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Carmona P, Medina-Armenteros Y, Cabral A, Monteiro SM, Gonçalves Fonseca S, Faria AC, Lemos F, Saitovitch D, Noronha IL, Kalil J, Coelho V. Regulatory/inflammatory cellular response discrimination in operational tolerance. Nephrol Dial Transplant 2019; 34:2143-2154. [PMID: 31280312 DOI: 10.1093/ndt/gfz114] [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: 05/18/2018] [Accepted: 05/03/2019] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Antigen-specific cellular response is essential in immune tolerance. We tested whether antigen-specific cellular response is differentially modulated in operational tolerance (OT) in renal transplantation with respect to critical antigenic challenges in allotransplantation-donor antigens, pathogenic antigens and self-antigens. METHODS We analysed the profile of immunoregulatory (REG) and pro-inflammatory (INFLAMMA) cytokines for the antigen-specific response directed to these three antigen groups, by Luminex. RESULTS We showed that, in contrast to chronic rejection and healthy individuals, OT gives rise to an immunoregulatory deviation in the cellular response to donor human leucocyte antigen DR isotype peptides, while preserving the pro-inflammatory response to pathogenic peptides. Cellular autoreactivity to the N6 heat shock protein 60 (Hsp60) peptide also showed a REG profile in OT, increasing IL4, IL-5, IL-10 and IL-13. CONCLUSIONS The REG shift of donor indirect alloreactivity in OT, with inhibition of interleukin (IL)-1B, IL-8, IL-12, IL-17, granulocyte colony-stimulating factor, Interferon-γ and monocyte chemoattractant protein-1, indicates that this may be an important mechanism in OT. In addition, the differential REG profile of cellular response to the Hsp60 peptide in OT suggests that REG autoimmunity may also play a role in human transplantation tolerance. Despite cross-reactivity of antigen-specific T cell responses, a systemic functional antigen-specific discrimination takes place in OT.
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Affiliation(s)
- Priscila Carmona
- Laboratório de Imunologia, Instituto do Coração (InCor), Universidade de São Paulo, Faculdade de Medicina, São Paulo, SP, Brazil.,Instituto de Investigação em Imunologia-Instituto Nacional de Ciências e Tecnologia-iii-INCT, Brazil
| | - Yordanka Medina-Armenteros
- Laboratório de Imunologia, Instituto do Coração (InCor), Universidade de São Paulo, Faculdade de Medicina, São Paulo, SP, Brazil.,Instituto de Investigação em Imunologia-Instituto Nacional de Ciências e Tecnologia-iii-INCT, Brazil
| | - Amanda Cabral
- Laboratório de Imunologia, Instituto do Coração (InCor), Universidade de São Paulo, Faculdade de Medicina, São Paulo, SP, Brazil.,Instituto de Investigação em Imunologia-Instituto Nacional de Ciências e Tecnologia-iii-INCT, Brazil
| | - Sandra Maria Monteiro
- Laboratório de Imunologia, Instituto do Coração (InCor), Universidade de São Paulo, Faculdade de Medicina, São Paulo, SP, Brazil.,Instituto de Investigação em Imunologia-Instituto Nacional de Ciências e Tecnologia-iii-INCT, Brazil
| | - Simone Gonçalves Fonseca
- Instituto de Investigação em Imunologia-Instituto Nacional de Ciências e Tecnologia-iii-INCT, Brazil.,Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, GO, Brazil
| | - Ana Caetano Faria
- Instituto de Investigação em Imunologia-Instituto Nacional de Ciências e Tecnologia-iii-INCT, Brazil.,Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Francine Lemos
- Serviço de Transplante Renal, Universidade de São Paulo, Faculdade de Medicina, São Paulo, SP, Brazil
| | - David Saitovitch
- Divisão de Nefrologia, Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Irene L Noronha
- Instituto de Investigação em Imunologia-Instituto Nacional de Ciências e Tecnologia-iii-INCT, Brazil.,Laboratório de Nefrologia Celular e Molecular, Divisão de Nefrologia, Universidade de São Paulo, Faculdade de Medicina, São Paulo, SP, Brazil
| | - Jorge Kalil
- Laboratório de Imunologia, Instituto do Coração (InCor), Universidade de São Paulo, Faculdade de Medicina, São Paulo, SP, Brazil.,Instituto de Investigação em Imunologia-Instituto Nacional de Ciências e Tecnologia-iii-INCT, Brazil
| | - Verônica Coelho
- Laboratório de Imunologia, Instituto do Coração (InCor), Universidade de São Paulo, Faculdade de Medicina, São Paulo, SP, Brazil.,Instituto de Investigação em Imunologia-Instituto Nacional de Ciências e Tecnologia-iii-INCT, Brazil
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Yu X, Wei B, Su R, Yao J, Feng X, Jiang G, Xie H, Wu J, Xu X, Zhang M, Zheng S, Zhou L. A risk assessment model of acute liver allograft rejection by genetic polymorphism of CD276. Mol Genet Genomic Med 2019; 7:e689. [PMID: 31044564 PMCID: PMC6603397 DOI: 10.1002/mgg3.689] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 03/01/2019] [Accepted: 03/01/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Liver transplantation is an effective therapy for end-stage liver diseases and acute liver failure. After the operation, however, recipients may suffer grafts loss induced by alloimmune reaction, which is termed as acute allograft rejection. The interaction between costimulatory molecules, CD276, and its ligand, TREML2, promotes T cell-mediated immune response, as well as acute or chronic allograft rejection. Our research aimed at correlating genetic polymorphisms of CD276/TREML2 with acute rejection, and evaluating its prognostic value of acute rejection after liver transplantation. METHODS The study enrolled a total of 388 recipients. Among them, acute allograft rejection was observed in 54 cases. We performed single nucleotide polymorphism genotyping of CD276, including rs11072431, rs11574495, rs12593558, rs12594627, rs2127015, rs3816661 and rs7176654, and TREML2, including rs4714431, rs6915083, rs7754593, and rs9394767 from preoperative peripheral blood genome DNA. RESULTS We found rs2127015 of CD276, rs6915083 and rs7754593 of TREML2, and HBV infection as well were associated with acute rejection. And, rs2127015 influences CD276 expression. Moreover, we established a risk assessment model, composited by statistically proved risk factors. CONCLUSION By integrating both clinical and genetic variables, liver transplant recipients can be categorized into different risk groups, and might benefit from individualized therapies.
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Mirzakhani M, Shahbazi M, Oliaei F, Mohammadnia-Afrouzi M. Immunological biomarkers of tolerance in human kidney transplantation: An updated literature review. J Cell Physiol 2018; 234:5762-5774. [PMID: 30362556 DOI: 10.1002/jcp.27480] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 09/06/2018] [Indexed: 12/11/2022]
Abstract
The half-life of transplanted kidneys is <10 years. Acute or chronic rejections have a negative impact on transplant outcome. Therefore, achieving to allograft tolerance for improving long-term transplant outcome is a desirable goal of transplantation field. In contrast, there are evidence that distinct immunological characteristics lead to tolerance in some transplant recipients. In contrast, the main reason for allograft loss is immunological responses. Various immune cells including T cells, B cells, dendritic cells, macrophages, natural killer, and myeloid-derived suppressor cells damage graft tissue and, thereby, graft loss happens. Therefore, being armed with the comprehensive knowledge about either preimmunological or postimmunological characteristics of renal transplant patients may help us to achieve an operational tolerance. In the present study, we are going to review and discuss immunological characteristics of renal transplant recipients with rejection and compare them with tolerant subjects.
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Affiliation(s)
- Mohammad Mirzakhani
- Student Research Committee, School of Medicine, Babol University of Medical Sciences, Babol, Iran.,Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mehdi Shahbazi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Farshid Oliaei
- Kidney Transplantation Center, Shahid Beheshti Hospital, Babol University of Medical Sciences, Babol, Iran
| | - Mousa Mohammadnia-Afrouzi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
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4
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Shahbazi M, Soltanzadeh-Yamchi M, Mohammadnia-Afrouzi M. T cell exhaustion implications during transplantation. Immunol Lett 2018; 202:52-58. [PMID: 30130559 DOI: 10.1016/j.imlet.2018.08.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 08/05/2018] [Accepted: 08/16/2018] [Indexed: 12/20/2022]
Abstract
Exhaustion of lymphocyte function, particularly T cell exhaustion, due to prolonged exposure to a high load of foreign antigen is commonly seen during chronic viral infection as well as antitumor immune responses. This phenomenon has been associated with a determined molecular mechanism and phenotypic manifestations on the cell surface. In spite of investigation of exhaustion, mostly about CD8 responses toward viral infections, recent studies have reported that chronic exposure to antigen may develop exhaustion in CD4 + T cells, B cells, and NK cells. Little is known with respect to lymphocyte exhaustion during transplantation and its effect on aberrant anti-graft responses. Through a same mechanobiology observed during chronic exposure of foreign viral antigens, alloantigen persistence mediated by allograft could develop a favorable circumstance for exhaustion of T cells responding to allograft. However, to achieve better manipulation approaches of this event to reduce the complications during transplantation, we need to be armed with a bulk of knowledge with regard to quality and quantity of T cell exhaustion occurring in various allografts, the kinetics of exhaustion development, the impression of immunosuppressive agents on the exhaustion, and the influence of exhaustion on graft survival and immune tolerance.
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Affiliation(s)
- Mehdi Shahbazi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mehdi Soltanzadeh-Yamchi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mousa Mohammadnia-Afrouzi
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran.
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5
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Xu CX, Shi BY, Jin ZK, Hao JJ, Duan WL, Han F, Zhao YL, Ding CG, Xue WJ, Ding XM, Zheng J, Tian PX. Multiple-biomarkers provide powerful prediction of early acute renal allograft rejection by combination of serum fractalkine, IFN-γ and IP-10. Transpl Immunol 2018; 50:68-74. [PMID: 30081186 DOI: 10.1016/j.trim.2018.08.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 07/29/2018] [Accepted: 08/02/2018] [Indexed: 01/10/2023]
Abstract
Biomarkers are urgently required for predicting rejection so that anti-rejection treatment can be taken early to protect the allograft from irreversible damage. We hypothesized that the combination of circulating fractalkine, IFN-γ and IP-10 might serve as effective biomarkers for predicting early acute renal allograft rejection. We conducted a retrospective study of 87 subjects, who were classified into acute rejection group (ARG; n = 38) and non-rejection group (NRG; n = 49). Serum fractalkine, IFN-γ and IP-10 levels were measured by Luminex. The levels of fractalkine on day 0 and 7th day, IP-10 on 4th and 7th day, and IFN-γ on 7th day in ARG was significantly higher than that in NRG. Kaplan-Meier survival analysis highlighted the higher-levels groups of fractalkine on day 0, 4th and 7th day, IFN-γ on day 0, 1st, 4th, and 7th day and IP-10 on the 4th and 7th day in rejection-free survival probability were significantly lower than low-levels groups. ROC analyses highlight the superiority of fractalkine on day 0, IP-10 on day 0, 4th and 7th day, and IFN-γ on day 0, 1st and 7th day in prediction of acute rejection. We found the combination of fractalkine on day 0, IP-10 on 7th day and IFN-γ on 7th day had the highest AUC (0.866) for predicting rejection with a sensitivity of 86.8% and a specificity of 89.8%. Our findings demonstrated a more powerful prediction of early acute renal allograft rejection during the first month after transplantation by combination of multiple-biomarkers of fractalkine, IFN-γ and IP-10, and the results might help stratify the immunologic risk of acute allograft rejection in recipients.
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Affiliation(s)
- Cui-Xiang Xu
- Department of Kidney Transplantation, Hospital of Nephropathy, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, People's Republic of China; Center of Shaanxi Provincial Clinical Laboratory, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
| | - Bin-Ya Shi
- Department of Primary Medical Service, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
| | - Zhan-Kui Jin
- Department of Orthopaedics, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
| | - Jun-Jun Hao
- Department of Cardiac Surgery, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Wan-Li Duan
- Department of Urology, Shaanxi Provincial People's Hospital, Xi'an, People's Republic of China
| | - Feng Han
- Department of Kidney Transplantation, Hospital of Nephropathy, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, People's Republic of China; Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Yan-Long Zhao
- Department of Kidney Transplantation, Hospital of Nephropathy, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, People's Republic of China; Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Cheng-Guang Ding
- Department of Kidney Transplantation, Hospital of Nephropathy, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, People's Republic of China; Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Wu-Jun Xue
- Department of Kidney Transplantation, Hospital of Nephropathy, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, People's Republic of China; Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Xiao-Ming Ding
- Department of Kidney Transplantation, Hospital of Nephropathy, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, People's Republic of China; Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Jin Zheng
- Department of Kidney Transplantation, Hospital of Nephropathy, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, People's Republic of China; Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Pu-Xun Tian
- Department of Kidney Transplantation, Hospital of Nephropathy, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, People's Republic of China; Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
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6
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Mathew JM, Ansari MJ, Gallon L, Leventhal JR. Cellular and functional biomarkers of clinical transplant tolerance. Hum Immunol 2018; 79:322-333. [PMID: 29374560 DOI: 10.1016/j.humimm.2018.01.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 01/20/2018] [Accepted: 01/22/2018] [Indexed: 12/16/2022]
Abstract
Development of tolerance protocols requires assays or biomarkers that distinguish tolerant recipients from non-tolerant ones to be established. In addition, a thorough understanding of the plausible mechanisms associated with clinical transplant tolerance is necessary to take the field forward. Unlike the majority of molecular signature analyses utilized by others, the emphasis of this article is on the cellular and functional biomarkers of induced transplant tolerance. Immunity to an organ transplant is very complex, comprised of two broad categories - innate and acquired or adaptive immune responses. Innate immunity can be avoided by eliminating or preventing ischemic injuries to the donor organ and tolerance at the level of adaptive immunity can be induced by infusions of a number of cellular products. Since adaptive immune response consists of inflammatory hypersensitivity, cellular (cytotoxic and helper) and humoral aspects, all these need to be measured, and the recipients who demonstrate donor-specific unresponsiveness in all can be considered tolerant or candidates for immunosuppression minimization and/or withdrawal. The mechanisms by which these agents bring about transplant tolerance include regulation, anergy, exhaustion, senescence and deletion of the recipient immune cells. Another proven mechanism of tolerance is full or mixed donor chimerism. However, it should be cautioned that non-deletional tolerance can be reversed.
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Affiliation(s)
- James M Mathew
- Department of Surgery - Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA; Department of Microbiology-Immunology, Northwestern University, Chicago, IL, USA.
| | - Mohammed Javeed Ansari
- Department of Surgery - Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA; Department of Medicine-Nephrology, Northwestern University, Chicago, IL, USA
| | - Lorenzo Gallon
- Department of Surgery - Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA; Department of Medicine-Nephrology, Northwestern University, Chicago, IL, USA
| | - Joseph R Leventhal
- Department of Surgery - Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA
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Takeuchi A, Kato K, Akashi K, Eto M. Cyclophosphamide-induced tolerance in kidney transplantation avoids long-term immunosuppressive therapy. Int J Urol 2017; 25:112-120. [PMID: 29105189 DOI: 10.1111/iju.13474] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 08/22/2017] [Indexed: 12/28/2022]
Abstract
There has recently been remarkable progress in immunosuppressive agents, such as tacrolimus and cyclosporine. Therefore, the rate of organ establishment has improved in transplantation. However, immunosuppressive agents generally suppress the function of T cells. Thus, opportunistic infections, such as cytomegalovirus infection, are still a major problem in kidney transplantation. Induction of specific tolerance to avoid immunosuppressive drug therapy after kidney transplantation is considered as the ultimate goal of transplantation. Various factors induce tolerance that involves establishment of hematopoietic chimerism and various cell subsets. In particular, we have carried out various studies regarding the cyclophosphamide-induced tolerance system. Tolerance is induced after establishment of hematopoietic chimerism after donor bone marrow transplantation. At the clinical stage, kidney transplantation before administration of cyclophosphamide after transfusion of bone marrow to create hematopoietic chimera is considered to be one of the most successful protocols. Furthermore, recent studies have shown the involvement of multiple populations of immune cells in preserving immunological tolerance and promoting long-term renal grafts. The present review focuses on how cyclophosphamide and other immune factors induce tolerance in kidney transplantation.
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Affiliation(s)
- Ario Takeuchi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koji Kato
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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8
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Salvadori M, Tsalouchos A. Biomarkers in renal transplantation: An updated review. World J Transplant 2017; 7:161-178. [PMID: 28698834 PMCID: PMC5487307 DOI: 10.5500/wjt.v7.i3.161] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 04/07/2017] [Accepted: 04/18/2017] [Indexed: 02/05/2023] Open
Abstract
Genomics, proteomics and molecular biology lead to tremendous advances in all fields of medical sciences. Among these the finding of biomarkers as non invasive indicators of biologic processes represents a useful tool in the field of transplantation. In addition to define the principal characteristics of the biomarkers, this review will examine the biomarker usefulness in the different clinical phases following renal transplantation. Biomarkers of ischemia-reperfusion injury and of delayed graft function are extremely important for an early diagnosis of these complications and for optimizing the treatment. Biomarkers predicting or diagnosing acute rejection either cell-mediated or antibody-mediated allow a risk stratification of the recipient, a prompt diagnosis in an early phase when the histology is still unremarkable. The kidney solid organ response test detects renal transplant recipients at high risk for acute rejection with a very high sensitivity and is also able to make diagnosis of subclinical acute rejection. Other biomarkers are able to detect chronic allograft dysfunction in an early phase and to differentiate the true chronic rejection from other forms of chronic allograft nephropathies no immune related. Finally biomarkers recently discovered identify patients tolerant or almost tolerant. This fact allows to safely reduce or withdrawn the immunosuppressive therapy.
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9
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Chong AS, Khiew SH. Transplantation tolerance: don't forget about the B cells. Clin Exp Immunol 2017; 189:171-180. [PMID: 28100001 DOI: 10.1111/cei.12927] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2017] [Indexed: 12/13/2022] Open
Abstract
Establishing a state of transplantation tolerance that leads to indefinite graft survival without the need for lifelong immunosuppression has been achieved successfully in limited numbers of transplant recipients in the clinic. These successes led to studies aimed at identifying potential biomarkers that diagnose allograft tolerance and identify the patients most amenable to drug minimization, and implicated an enriched B cell signature of tolerance. The emergence of a specialized subset of regulatory B cell (Bregs ), that possess immune-modulatory function in inflammation and autoimmune disease, raised the possibility that Bregs play critical roles in the promotion of transplantation tolerance and that Bregs are the underlying explanation for the B cell signature of tolerance. However, B cells are best known to play a key role in humoral immunity, and excessive production of donor specific antibodies has clear deleterious effects in transplantation. Thus, for tolerance to be persistent, alloantibody responses must also be curtailed, either through the suppression of T cell help or the induction of B cell-intrinsic dysfunction. Recent findings indicate a unique subset of follicular regulatory T cells (Tfr) that can suppress B cell function and induce epigenetic modifications that result in sustained defects in B cell differentiation and function. In this review, we summarize studies in animals and humans that suggest roles for Bregs and dysfunctional B cells in transplantation tolerance, and discuss how these insights may provide a roadmap for new approaches to diagnose, and new therapies to induce allograft tolerance.
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Affiliation(s)
- A S Chong
- Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL, USA
| | - S H Khiew
- Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, IL, USA
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10
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Maier M, Takano T, Sapir-Pichhadze R. Changing Paradigms in the Management of Rejection in Kidney Transplantation: Evolving From Protocol-Based Care to the Era of P4 Medicine. Can J Kidney Health Dis 2017; 4:2054358116688227. [PMID: 28270929 PMCID: PMC5308536 DOI: 10.1177/2054358116688227] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 11/17/2016] [Indexed: 12/30/2022] Open
Abstract
PURPOSE OF REVIEW P4 medicine denotes an evolving field of medicine encompassing predictive, preventive, personalized, and participatory medicine. Using the example of kidney allograft rejection because of donor-recipient incompatibility in human leukocyte antigens, this review outlines P4 medicine's relevance to the various stages of the kidney transplant cycle. SOURCES OF INFORMATION A search for English articles was conducted in Medline via OvidSP (up to August 18, 2016) using a combination of subject headings (MeSH) and free text in titles, abstracts, and author keywords for the concepts kidney transplantation and P4 medicine. The electronic database search was expanded further on particular subject headings. FINDINGS Available histocompatibility methods exemplify current applications of the predictive and preventive domains of P4 medicine in kidney transplant recipients' care. Pharmacogenomics are discussed as means to facilitate personalized immunosuppression regimens and promotion of active patient participation as a means to improve adherence. LIMITATIONS For simplicity, this review focuses on rejection. P4 medicine, however, should more broadly address health concerns in kidney transplant recipients, including competing outcomes such as infections, malignancies, and cardiovascular disease. This review highlights how biomarkers to evaluate these competing outcomes warrant validation and standardization prior to their incorporation into clinical practice. IMPLICATIONS Consideration of all 4 domains of the P4 medicine framework when caring for and/or studying kidney transplant recipients has the potential of increasing therapeutic efficiency, minimizing adverse effects, decreasing health care costs, and maximizing wellness. Technologies to gauge immune competency, immunosuppression requirements, and early/reversible immune-mediated injuries are required to optimize kidney transplant care.
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Affiliation(s)
- Mirela Maier
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
- Metabolic Disorders and Complications, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
| | - Tomoko Takano
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
- Metabolic Disorders and Complications, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
| | - Ruth Sapir-Pichhadze
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
- Metabolic Disorders and Complications, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
- Multi-Organ Transplant Program, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada
- Centre for Outcomes Research and Evaluation, McGill University Health Centre, Montreal, Quebec, Canada
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11
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Lu J, Zhang X. Immunological characteristics of renal transplant tolerance in humans. Mol Immunol 2016; 77:71-8. [PMID: 27479171 DOI: 10.1016/j.molimm.2016.07.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 07/13/2016] [Accepted: 07/13/2016] [Indexed: 10/21/2022]
Abstract
Establishing allograft tolerance is a highly desirable therapeutic goal in kidney transplantation, from which recipients would greatly benefit by withdrawing or minimizing immunosuppression. Identifying biomarkers in predicting tolerance or early diagnosing rejection is essential to direct personalized management. Recent findings have revealed that multiple populations of immune cells have involved in promoting long-term graft function or inducing rejection in renal transplant recipients. Thus, roles of immune cells add another level to predict the renal tolerant state; tailoring their functional and/or phenotypic characteristics would provide insights into mechanism involved in transplant tolerance that may aid in designing new therapies. Here, we review these findings and discuss the current understanding immunological characteristics of renal transplant tolerance in humans, and their potential clinical translation to immune tolerance biomarkers.
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Affiliation(s)
- Jingli Lu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaojian Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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Abstract
Advancing the field of transplantation by developing improved and novel treatment strategies will require a detailed understanding of changes and adaptations of alloimmunity, both over the short-term and long-term. Presently, we rely on traditional measures that may not optimally reflect benefits of new treatments. Thus, collecting reliable basic information about changes of the immune response along the entire posttransplantation course will improve our understanding of how immune mechanisms evolve and guide the introduction of novel clinical approaches. The gathering of good quality data from transplant recipients in various clinical trials will require immune monitoring that is reliable and comparable so that large sets of information from individual trials can be confidently analyzed to reach rigorous conclusions. A uniform standard of testing is thus a prerequisite toward this goal. Based on the assumption that the transplantation community will in general be supportive of this concept, this meeting proposed establishing a global virtual laboratory as a means of developing and disseminating detailed and rigorous protocols for the monitoring of alloimmune responses.
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Abstract
PURPOSE OF REVIEW The role of T-cell exhaustion in the failure of clearance of viral infections and tumors is well established. There are several ongoing trials to reverse T-cell exhaustion for treatment of chronic viral infections and tumors. The mechanisms leading to T-cell exhaustion and its role in transplantation, however, are only beginning to be appreciated and are the focus of the present review. RECENT FINDINGS Exhausted T cells exhibit a distinct molecular profile reflecting combinatorial mechanisms involving the interaction of multiple transcription factors important in control of cell metabolism, acquisition of effector function and memory capacity. Change of microenvironmental cues and limiting leukocyte recruitment can modulate T-cell exhaustion. Impaired leukocyte recruitment induces T-cell exhaustion and prevents allograft rejection. SUMMARY Preventing or reversing T-cell exhaustion may lead to prevention of transplant tolerance or triggering of rejection; therefore, caution should be exercised in the use of agents blocking inhibitory receptors for the treatment of chronic viral infections or tumors in transplant recipients. Further definition of the role of T-cell exhaustion in clinical transplantation and an understanding of the mechanisms of induction of T-cell exhaustion are needed to develop strategies for preventing allograft rejection and induction of tolerance.
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Baron D, Giral M, Brouard S. Reconsidering the detection of tolerance to individualize immunosuppression minimization and to improve long-term kidney graft outcomes. Transpl Int 2015; 28:938-59. [DOI: 10.1111/tri.12578] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 02/03/2015] [Accepted: 04/02/2015] [Indexed: 01/03/2023]
Affiliation(s)
- Daniel Baron
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| | - Magali Giral
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
| | - Sophie Brouard
- INSERM; UMR 1064; Nantes France
- CHU de Nantes; ITUN; Nantes France
- Faculté de Médecine; Université de Nantes; Nantes France
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15
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Millán O, Rafael-Valdivia L, San Segundo D, Boix F, Castro-Panete M, López-Hoyos M, Muro M, Valero-Hervás D, Rimola A, Navasa M, Muñoz P, Miras M, Andrés A, Guirado L, Pascual J, Brunet M. Should IFN-γ, IL-17 and IL-2 be considered predictive biomarkers of acute rejection in liver and kidney transplant? Results of a multicentric study. Clin Immunol 2014; 154:141-54. [DOI: 10.1016/j.clim.2014.07.007] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 07/16/2014] [Accepted: 07/23/2014] [Indexed: 02/06/2023]
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16
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Recipients with in utero induction of tolerance upregulated MHC class I in the engrafted donor skin. DISEASE MARKERS 2014; 2014:531092. [PMID: 25143665 PMCID: PMC4131087 DOI: 10.1155/2014/531092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 06/23/2014] [Accepted: 06/23/2014] [Indexed: 11/21/2022]
Abstract
The alterations in MHC class I expression play a crucial step in immune evasion of cancer or virus-infected cells. This study aimed to examine whether tolerized grafts modified MHC class I expression. FVB/N mice were rendered tolerant of C57BL/6 alloantigens by in utero transplantation of C57BL/6 marrows. Postnatally, engrafted donor skins and leukocytes were examined for their MHC expression by quantitative real-time PCR and flow cytometry. Engrafted donor skins upregulated their MHC class I related gene transcripts after short-term (1~2 weeks) or long-term (>1 month) engraftment. This biological phenomenon was simultaneously associated with upregulation of TAP1 gene transcripts, suggesting an important role of TAP1 in the regulation of MHC class I pathway. The surface MHC class I molecules of H-2Kb in engrafted donor leukocytes consistently showed overexpression. Conclusively, the induction of allograft tolerance involved biological modifications of donor transplants. The overexpression of MHC class I within engrafted transplants of tolerant mice might be used as the tolerance biomarkers for identifying a state of graft tolerance.
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Lipshultz SE, Chandar JJ, Rusconi PG, Fornoni A, Abitbol CL, Burke GW, Zilleruelo GE, Pham SM, Perez EE, Karnik R, Hunter JA, Dauphin DD, Wilkinson JD. Issues in solid-organ transplantation in children: translational research from bench to bedside. Clinics (Sao Paulo) 2014; 69 Suppl 1:55-72. [PMID: 24860861 PMCID: PMC3884162 DOI: 10.6061/clinics/2014(sup01)11] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
In this review, we identify important challenges facing physicians responsible for renal and cardiac transplantation in children based on a review of the contemporary medical literature. Regarding pediatric renal transplantation, we discuss the challenge of antibody-mediated rejection, focusing on both acute and chronic antibody-mediated rejection. We review new diagnostic approaches to antibody-mediated rejection, such as panel-reactive antibodies, donor-specific cross-matching, antibody assays, risk assessment and diagnosis of antibody-mediated rejection, the pathology of antibody-mediated rejection, the issue of ABO incompatibility in renal transplantation, new therapies for antibody-mediated rejection, inhibiting of residual antibodies, the suppression or depletion of B-cells, genetic approaches to treating acute antibody-mediated rejection, and identifying future translational research directions in kidney transplantation in children. Regarding pediatric cardiac transplantation, we discuss the mechanisms of cardiac transplant rejection, including the role of endomyocardial biopsy in detecting graft rejection and the role of biomarkers in detecting cardiac graft rejection, including biomarkers of inflammation, cardiomyocyte injury, or stress. We review cardiac allograft vasculopathy. We also address the role of genetic analyses, including genome-wide association studies, gene expression profiling using entities such as AlloMap®, and adenosine triphosphate release as a measure of immune function using the Cylex® ImmuKnow™ cell function assay. Finally, we identify future translational research directions in heart transplantation in children.
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Affiliation(s)
- Steven E Lipshultz
- Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI, United States
| | - Jayanthi J Chandar
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Paolo G Rusconi
- Division of Pediatric Cardiology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Alessia Fornoni
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Carolyn L Abitbol
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
| | - George W Burke
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Gaston E Zilleruelo
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Si M Pham
- Artificial Heart Programs, Transplant Institute, Jackson Memorial Division of Heart/Lung Transplant, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Elena E Perez
- Division of Pediatric Immunology and Allergy, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Ruchika Karnik
- Division of Pediatric Cardiology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Juanita A Hunter
- Division of Pediatric Cardiology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Danielle D Dauphin
- Division of Pediatric Clinical Research, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
| | - James D Wilkinson
- Division of Pediatric Clinical Research, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
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18
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Morris MW, Anderson C. The holy grail: a biomarker for acute rejection in liver transplantation. J Surg Res 2013; 185:535-6. [DOI: 10.1016/j.jss.2012.08.058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2012] [Revised: 08/27/2012] [Accepted: 08/30/2012] [Indexed: 12/21/2022]
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19
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Abstract
PURPOSE OF REVIEW As the induction and maintenance of donor-specific tolerance is a central aim in solid organ transplantation, it is essential that clinicians are able to identify and monitor tolerance accurately and reliably. This review highlights recent advances in defining sets of biomarkers in noninvasive samples that may guide minimization and withdrawal of immunosuppression in tolerant recipients. RECENT FINDINGS Recent studies in liver and kidney transplant recipients have identified distinct biomarker profiles that are associated with operational tolerance. Although there is some heterogeneity in the findings of these studies, these have suggested novel cellular mechanisms for the development of tolerance. SUMMARY Multiple platforms such as microarray gene expression analysis, flow cytometry, and immune cell functional assays have been used to discover and validate composite sets of biomarkers, which identify recipients with operational tolerance both in liver and kidney transplantation. These studies suggest that distinct cellular and molecular mechanisms lead to the development of tolerance in different transplanted organs. These putative biomarker profiles now need to be validated prospectively in trials of immunosuppression withdrawal and in novel approaches to induce transplant tolerance.
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20
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Jin ZK, Tian PX, Wang XZ, Xue WJ, Ding XM, Zheng J, Ding CG, Mao TC, Duan WL, Xi M. Kidney injury molecule-1 and osteopontin: New markers for prediction of early kidney transplant rejection. Mol Immunol 2013; 54:457-64. [DOI: 10.1016/j.molimm.2013.01.013] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2012] [Revised: 01/26/2013] [Accepted: 01/28/2013] [Indexed: 12/21/2022]
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21
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Lim DG, Park YH, Kim SE, Jeong SH, Kim SC. Diagnostic value of tolerance-related gene expression measured in the recipient alloantigen-reactive T cell fraction. Clin Immunol 2013; 148:219-26. [PMID: 23778261 DOI: 10.1016/j.clim.2013.05.013] [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: 02/05/2013] [Revised: 04/17/2013] [Accepted: 05/19/2013] [Indexed: 10/26/2022]
Abstract
The efficient development of tolerance-inducing therapies and safe reduction of immunosuppression should be supported by early diagnosis and prediction of tolerance in transplantation. Using mouse models of donor-specific tolerance to allogeneic skin and islet grafts we tested whether measurement of tolerance-related gene expression in their alloantigen-reactive peripheral T cell fraction efficiently reflected the tolerance status of recipients. We found that Foxp3, Nrn1, and Klrg1 were preferentially expressed in conditions of tolerance compared with rejection or unmanipulated controls if their expression is measured in CD69(+) T cells prepared from coculture of recipient peripheral T cells and donor antigen-presenting cells. The same pattern of gene expression was observed in recipients grafted with either skin or islets, recipients of different genetic origins, and even those taking immunosuppressive drugs. These findings suggest that the expression of tolerance-related genes in the alloantigen-reactive T cell fraction could be used to detect tolerance in the clinic.
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Affiliation(s)
- Dong-Gyun Lim
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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22
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Immune Monitoring in Kidney Transplant Recipients Could Predict Acute Rejection by a New Method: Flow Cytometric Microcarrier Assay. Transplant Proc 2013; 45:1508-10. [DOI: 10.1016/j.transproceed.2013.01.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 01/15/2013] [Indexed: 12/26/2022]
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23
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Non-invasive biomarkers to guide management following renal transplantation: the need for a multiplatform approach. Curr Opin Organ Transplant 2013; 18:1-5. [PMID: 23283248 DOI: 10.1097/mot.0b013e32835c8025] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
PURPOSE OF REVIEW Balancing the level of anti-rejection therapy is the key challenge facing clinicians managing recipients of a solid organ transplant. Identification of biomarkers in non-invasive samples will allow serial monitoring which can prompt changes in therapy at an earlier stage without the need for invasive tests, and before significant damage to the graft or side effects have occurred. In this review we provide an update on the present status of such biomarker discovery in renal transplantation. RECENT FINDINGS Previous studies focusing on candidate biomarkers have identified a number of genes that have the potential to identify patients undergoing rejection. Advances in technology now allow screening of samples for markers which have led to identification of further genes as well as adding microRNAs and proteins to the list. Similarly, by studying patients in whom anti-rejection therapy has been withdrawn, a gene signature for operational tolerance has been described. SUMMARY It has become clear that to obtain a test suitable for clinical purposes, combinations of markers are required to identify specific clinical phenotypes. Identification and validation of such marker sets in large cohorts is urgently required to allow progression to clinical trials with the ultimate goal of offering recipients personalized anti-rejection therapy regimes.
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24
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Memory T cells and their exhaustive differentiation in allograft tolerance and rejection. Curr Opin Organ Transplant 2013; 17:15-9. [PMID: 22186090 DOI: 10.1097/mot.0b013e32834ee443] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW Memory T cells have emerged as a major threat to transplant survival; they are well equipped and well positioned to respond to antigens in an accelerated fashion. They participate in transplant rejection and resist interventions that usually contain naïve T cells. Thus, the means to prevent memory T cells from attacking allotransplants are an important issue in transplantation. RECENT FINDINGS Recent studies in other models suggest that effector T cells, which include both freshly activated T cells and memory T cells, can acquire 'an exhausted phenotype' in that they progressively lose their effector activities. This response is highly regulated, antigen specific, and driven primarily by antigen persistence. This exhausted phenotype has not been carefully explored in transplant models, and its role in transplant survival remains largely unknown. SUMMARY Studies of T-cell exhaustion may reveal additional facets of the fundamental mechanisms of transplant survival. T-cell exhaustion may be an alternative way of preventing memory development. Future studies are needed to further improve our understanding of T-cell exhaustion in transplantation.
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25
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Abstract
PURPOSE OF REVIEW Tailoring immunosuppressive drugs to an individual's needs is crucial to improve long-term outcomes of organ transplant patients. The purpose of this review is to summarize the data on promising biomarkers able to detect the risk of acute or chronic rejection and to discuss the potential issues for their implementation in the clinic. RECENT FINDINGS Multiple publications have indicated that circulating antibodies targeting human leukocyte antigen (HLA) and non-HLA antigens as well as donor-specific memory T cells are associated with accelerated graft failure. Other studies published within the year show that specific genomic and proteomic signatures obtained from urine, blood, and graft tissue correlate with acute rejection in kidney and heart transplant patients. SUMMARY The development of reliable biomarkers is crucial for individualizing therapy aimed at extending allograft survival and improving patient health. Emerging data indicate that monitoring assays, likely used in panels, have the potential to be diagnostic and possibly predictive of long-term outcome. In addition to ongoing discovery efforts, progress in the field will require multicenter validation, assay standardization, and commercialization so as to efficiently deliver reliable testing strategies to the practicing clinician.
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26
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Zuber J, Grimbert P, Blancho G, Thaunat O, Durrbach A, Baron C, Lebranchu Y. Prognostic significance of graft Foxp3 expression in renal transplant recipients: a critical review and attempt to reconcile discrepancies. Nephrol Dial Transplant 2012; 28:1100-11. [PMID: 23262436 DOI: 10.1093/ndt/gfs570] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
A large body of evidence has been accumulated from experimental models in the past decade to support the critical role of Foxp3-expressing regulatory T cells (Tregs) in the suppression of alloimmune responses. This has prompted transplant clinicians to investigate whether Foxp3 analysis might be used as an immunodiagnostic tool for better assessment of the significance of graft infiltrate and to predict its impact on graft outcome. However, conflicting results have emerged from these studies and may have generated more confusion than clarification. Foxp3 expression has been antagonistically correlated with either good or poor prognosis. We discuss here how methodological issues and specific clinical settings may have accounted for the discrepancies between the results of these studies. Depending on many factors, including the techniques used, the method of sampling normalization, the extent of intra-graft inflammation, the immunosuppressive regimen and the depletion or repletion of T lymphocyte compartment, the significance of Foxp3 expression may vary. We propose here the conditions to be fulfilled in order to use Foxp3 analysis as a relevant biomarker for graft outcome assessment. Far from challenging the key role of Tregs in dampening alloimmune responses, this review highlights the need for technical harmonization and standards.
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Affiliation(s)
- Julien Zuber
- Department of Renal Transplantation, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
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27
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Impact of HLA-G 14-bp polymorphism on acute rejection and cytomegalovirus infection in kidney transplant recipients from northwestern China. Transpl Immunol 2012; 27:69-74. [DOI: 10.1016/j.trim.2012.06.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2012] [Revised: 06/21/2012] [Accepted: 06/22/2012] [Indexed: 11/21/2022]
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28
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Importance of liver biopsy findings in immunosuppression management: biopsy monitoring and working criteria for patients with operational tolerance. Liver Transpl 2012; 18:1154-70. [PMID: 22645090 DOI: 10.1002/lt.23481] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Obstacles to morbidity-free long-term survival after liver transplantation (LT) include complications of immunosuppression (IS), recurrence of the original disease and malignancies, and unexplained chronic hepatitis and graft fibrosis. Many programs attempt to minimize chronic exposure to IS by reducing dosages and stopping steroids. A few programs have successfully weaned a highly select group of recipients from all IS without apparent adverse consequences, but long-term follow-up is limited. Patients subjected to adjustments in IS are usually followed by serial liver chemistry tests, which are relatively insensitive methods for detecting allograft damage. Protocol biopsy has largely been abandoned for hepatitis C virus-negative recipients, at least in part because of the inability to integrate routine histopathological findings into a rational clinical management algorithm. Recognizing a need to more precisely categorize and determine the clinical significance of findings in long-term biopsy samples, the Banff Working Group on Liver Allograft Pathology has reviewed the literature, pooled the experience of its members, and proposed working definitions for biopsy changes that (1) are conducive to lowering IS and are compatible with operational tolerance (OT) and (2) raise concern for closer follow-up and perhaps increased IS during or after IS weaning. The establishment of guidelines should help us to standardize analyses of the effects of various treatments and/or weaning protocols and more rigorously categorize patients who are assumed to show OT. Long-term follow-up using standardized criteria will help us to determine the consequences of lowering IS and to define and determine the incidence and robustness of OT in liver allografts.
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Affiliation(s)
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- University of Pittsburgh Medical Center, 3459 5th Avenue, UPMC Montefiore E741, Pittsburgh, PA 15213, USA
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29
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Why do we need biomarkers in solid organ transplantation. Clin Chim Acta 2012; 413:1310-1. [DOI: 10.1016/j.cca.2012.04.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Revised: 04/19/2012] [Accepted: 04/23/2012] [Indexed: 11/17/2022]
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30
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Shields AM, Panayi GS, Corrigall VM. A New-Age for Biologic Therapies: Long-Term Drug-Free Therapy with BiP? Front Immunol 2012; 3:17. [PMID: 22566902 PMCID: PMC3342250 DOI: 10.3389/fimmu.2012.00017] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2011] [Accepted: 02/01/2012] [Indexed: 12/21/2022] Open
Abstract
Heat shock proteins (HSPs) and other members of the much broader stress protein family have been shown to play important roles in coordinating multiple phases of immunological reactions; from facilitating immunological recognition, to promoting and regulating immunological responses and finally augmenting the resolution of inflammation and return to immunological homeostasis. In this review, we consider the challenges facing the stress protein field as we enter 2012; in particular we consider the role that HSPs and stress proteins may play in the initiation and termination of immunological responses. Special attention is afforded to the resolution-associated molecular pattern, binding immunoglobulin protein (BiP, also known as glucose regulated protein-78). We review the evidence that resolution-promoting proteins such as BiP may herald a new generation of biologics for inflammatory disease and reflect on the challenges of achieving clinical remission in rheumatoid arthritis with novel therapeutics and correlating clinical remission with immunological parameters of resolution of inflammation.
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Affiliation(s)
- Adrian M Shields
- Department of Academic Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, King's College London London, UK
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31
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Cippà PE, Fehr T. Spontaneous tolerance in kidney transplantation--an instructive, but very rare paradigm. Transpl Int 2011; 24:534-5. [PMID: 21535235 DOI: 10.1111/j.1432-2277.2011.01260.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Pietro E Cippà
- Division of Nephrology, University Hospital Zürich, Rämistrasse 100, Zürich, Switzerland
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32
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Mas VR, Mueller TF, Archer KJ, Maluf DG. Identifying biomarkers as diagnostic tools in kidney transplantation. Expert Rev Mol Diagn 2011; 11:183-96. [PMID: 21405969 DOI: 10.1586/erm.10.119] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
There is a critical need for biomarkers for early diagnosis, treatment response, and surrogate end point and outcome prediction in organ transplantation, leading to a tailored and individualized treatment. Genomic and proteomic platforms have provided multiple promising new biomarkers during the last few years. However, there is still no routine application of any of these markers in clinical transplantation. This article will discuss the existing gap between biomarker discovery and clinical application in the kidney transplant setting. Approaches to implementing biomarker monitoring into clinical practice will also be discussed.
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Affiliation(s)
- Valeria R Mas
- Molecular Transplant Research Laboratory, Transplant Division, Department of Surgery, Molecular Medicine Research Building, Virginia Commonwealth University, 1220 East Broad Street, Richmond, VA 23298, USA.
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33
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Abstract
Self tolerance is dependent on mechanisms that operate on T cells and B cells from the earliest stages, that is, from when they first express anti-self-receptors in the primary lymphoid organs of the thymus and bone marrow, all the way through to when they engage with self antigens in the peripheral immune system and within tissues themselves. This continuum of checkpoints and fail-safes ensures that the risk of developing harmful autoimmune diseases remains very small. Certain tissues have a degree of privilege that allows them to mute the immune response against them by mechanisms that are also well represented in cancers. An understanding of the underlying mechanisms of self tolerance is hoped to spawn a new range of therapeutics designed to both reprogram the immune system to avoid long-term intense immunosuppression, and to override the immune system to achieve more effective immunity against cancers and persistent viral infections.
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