seven companies tested at least 69 different polymorphisms in 56 genes. Of the 56 genes tested, 24 (43%) were not reviewed in meta-analyses. For the remaining 32 genes, we found 260 meta-analyses that examined 160 unique polymorphism-disease associations, of which only 60 (38%) were found to be statistically significant. Even the 60 significant associations, which involved 29 different polymorphisms and 28 different diseases, were generally modest, with synthetic odds ratios ranging from 0.54 to 0.88 for protective variants and from 1.04 to 3.2 for risk variants. Furthermore, genes in cardiogenomic profiles were more frequently associated with noncardiovascular diseases than with cardiovascular diseases, and though two of the five genes of the osteogenomic profiles did show significant associations with disease, the associations were not with bone diseases. There is insufficient scientific evidence to conclude that genomic profiles are useful in measuring genetic risk for common diseases or in developing personalized diet and lifestyle recommendations for disease prevention.
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Affiliation(s)
- A Cecile J W Janssens
- Department of Public Health, Erasmus MC University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
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27
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The TNF (-308A) polymorphism is associated with microchimerism in transfused trauma patients. Blood 2008; 111:3880-3. [PMID: 18199828 DOI: 10.1182/blood-2007-08-107144] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Microchimerism (MC), defined as the persistence of allogeneic cells at low concentrations, is well documented in transfused trauma patients. We hypothesized that genetic polymorphisms linked to cytokine production could contribute to trauma-induced immune modulation and development of microchimerism after transfusion of trauma patients. We used high-throughput SYBR-green-based genotyping of single nucleotide polymorphisms (SNPs) to characterize 59 transfused trauma patients, with MC (n=30) and without MC (n=29), for 4 functionally significant SNPs: TNF (-308), IL 10 (-1082), IFNG (+874), and TGFB1 (+915). We then compared likelihood for development of MC and the magnitude of immune suppression among subjects with and without these selected immune response SNPs. We identified a significant association between TNF (-308A) SNP and both development of MC and diminished immune responsiveness. Hence predisposing genetic factors may explain, in part, why only a subset of trauma patients develops transfusion-associated microchimerism.
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28
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Li D, Zhu JY, Gao J, Wang X, Lou YQ, Zhang GL. Polymorphisms of tumor necrosis factor-alpha, interleukin-10, cytochrome P450 3A5 and ABCB1 in Chinese liver transplant patients treated with immunosuppressant tacrolimus. Clin Chim Acta 2007; 383:133-9. [PMID: 17568575 DOI: 10.1016/j.cca.2007.05.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2007] [Revised: 04/17/2007] [Accepted: 05/11/2007] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cytokine production in the host immune response after transplantation may contribute to the variable CYP3A-dependent drug disposition. We investigated the effect of TNF-alpha, IL-10, CYP3A5 and ABCB1 polymorphisms on immunosuppressant tacrolimus pharmacokinetics in liver transplant patients. METHODS Genetic polymorphisms in TNF-alpha, IL-10, CYP3A5 and ABCB1 were studied in 70 liver transplant recipients and 70 donors. Tacrolimus dosage and blood concentration were investigated at 1, 2 and 3 weeks after transplantation. RESULTS The IL-10 G-1082A polymorphism in recipients was significantly associated with tacrolimus concentration/dose (C/D) ratios (IL-10-1082GG < GA < AA) within the first 3weeks posttransplantation (P < 0.05). Recipients with the capacity for low IL-10 production (-1082AA) carrying CYP3A5 non-expressor (CYP3A5()3/()3) liver had the highest C/D ratios (mean: 172.4, 161.7, 160.3 for 1, 2 and 3 weeks posttransplantation, respectively), whereas recipients with intermediate or high production of IL-10 (-1082GA or GG) engrafted with CYP3A5 expressor (CYP3A5()1 carrier) liver were found to have the lowest ratios (96.4, 78.0 and 75.4, respectively, P < 0.01). CONCLUSIONS The IL-10 G-1082A and CYP3A5()3 polymorphisms may influence the interindividual variability of tacrolimus pharmacokinetics in Chinese liver transplant patients. This finding provided a new interpretation for the variable immunosuprressant disposition after transplantation.
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Affiliation(s)
- Dan Li
- Department of Pharmacology, Basic Medical School, Beijing University, Beijing, China
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Falleti E, Fabris C, Toniutto P, Fontanini E, Cussigh A, Caldato M, Rossi E, Bitetto D, Minisini R, Smirne C, Pirisi M. Genetic polymorphisms of inflammatory cytokines and liver fibrosis progression due to recurrent hepatitis C. J Interferon Cytokine Res 2007; 27:239-46. [PMID: 17348823 DOI: 10.1089/jir.2006.0062] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
To ascertain whether single nucleotide polymorphisms (SNPs) regulating the expression of interferon-gamma (IFN-gamma), IFN-gamma receptor-1 (IFNGR-1), interleukin-6 (IL-6), IL-10, IL-18, and tumor necrosis factor-alpha (TNF-alpha) may be associated with early fibrosis progression of recurrent hepatitis C, 50 liver transplantation recipients (32 men, 18 women, median age 56 years) with a median histologic follow-up time of 54 months were studied; 98 healthy blood donors served as controls. Cytokine SNPs were determined by means of previously described PCR-based methods. On the basis of the SNP studies, a low, intermediate, or high producer cytokine phenotype was attributed to each patient. Only 1 of the 17 low IL-10 producers reached an Ishak staging score > 2, in contrast to 20 of the 33 patients who were intermediate or high IL-10 producers (Mantel-Cox, p < 0.005). Recipients who were low IL-10 producers and high IFN-gamma producers had significantly slower fibrosis progression in comparison to intermediate/high IL-10 producers and low IFN-gamma producers (p < 0.005). In conclusion, cytokine SNPs resulting in high and low producer phenotypes of both Th1 and Th2 cytokines appear to modulate the course of recurrent hepatitis C. Low IL-10 producers are those with the slowest histologic fibrosis progression.
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Affiliation(s)
- Edmondo Falleti
- Department of Pathology and Medicine Experimental and Clinical, Medical Liver Transplant Unit, University of Udine, Italy
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30
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Perrella O, Sbreglia C, Arenga G, Perrella A, Ferrara A, D'Antonio A, Di Costanzo G, Atripaldi L, Alone C, Sciano D, Cuomo O. Acute rejection after liver transplantation: Is there a specific immunological pattern? Transplant Proc 2007; 38:3594-6. [PMID: 17175341 DOI: 10.1016/j.transproceed.2006.10.102] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2006] [Indexed: 02/08/2023]
Abstract
The aim of the study was to assess various T-cell subsets and cytokine secretion patterns both in liver tissue and in the peripheral blood of 24 liver transplant patients to assess possible specific immunological involvement in early acute rejection episodes after liver transplantation. Particularly, we studied CD4+ CD7+, CD8+ CD38+, and CD4+ CD25+ T cells by flow cytometry, as well as contemporaneously, interleukin (IL)-2 and IL-10 secretion by ELISpot to determine possible Th1-like immune responses and the immunomodulation expressed by Treg cells in acute liver rejection, respectively. As a control group we included patients transplanted without acute rejection. Early acute rejection within the first 4 weeks was proven histologically in 42% of patients. It was associated with a greater expression of CD4+ CD7+ and CD8+ CD38+ T cells in the liver than in the blood (P < .001). A contemporaneous reduced expansion of liver Treg cells was evident in patients with acute rejection (P < .001). Our data suggested that a preferential Th1-like immune mechanism operated in local fashion as characterized by a decreased presence in the liver and blood of Treg cells.
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Affiliation(s)
- O Perrella
- Department of Laparascopic, Hepatic Surgery and Liver Transplant Unit, AORN, A. Cardarelli Hospital, Naples, Italy
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31
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Girnita DM, Webber SA, Ferrell R, Burckart GJ, Brooks MM, McDade KK, Chinnock R, Canter C, Addonizio L, Bernstein D, Kirklin JK, Girnita AL, Zeevi A. Disparate Distribution of 16 Candidate Single Nucleotide Polymorphisms Among Racial and Ethnic Groups of Pediatric Heart Transplant Patients. Transplantation 2006; 82:1774-80. [PMID: 17198275 DOI: 10.1097/01.tp.0000250656.33731.08] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Allograft failure in African-Americans remains higher than in Caucasians. Single nucleotide polymorphisms (SNPs) have been associated with altered allograft outcomes. METHODS In this multi-center study we compared SNP frequencies in 364 pediatric heart recipients from three ethnic/racial groups: Caucasian (n = 243), African-American (n = 39), and Hispanic (n = 82). The target genes were: tumor necrosis factor-alpha, interleukin (IL)-10, IL-6, interferon (IFN)-gamma, vascular endothelial growth factor (VEGF), transforming growth factor-beta1, Fas, FasL, granzyme B, ABCB1, CYP3A5. RESULTS Compared to Caucasians, African-Americans exhibited a higher prevalence of genotypes associated with low expression of IFN-gamma (24% vs. 45.7%, P < 0.001) and IL-10 (33% vs. 57.1%, P = 0.052). African-Americans also exhibited an increased prevalence of high IL-6 (82.9% vs. 38.1%; P < 0.001). VEGF -2578 C/C and -460 C/C genotypes were found more frequently in African-Americans and Hispanics as compared to Caucasians (P < 0.001). G/G genotype of Fas and T/T genotype of FasL were expressed more often by African-American recipients. The prevalence of Granzyme B (-295A/G) genotype was differentially distributed in the three groups. Compared with Caucasians, African-Americans were twice as likely to carry the ABCB1 2677 G/G genotype (78.6% vs. 33.7%, P < 0.0025), and they were more frequent carriers of the CYP3A5 *1/*1 genotype (35.7% vs. 0.6% in Caucasians and 7.2% in Hispanics; P < 0.001). CONCLUSION African-Americans have a genetic background that may predispose to proinflammatory/lower regulatory environment, reduced drug exposure and immunosuppressive efficacy. In this ongoing multicenter study, these gene polymorphisms differences among ethnic/racial groups are being documented so that therapeutic strategies can be devised to optimize outcomes for pediatric transplant recipients.
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Affiliation(s)
- Diana M Girnita
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
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Beaudreuil S, Samuel D, Rouas-Freiss N, Durrbach A. New aspect of immunosuppressive treatment in liver transplantation. How could you induce tolerance in liver transplantation? Transpl Immunol 2006; 17:98-107. [PMID: 17306740 DOI: 10.1016/j.trim.2006.11.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2006] [Accepted: 11/10/2006] [Indexed: 12/13/2022]
Abstract
New immunosuppressive strategies have improved short- and long-term graft survival. The current aim is to decrease the intensity of the immunosuppressive regimen, in an attempt to limit side effects and the direct toxicity of calcineurin inhibitor (CNI) for kidney function. We describe here current experience in liver and liver-kidney transplantation, the mechanism of tolerance and the immunosuppressive strategy used in liver transplantation.
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Affiliation(s)
- Severine Beaudreuil
- Department of Nephrology, IFRNT University Hospital of Kremlin-Bicetre, 78 avenue du General Leclerc, 94275 Le Kremlin-Bicetre cedex, France
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Moya-Quiles MR, Alvarez R, Miras M, Gomez-Mateo J, Lopez-Alvarez MR, Marin-Moreno I, Martínez-Barba E, Sanchez-Mozo MPS, Gomez M, Arnal F, Sanchez-Bueno F, Marin LA, Garcia-Alonso AM, Minguela A, Muro M, Parrilla P, Alonso C, Alvarez-López MR. Impact of recipient HLA-C in liver transplant: a protective effect of HLA-Cw*07 on acute rejection. Hum Immunol 2006; 68:51-8. [PMID: 17207712 DOI: 10.1016/j.humimm.2006.10.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2006] [Revised: 10/05/2006] [Accepted: 10/13/2006] [Indexed: 01/09/2023]
Abstract
The involvement of the human leukocyte antigen (HLA) in liver graft acceptance is controversial, but the frequency of acute rejection (AR) remains high in spite of the use of the modern immunosuppressive agents. The present study was aimed at determining whether an association exists between liver recipient HLA-C polymorphism and AR development that could influence graft acceptance. Four hundred and forty-six liver recipients and 473 controls were studied within the framework of a collaborative study carried out by the Spanish Transplant Immunotolerance Group (RED-GIT). HLA-A and -B were typed by the standard microlymphocytotoxicity technique, and HLA-C by polymerase chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP). A statistically significant decrease in the HLA-Cw*07 allele frequency was found in liver recipients suffering AR episodes compared to those without AR (NAR). Studies regarding the possible influence of the Asn80 and Lys80 epitopes showed that the Asn80 epitope also could be associated with AR. However, further analysis considering Asn80 alleles others than HLA-Cw*07, confirmed that the apparent protective effect of the Asn80 epitope was actually from the HLA-Cw*07 allele. In conclusion, the HLA-Cw*07 allele carried by the liver recipient is negatively associated with AR development, and could be considered a predictive factor for liver graft acceptance.
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Affiliation(s)
- Maria R Moya-Quiles
- Immunology Service, University Hospital Virgen de la Arrixaca, 30120 El Palmar, Murcia, Spain
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Gómez-Mateo J, Marin L, López-Alvarez MR, Moya-Quiles MR, Miras M, Marin-Moreno I, Botella C, Parrilla P, Alvarez-López MR, Muro M. TGF-beta1 gene polymorphism in liver graft recipients. Transpl Immunol 2006; 17:55-7. [PMID: 17157217 DOI: 10.1016/j.trim.2006.09.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2006] [Accepted: 09/13/2006] [Indexed: 11/25/2022]
Abstract
Cytokines are known to be important mediators during liver graft outcome and their gene polymorphism could affect the overall expression and secretion of cytokines. In this retrospective study, we analyzed the effect of TGF-beta1 polymorphism in 150 liver allograft recipients. Genotyping PCR-SSP were performed for TGF-beta1 gene (codon 10T/C and 25C/G). TGF-beta1 polymorphism at codon 10 and 25 correlate borderline with liver graft acceptance and when the combination between codon 10 and 25 was analyzed, it revealed that T/T G/C genotype and the TC haplotype were significantly associated with graft acceptance (p<0.05). TGF-beta1 high secretor phenotype was also increased in the acute rejection group close to significance (p=0.06). In conclusion, these findings show a correlation between TGF-beta1 gene polymorphism and liver graft acceptance.
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Affiliation(s)
- Jorge Gómez-Mateo
- Immunology, Hospital Universitario Virgen de la Arrixaca, 30120 Murcia, Spain
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Wieërs G, Gras J, Bourdeaux C, Truong DQ, Latinne D, Reding R. Monitoring tolerance after human liver transplantation. Transpl Immunol 2006; 17:83-93. [PMID: 17306738 DOI: 10.1016/j.trim.2006.09.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2006] [Accepted: 09/13/2006] [Indexed: 01/25/2023]
Abstract
The validation of reliable, non-invasive immunological assays evaluating anti-donor responsiveness in allograft recipients would provide a clinically relevant tool for the early detection of ongoing rejection process as well as for the identification of operational tolerance in the long term. A sequential approach towards immunological monitoring of allografts is proposed in this review: (i) investigations exploring the initial donor-recipient alloresponses, including the analysis of the cytokine network; (ii) investigations regarding graft acceptance and operational tolerance in long-term transplant patients, consisting in the analysis of regulatory T cells and of circulating precursors of dendritic cells, in the measurement of T cell alloreactivity as well as in the study of T cell receptor repertoires. Beside the conventional in vivo and in vitro immunological techniques, the potential applications of molecular imaging in transplantation also deserve further exploration, with particular respect to allograft immune monitoring. Enforced collaboration between transplant clinicians and immunologists will be required to develop the translational research protocols required for the development of immunological monitoring, within an international multicentric network.
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Affiliation(s)
- Grégoire Wieërs
- Pediatric Liver Transplant Program, Saint-Luc University Clinics, Université catholique de Louvain, Brussels, Belgium
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Corti B, Altimari A, Gabusi E, Pinna AD, Gruppioni E, Lauro A, Pirini MG, Fiorentino M, Ridolfi L, Grigioni WF, Grigioni AD. Two Years’ Experience of Acute Rejection Monitoring of Intestinal Transplant Recipients by Real-Time PCR Assessment of Granzyme B and Perforin Up-Regulation: Considerations on Diagnostic Accuracy. Transplant Proc 2006; 38:1726-7. [PMID: 16908262 DOI: 10.1016/j.transproceed.2006.05.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Granzyme B (GrB) and perforin are promising immunological markers to predict acute rejection of transplanted organs. Based on 2 years of experience with molecular monitoring on peripheral blood samples, we investigated the diagnostic accuracy of GrB/perforin gene up-regulation using real-time polymerase chain reaction (PCR) for prediction of acute cellular rejection (ACR) in intestinal transplantation recipients. Histology used as the reference standard. According to our definition of disease positivity (anything other than ACR score 0), GrB/perforin up-regulation showed 84% specificity but only 49% sensitivity. However, among the 26 false-negatives, 12 (46%) had an ACR score 1, which is indeterminate for rejection and no associated clinical manifestations; a further 10 (39%) had a score of 2 following rejection therapy (a confounder for GrB/perforin analysis). Thus only 4 (15%) false-negatives were actually associated with the onset of robust acute rejection. These data suggest that real-time PCR analysis for GrB/perforin up-regulation might play a role along with clinical criteria for detection of presymptomatic acute rejection episodes in intestinal recipients who require immediate endoscopy and pathological examination, especially during long-term follow-up.
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Affiliation(s)
- B Corti
- Pathology Division, Felice Addarii Institute, S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Viale Ercolani 4/2, 40138 Bologna, Italy
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Burckart GJ, Hutchinson IV, Zeevi A. Pharmacogenomics and lung transplantation: clinical implications. THE PHARMACOGENOMICS JOURNAL 2006; 6:301-10. [PMID: 16520825 DOI: 10.1038/sj.tpj.6500376] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- G J Burckart
- Department of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA.
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Reding R, Gras J, Truong DQ, Wieërs G, Latinne D. The immunological monitoring of alloreactive responses in liver transplant recipients: a review. Liver Transpl 2006; 12:373-83. [PMID: 16498661 DOI: 10.1002/lt.20704] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The aim of this work is to review the current knowledge in the field of immunological monitoring of allogenic responsiveness in clinical liver transplantation. When compared to other solid-organ transplants, liver allografts are considered as immunologically privileged, and, accordingly, constitute a favorable setting to develop experimental as well as clinical strategies for minimization of immunosuppression and even induction of operational tolerance. The validation of simple, reliable, noninvasive assays exploring antidonor alloreactivity will constitute a crucial step toward implementing such approaches in the clinic. In contrast to research in rodents claiming the development of donor-specific tolerance in case of graft survivals of over 100 days without immunosuppression, it is impractical to confirm tolerance induction in this way in humans. Promising candidate assays include the detection of post-transplant immune deviation, of circulating precursors of dendritic cells subtypes, and of regulatory T cells. A conceptual framework for the development of tolerance assays in clinical liver transplantation is also proposed.
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Affiliation(s)
- Raymond Reding
- Pediatric Liver Transplant Program, Saint-Luc University Clinics, Université Catholique de Louvain, Brussels, Belgium.
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Dei Malatesta MF, Rossi M, Rocca B, Iappelli M, Giorno MP, Berloco P, Cortesini R. Pregnancy after liver transplantation: report of 8 new cases and review of the literature. Transpl Immunol 2006; 15:297-302. [PMID: 16635752 DOI: 10.1016/j.trim.2006.01.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2005] [Accepted: 01/13/2006] [Indexed: 01/01/2023]
Abstract
Improved survival and quality of life following liver transplantation are associated with an increased frequency of pregnancies in liver-transplanted women. We investigated the outcome, complications, and management of those pregnancies. We have reviewed the literature and report 8 pregnancies in 6 transplant recipients. Seven pregnancies were completed at 38+/-2 (mean+/-standard deviation) weeks. One miscarriage occurred at week 12. Newborns' weight averaged 2938+/-156 g. Main complications were preeclampsia (n=1) and reversible cholestasis (n=1). Among 285 pregnancies reported in literature, 78+/-20% were successful and the main complications were: preeclampsia (26+/-19%), hypertension (28+/-19%), reversible liver dysfunction (27+/-21%), cesarean delivery (23+/-10%), preterm birth (31+/-28%), small for gestational age infants (23+/-10%), rejection (10+/-7%). Gestational weeks were 36.7+/-1.3, perinatal mortality was 4+/-10%, malformation rate 3%. The rates of both abortions and complications (preeclampsia and/or hypertension) were inversely related to the time interval between transplantation and conception (p<0.05). Abortions occurred more often in recipients whose underlying disease was autoimmune cirrhosis than in recipients with inherited disorders. Rejection rate was approx. 10%, which appears higher than reported in a non-pregnant population after a comparable time interval from transplant (2-3%). Up to 28 months after delivery, maternal death was 5.5+/-7%. We conclude that: the time intervals between transplantation and conception as well as the original cause of liver failure influence the outcome and complications of pregnancies in liver recipients. However, neonatal survival is high, while malformations are relatively rare.
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Dmitrienko S, Hoar DI, Balshaw R, Keown PA. Immune Response Gene Polymorphisms in Renal Transplant Recipients. Transplantation 2005; 80:1773-82. [PMID: 16378074 DOI: 10.1097/01.tp.0000184624.54005.9f] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND T-cell activation and regulation are under genetic control and vary between individuals. However, the influence of functional immune response gene polymorphisms on transplant outcomes remains controversial. METHODS A case-control design compared 100 white renal transplant recipients with or without acute graft rejection during the first year posttransplant and 50 normal controls. The polymorphic frequencies of the T-cell signaling genes CD45, CD40L and CTLA-4, and the cytokine genes TNF-alpha, IFN-gamma, IL-10 and TGF-beta1 were studied. The primary analysis examined rejection risk, and subsidiary analyses graft failure and patient death. RESULTS Multivariate analysis showed no significant association between acute rejection and single nucleotide polymorphisms in CTLA-4, TGF-beta1, IL-10 or TNF-alpha genes or dinucleotide repeat polymorphisms in IFN-gamma and CD40L genes. Allele CD40L-147 was associated with reduced graft failure (P=0.004), and TGFb-25pro with increased graft failure (P=0.0007), although the latter showed a bidirectional dose effect. There was no significant association between patient death and any polymorphisms in the genes examined. The variant (G) allele of the CD45 gene was not detected in the study population. Minor differences in carriage rates observed by univariate analysis did not predict graft or patient outcome in multivariate analysis. CONCLUSION The primary analysis demonstrated no significant association between the immune response gene polymorphisms examined and acute renal graft rejection in Caucasian patients receiving triple immunosuppression. Subsidiary analyses suggesting an influence of CD40L and TGFbeta1 genes on graft survival require independent confirmation.
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Affiliation(s)
- Svetlana Dmitrienko
- Immunology Laboratory, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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Corti B, Altimari A, Gabusi E, Pinna AD, Lauro A, Morselli-Labate AM, Gruppioni E, Pirini MG, Fiorentino M, Ridolfi L, Grigioni WF, D'Errico-Grigioni A. Potential of Real-Time PCR Assessment of Granzyme B and Perforin Up-Regulation for Rejection Monitoring in Intestinal Transplant Recipients. Transplant Proc 2005; 37:4467-71. [PMID: 16387147 DOI: 10.1016/j.transproceed.2005.11.035] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Granzyme B (GrB) and perforin are promising markers to predict acute rejection episodes of transplanted organs. Having recently reported that immunohistochemical expression of GrB/perforin correlates with histologically assessed acute cellular rejection (ACR) episodes in intestinal transplantation recipients, herein we have additionally explored the potential of real-time polymerase chain reaction (PCR) assessment of GrB/perforin gene up-regulation in peripheral blood mononuclear cells. Both immunohistochemical evaluation of GrB/perforin expression and real-time PCR assessment of up-regulation, which was defined as a 2-fold increase with respect to "basal" levels during maintenance immunosuppressive protocols, were performed among a population of 23 intestinal transplant recipients under routine surveillance, in addition to histological analysis of ACR. The ACR scores showed direct relationships both with GrB/perforin immunohistochemistry (IHC) scores (P < .001) and with gene up-regulation by real-time PCR (P = .004). Furthermore, real-time PCR upregulation was associated with the IHC score (P < .001). A preliminary analysis of diagnostic accuracy-performed to gain information to plan future studies-indicated that when using histological assessment as the reference technique, our current definition of PCR up-regulation provided good specificity (84%) but insufficient sensitivity (44%) for a noninvasive prediction of ACR. The results of this pilot study suggested that real-time PCR analysis of GrB/perforin upregulation may help therapeutic decision making, and have the potential for detection of presymptomatic rejection. More extensive studies must investigate strategies to improve the sensitivity of the analyses of GrB/perforin up-regulation.
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Affiliation(s)
- B Corti
- Department of Oncology and Hematology, University of Bologna, Bologna, Italy
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Bradley BA. Prognostic assays for rejection and tolerance in organ transplantation. Transpl Immunol 2005; 14:193-201. [PMID: 15982563 DOI: 10.1016/j.trim.2005.03.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2005] [Indexed: 10/25/2022]
Abstract
In this review, I have summarised our understanding of acute rejection of organ transplants, and for convenience I have identified three processes, recognition, rejection and regulation. In stark contrast to this text-book picture of acute rejection, I have drawn attention to some of the clinical realities, where processes are altered by powerful immunosuppressive drugs, and where many transplant recipients are pre-sensitised to transplantation antigens prior to engraftment. The ultimate goal is to encourage the emergence of a utopian immunological state, wherein patients tolerate organ transplants for life after being weaned from all immunosuppressive drugs. Assays that may be used in the future to reliably monitor this process are still at a very exciting stage of development.
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Affiliation(s)
- Benjamin A Bradley
- The East Barn, The Pound, Lower Almondsbury, Bristol BS32 4EF, England, United Kingdom.
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Perrella O, Sbreglia C, Perrella A, Cuomo O, Perrella M. Immune response and liver transplantation. Liver Transpl 2005; 11:1147; author reply 1148-9. [PMID: 16123961 DOI: 10.1002/lt.20488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Rizzo R, Hviid TVF, Stignani M, Balboni A, Grappa MT, Melchiorri L, Baricordi OR. The HLA-G genotype is associated with IL-10 levels in activated PBMCs. Immunogenetics 2005; 57:172-81. [PMID: 15900488 DOI: 10.1007/s00251-005-0788-0] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2005] [Accepted: 02/03/2005] [Indexed: 01/14/2023]
Abstract
Human leukocyte antigen (HLA)-G is an MHC class Ib molecule that is expressed at the feto-maternal interface during pregnancy. However, recent results have also shown that it may have important functions as an immuno-modulatory factor in adult life. Differences in the pattern of alternative splicing and in the stability of HLA-G mRNA transcripts have been associated with HLA-G polymorphisms, especially a 14 bp deletion/insertion polymorphism in the 3' untranslated region of the HLA-G gene. We have investigated the secretion of HLA-G5/soluble HLA-G1 and interleukin-10 (IL-10) in lipopolysaccharide (LPS)-activated peripheral blood mononuclear lymphocytes (PBMCs) in relation to the HLA-G 14 bp genotype. No HLA-G5/sHLA-G1 could be detected in the non-activated control PBMC culture media, and there were no significant differences among the three HLA-G 14 bp genotypes regarding IL-10 concentrations. In LPS-activated PBMC cultures, no significant differences among the three HLA-G 14 bp genotypes regarding HLA-G5/sHLA-G1 concentrations were observed. However, this was in contrast to the IL-10 levels (P=0.0004, Kruskal-Wallis test). The +14/+14 bp PBMC samples expressed higher levels of IL-10 when compared to the -14/+14 bp genotype and the -14/-14 bp genotype. Interestingly, the IL-10 G/G polymorphism at position -1082 was more frequent in the +14/+14 bp genotype (P=0.024, chi2 test). These results support an autocrine loop between HLA-G5/sHLA-G1 and IL-10 expression in activated PBMCs, which may result in higher IL-10 levels in +14/+14 bp HLA-G genotypes.
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Affiliation(s)
- Roberta Rizzo
- Department of Experimental and Diagnostic Medicine, University of Ferrara, Via Luigi Borsari 46, 44100 Ferrara, Italy.
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