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1
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Nellore A, Zumaquero E, Seifert M. T-bet + B Cells in Humans: Protective and Pathologic Functions. Transplantation 2024; 108:1709-1714. [PMID: 38051131 PMCID: PMC11150333 DOI: 10.1097/tp.0000000000004889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 10/28/2023] [Accepted: 10/31/2023] [Indexed: 12/07/2023]
Abstract
The humoral immune system comprises B cells and plasma cells, which play important roles in organ transplantation, ranging from the production of both protective and injurious antibodies as well as cytokines that can promote operational tolerance. Recent data from conditions outside of transplantation have identified a novel human B-cell subset that expresses the transcription factor T-bet and exerts pleiotropic functions by disease state. Here, we review the generation, activation, and functions of the T-bet + B-cell subset outside of allotransplantation, and consider the relevance of this subset as mediators of allograft injury.
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Affiliation(s)
- Anoma Nellore
- Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL
| | - Esther Zumaquero
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL
| | - Michael Seifert
- Division of Pediatric Nephrology, University of Alabama at Birmingham, Birmingham, AL
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2
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Steines L, Poth H, Herrmann M, Schuster A, Banas B, Bergler T. B Cell Activating Factor (BAFF) Is Required for the Development of Intra-Renal Tertiary Lymphoid Organs in Experimental Kidney Transplantation in Rats. Int J Mol Sci 2020; 21:ijms21218045. [PMID: 33126753 PMCID: PMC7662293 DOI: 10.3390/ijms21218045] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/23/2020] [Accepted: 10/25/2020] [Indexed: 12/22/2022] Open
Abstract
Intra-renal tertiary lymphoid organs (TLOs) are associated with worsened outcome in kidney transplantation (Ktx). We used an anti-BAFF (B cell activating factor) intervention to investigate whether BAFF is required for TLO formation in a full MHC-mismatch Ktx model in rats. Rats received either therapeutic immunosuppression (no rejection, NR) or subtherapeutic immunosuppression (chronic rejection, CR) and were sacrificed on d56. One group additionally received an anti-BAFF antibody (CR + AB). Intra-renal T (CD3+) and B (CD20+) cells, their proliferation (Ki67+), and IgG+ plasma cells were analyzed by immunofluorescence microscopy. Formation of T and B cell zones and TLOs was assessed. Intra-renal expression of TLO-promoting factors, molecules of T:B crosstalk, and B cell differentiation was analyzed by qPCR. Intra-renal B and T cell zones and TLOs were detected in CR and were associated with elevated intra-renal mRNA expression of TLO-promoting factors, including CXCL13, CCL19, lymphotoxin-β, and BAFF. Intra-renal plasma cells were also elevated in CR. Anti-BAFF treatment significantly decreased intra-renal B cell zones and TLO, as well as intra-renal B cell-derived TLO-promoting factors and B cell differentiation markers. We conclude that BAFF-dependent intra-renal B cells promote TLO formation and advance local adaptive alloimmune responses in chronic rejection.
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Affiliation(s)
- Louisa Steines
- Correspondence: ; Tel.: +49-941-9447301; Fax: +49-941-9447302
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3
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Steen EH, Wang X, Balaji S, Butte MJ, Bollyky PL, Keswani SG. The Role of the Anti-Inflammatory Cytokine Interleukin-10 in Tissue Fibrosis. Adv Wound Care (New Rochelle) 2020; 9:184-198. [PMID: 32117582 PMCID: PMC7047112 DOI: 10.1089/wound.2019.1032] [Citation(s) in RCA: 241] [Impact Index Per Article: 48.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 06/18/2019] [Indexed: 02/06/2023] Open
Abstract
Significance: Fibrosis is the endpoint of chronic disease in multiple organs, including the skin, heart, lungs, intestine, liver, and kidneys. Pathologic accumulation of fibrotic tissue results in a loss of structural integrity and function, with resultant increases in morbidity and mortality. Understanding the pathways governing fibrosis and identifying therapeutic targets within those pathways is necessary to develop novel antifibrotic therapies for fibrotic disease. Recent Advances: Given the connection between inflammation and fibrogenesis, Interleukin-10 (IL-10) has been a focus of potential antifibrotic therapies because of its well-known role as an anti-inflammatory mediator. Despite the apparent dissimilarity of diseases associated with fibrotic progression, pathways involving IL-10 appear to be a conserved molecular theme. More recently, many groups have worked to develop novel delivery tools for recombinant IL-10, such as hydrogels, and cell-based therapies, such as ex vivo activated macrophages, to directly or indirectly modulate IL-10 signaling. Critical Issues: Some efforts in this area, however, have been stymied by IL-10's pleiotropic and sometimes conflicting effects. A deeper, contextual understanding of IL-10 signaling and its interaction with effector cells, particularly immune cells, will be critical to future studies in the field. Future Directions: IL-10 is clearly a gatekeeper of fibrotic/antifibrotic signaling. The development of novel therapeutics and cell-based therapies that capitalize on targets within the IL-10 signaling pathway could have far-reaching implications for patients suffering from the consequences of organ fibrosis.
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Affiliation(s)
- Emily H. Steen
- Department of Surgery, Baylor College of Medicine, Houston, Texas
- Laboratory for Regenerative Tissue Repair, Texas Children's Hospital, Houston, Texas
| | - Xinyi Wang
- Laboratory for Regenerative Tissue Repair, Texas Children's Hospital, Houston, Texas
| | - Swathi Balaji
- Laboratory for Regenerative Tissue Repair, Texas Children's Hospital, Houston, Texas
| | - Manish J. Butte
- Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, University of California, Los Angeles, Los Angeles, California
| | - Paul L. Bollyky
- Division of Infectious Diseases, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Sundeep G. Keswani
- Department of Surgery, Baylor College of Medicine, Houston, Texas
- Laboratory for Regenerative Tissue Repair, Texas Children's Hospital, Houston, Texas
- Division of Pediatric Surgery, Department of Surgery, Texas Children's Hospital, Houston, Texas
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4
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Moreso F, Sellarès J, Soler MJ, Serón D. Transcriptome Analysis in Renal Transplant Biopsies Not Fulfilling Rejection Criteria. Int J Mol Sci 2020; 21:ijms21062245. [PMID: 32213927 PMCID: PMC7139324 DOI: 10.3390/ijms21062245] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/11/2020] [Accepted: 03/20/2020] [Indexed: 01/02/2023] Open
Abstract
The clinical significance of renal transplant biopsies displaying borderline changes suspicious for T-cell mediated rejection (TCMR) or interstitial fibrosis and tubular atrophy (IFTA) with interstitial inflammation has not been well defined. Molecular profiling to evaluate renal transplant biopsies using microarrays has been shown to be an objective measurement that adds precision to conventional histology. We review the contribution of transcriptomic analysis in surveillance and indication biopsies with borderline changes and IFTA associated with variable degrees of inflammation. Transcriptome analysis applied to biopsies with borderline changes allows to distinguish patients with rejection from those in whom mild inflammation mainly represents a response to injury. Biopsies with IFTA and inflammation occurring in unscarred tissue display a molecular pattern similar to TCMR while biopsies with IFTA and inflammation in scarred tissue, apart from T-cell activation, also express B cell, immunoglobulin and mast cell-related genes. Additionally, patients at risk for IFTA progression can be identified by genes mainly reflecting fibroblast dysregulation and immune activation. At present, it is not well established whether the expression of rejection gene transcripts in patients with fibrosis and inflammation is the consequence of an alloimmune response, tissue damage or a combination of both.
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5
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Muczynski KA, Leca N, Anderson AE, Kieran N, Anderson SK. Multicolor Flow Cytometry and Cytokine Analysis Provides Enhanced Information on Kidney Transplant Biopsies. Kidney Int Rep 2018; 3:956-969. [PMID: 29989006 PMCID: PMC6035131 DOI: 10.1016/j.ekir.2018.02.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 02/26/2018] [Indexed: 12/31/2022] Open
Abstract
Introduction Current processing of renal biopsy samples provides limited information about immune mechanisms causing kidney injury and disease activity. We used flow cytometry with transplanted kidney biopsy samples to provide more information on the immune status of the kidney. Methods To enhance the information available from a biopsy, we developed a technique for reducing a fraction of a renal biopsy sample to single cells for multicolor flow cytometry and quantitation of secreted cytokines present within the biopsy sample. As proof of concept, we used our technique with transplant kidney biopsy samples to provide examples of clinically relevant immune information obtainable with cytometry. Results A ratio of CD8+ to CD4+ lymphocytes greater than or equal to 1.2 in transplanted allografts is associated with rejection, even before it is apparent by microscopy. Elevated numbers of CD45 leukocytes and higher levels of interleukin (IL)−6, IL-8, and IL-10 indicate more severe injury. Antibody binding to renal microvascular endothelial cells can be measured and corresponds to antibody-mediated forms of allograft rejection. Eculizumab binding to endothelial cells suggests complement activation, which may be independent of bound antibody. We compared intrarenal leukocyte subsets and activation states to those of peripheral blood from the same donor at the time of biopsy and found significant differences; thus the need for new techniques to evaluate immune responses within the kidney. Conclusion Assessment of leukocyte subsets, renal microvascular endothelial properties, and measurement of cytokines within a renal biopsy by flow cytometry enhance understanding of pathogenesis, indicate disease activity, and identify potential targets for therapy.
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Affiliation(s)
| | - Nicolae Leca
- Division of Nephrology, University of Washington, Seattle, Washington, USA
| | - Arthur E Anderson
- Division of Nephrology, University of Washington, Seattle, Washington, USA
| | - Niamh Kieran
- Division of Nephrology, University of Washington, Seattle, Washington, USA
| | - Susan K Anderson
- Division of Nephrology, University of Washington, Seattle, Washington, USA
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6
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Nankivell BJ, Shingde M, Keung KL, Fung CLS, Borrows RJ, O'Connell PJ, Chapman JR. The causes, significance and consequences of inflammatory fibrosis in kidney transplantation: The Banff i-IFTA lesion. Am J Transplant 2018; 18:364-376. [PMID: 29194971 DOI: 10.1111/ajt.14609] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 10/25/2017] [Accepted: 10/28/2017] [Indexed: 01/25/2023]
Abstract
Inflammation within areas of interstitial fibrosis and tubular atrophy (i-IFTA) is associated with adverse outcomes in kidney transplantation. We evaluated i-IFTA in 429 indication- and 2052 protocol-driven biopsy samples from a longitudinal cohort of 362 kidney-pancreas recipients to determine its prevalence, time course, and relationships with T cell-mediated rejection (TCMR), immunosuppression, and outcome. Sequential histology demonstrated that i-IFTA was preceded by cellular interstitial inflammation and followed by IF/TA. The prevalence and intensity of i-IFTA increased with developing chronic fibrosis and correlated with inflammation, tubulitis, and immunosuppression era (P < .001). Tacrolimus era-based immunosuppression was associated with reduced histologic inflammation in unscarred and scarred i-IFTA compartments, ameliorated progression of IF, and increased conversion to inactive IF/TA (compared with cyclosporine era, P < .001). Prior acute (including borderline) TCMR and subclinical TCMR were followed by greater 1-year i-IFTA, remaining predictive by multivariate analysis and independent of humoral markers. One-year i-IFTA was associated with accelerated IF/TA, arterial fibrointimal hyperplasia, and chronic glomerulopathy and with reduced renal function (P < .001 versus no i-IFTA). In summary, i-IFTA is the histologic consequence of active T cell-mediated alloimmunity, representing the interface between inflammation and tubular injury with fibrotic healing. Uncontrolled i-IFTA is associated with adverse structural and functional outcomes.
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Affiliation(s)
| | - Meena Shingde
- Tissue Pathology and Diagnostic Oncology, Westmead Hospital, Sydney, Australia
| | - Karen L Keung
- Department of Renal Medicine, Westmead Hospital, Sydney, Australia
| | - Caroline L-S Fung
- Tissue Pathology and Diagnostic Oncology, Westmead Hospital, Sydney, Australia
| | | | | | - Jeremy R Chapman
- Department of Renal Medicine, Westmead Hospital, Sydney, Australia
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7
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Kühne L, Jung B, Poth H, Schuster A, Wurm S, Ruemmele P, Banas B, Bergler T. Renal allograft rejection, lymphocyte infiltration, and de novo donor-specific antibodies in a novel model of non-adherence to immunosuppressive therapy. BMC Immunol 2017; 18:52. [PMID: 29258420 PMCID: PMC5735914 DOI: 10.1186/s12865-017-0236-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Accepted: 12/07/2017] [Indexed: 12/18/2022] Open
Abstract
Background Non-adherence has been associated with reduced graft survival. The aim of this study was to investigate the immunological mechanisms underlying chronic renal allograft rejection using a model of non-adherence to immunosuppressive therapy. We used a MHC (major histocompatibility complex) -mismatched rat model of renal transplantation (Brown Norway to Lewis), in which rats received daily oral cyclosporine A. In analogy to non-adherence to therapy, one group received cyclosporine A on alternating days only. Rejection was histologically graded according to the Banff classification. We quantified fibrosis by trichrome staining and intra-graft infiltration of T cells, B cells, and monocytes/macrophages by immunohistochemistry. The distribution of B lymphocytes was assessed using immunofluorescence microscopy. Intra-graft chemokine, chemokine receptor, BAFF (B cell activating factor belonging to the TNF family), and immunoglobulin G transcription levels were analysed by RT-PCR. Finally, we evaluated donor-specific antibodies (DSA) and complement-dependent cytotoxicity using flow cytometry. Results After 28 days, cellular rejection occurred during non-adherence in 5/6 animals, mixed with humoral rejection in 3/6 animals. After non-adherence, the number of T lymphocytes were elevated compared to daily immunosuppression. Monocyte numbers declined over time. Accordingly, lymphocyte chemokine transcription was significantly increased in the graft, as was the transcription of BAFF, BAFF receptor, and Immunoglobulin G. Donor specific antibodies were elevated in non-adherence, but did not induce complement-dependent cytotoxicity. Conclusion Cellular and humoral rejection, lymphocyte infiltration, and de novo DSA are induced in this model of non-adherence. Electronic supplementary material The online version of this article (doi: 10.1186/s12865-017-0236-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Louisa Kühne
- Department of Nephrology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, D-93053, Regensburg, Germany.
| | - Bettina Jung
- Department of Nephrology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, D-93053, Regensburg, Germany
| | - Helen Poth
- Department of Nephrology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, D-93053, Regensburg, Germany
| | - Antonia Schuster
- Department of Nephrology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, D-93053, Regensburg, Germany
| | - Simone Wurm
- Department of Nephrology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, D-93053, Regensburg, Germany
| | - Petra Ruemmele
- Department of Pathology, University Hospital Erlangen, Erlangen, Germany
| | - Bernhard Banas
- Department of Nephrology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, D-93053, Regensburg, Germany
| | - Tobias Bergler
- Department of Nephrology, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, D-93053, Regensburg, Germany
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8
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Alsughayyir J, Pettigrew GJ, Motallebzadeh R. Spoiling for a Fight: B Lymphocytes As Initiator and Effector Populations within Tertiary Lymphoid Organs in Autoimmunity and Transplantation. Front Immunol 2017; 8:1639. [PMID: 29218052 PMCID: PMC5703719 DOI: 10.3389/fimmu.2017.01639] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Accepted: 11/09/2017] [Indexed: 12/13/2022] Open
Abstract
Tertiary lymphoid organs (TLOs) develop at ectopic sites within chronically inflamed tissues, such as in autoimmunity and rejecting organ allografts. TLOs differ structurally from canonical secondary lymphoid organs (SLOs), in that they lack a mantle zone and are not encapsulated, suggesting that they may provide unique immune function. A notable feature of TLOs is the frequent presence of structures typical of germinal centers (GCs). However, little is known about the role of such GCs, and in particular, it is not clear if the B cell response within is autonomous, or whether it synergizes with concurrent responses in SLOs. This review will discuss ectopic lymphoneogenesis and the role of the B cell in TLO formation and subsequent effector output in the context of autoimmunity and transplantation, with particular focus on the contribution of ectopic GCs to affinity maturation in humoral immune responses and to the potential breakdown of self-tolerance and development of humoral autoimmunity.
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Affiliation(s)
- Jawaher Alsughayyir
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Gavin J Pettigrew
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Reza Motallebzadeh
- Division of Surgery and Interventional Science, University College London, London, United Kingdom.,Institute of Immunity and Transplantation, University College London, London, United Kingdom.,Department of Nephrology, Urology and Transplantation, Royal Free Hospital, London, United Kingdom
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9
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Van Loon E, Lerut E, Naesens M. The time dependency of renal allograft histology. Transpl Int 2017; 30:1081-1091. [DOI: 10.1111/tri.13042] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 07/05/2017] [Accepted: 08/21/2017] [Indexed: 01/27/2023]
Affiliation(s)
- Elisabet Van Loon
- Laboratory of Nephrology; Department of Microbiology and Immunology; KU Leuven; Leuven Belgium
- Department of Nephrology and Renal Transplantation; University Hospitals Leuven; Leuven Belgium
| | - Evelyne Lerut
- Translational Cell and Tissue Research; Department of Imaging and Pathology; KU Leuven; Leuven Belgium
- Department of Morphology and Molecular Pathology; University Hospitals Leuven; Leuven Belgium
| | - Maarten Naesens
- Laboratory of Nephrology; Department of Microbiology and Immunology; KU Leuven; Leuven Belgium
- Department of Nephrology and Renal Transplantation; University Hospitals Leuven; Leuven Belgium
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10
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Zhu F, Bai X, Chen X. B lymphocytes in renal interstitial fibrosis. J Cell Commun Signal 2017; 11:213-218. [PMID: 28210941 DOI: 10.1007/s12079-017-0382-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 02/07/2017] [Indexed: 12/11/2022] Open
Abstract
Fibrosis is defined as an excessive deposition of extracellular matrix (ECM), which leads to the destruction of organ structure and impairment of organ function. Fibrosis occurs not only in kidney but also in lung, liver, heart, and skin. Common pathways of fibrosis are thought to exist. Renal interstitial fibrosis is a complex process that involves multiple molecular signaling and multiple cellular components, in which B cells appear to be one of the emerging important players. B cells may affect fibrosis through cytokine production and through interaction with other cells including fibroblasts, macrophages and T cells. This review summarizes recent research findings of B cells in fibrosis and provides an insight of how the future therapeutics of fibrosis could be developed from a B-cell point of view.
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Affiliation(s)
- Fengge Zhu
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Xueyuan Bai
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China.
| | - Xiangmei Chen
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China.
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11
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Loupy A, Haas M, Solez K, Racusen L, Glotz D, Seron D, Nankivell BJ, Colvin RB, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell L, Drachenberg C, Dragun D, de Kort H, Gibson IW, Kraus ES, Lefaucheur C, Legendre C, Liapis H, Muthukumar T, Nickeleit V, Orandi B, Park W, Rabant M, Randhawa P, Reed EF, Roufosse C, Seshan SV, Sis B, Singh HK, Schinstock C, Tambur A, Zeevi A, Mengel M. The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology. Am J Transplant 2017; 17:28-41. [PMID: 27862883 PMCID: PMC5363228 DOI: 10.1111/ajt.14107] [Citation(s) in RCA: 506] [Impact Index Per Article: 63.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Revised: 10/25/2016] [Accepted: 10/28/2016] [Indexed: 01/25/2023]
Abstract
The XIII Banff meeting, held in conjunction the Canadian Society of Transplantation in Vancouver, Canada, reviewed the clinical impact of updates of C4d-negative antibody-mediated rejection (ABMR) from the 2013 meeting, reports from active Banff Working Groups, the relationships of donor-specific antibody tests (anti-HLA and non-HLA) with transplant histopathology, and questions of molecular transplant diagnostics. The use of transcriptome gene sets, their resultant diagnostic classifiers, or common key genes to supplement the diagnosis and classification of rejection requires further consensus agreement and validation in biopsies. Newly introduced concepts include the i-IFTA score, comprising inflammation within areas of fibrosis and atrophy and acceptance of transplant arteriolopathy within the descriptions of chronic active T cell-mediated rejection (TCMR) or chronic ABMR. The pattern of mixed TCMR and ABMR was increasingly recognized. This report also includes improved definitions of TCMR and ABMR in pancreas transplants with specification of vascular lesions and prospects for defining a vascularized composite allograft rejection classification. The goal of the Banff process is ongoing integration of advances in histologic, serologic, and molecular diagnostic techniques to produce a consensus-based reporting system that offers precise composite scores, accurate routine diagnostics, and applicability to next-generation clinical trials.
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12
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Li L, Zhang Y, Xu M, Rong R, Wang J, Zhu T. Inhibition of histone methyltransferase EZH2 ameliorates early acute renal allograft rejection in rats. BMC Immunol 2016; 17:41. [PMID: 27784285 PMCID: PMC5080725 DOI: 10.1186/s12865-016-0179-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 10/17/2016] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Although histone methyltransferases EZH2 has been proved to have significant regulatory effect on the immune rejection after hematopoietic stem cell transplantation, its role in solid-organ transplantation remains uncovered. In this study, we investigate whether histone methylation regulation can impact renal allograft rejection in rat models. RESULTS Allogeneic rat renal transplantation model (Wistar to Lewis) was established, and the recipients were administrated with EZH2 inhibitor DZNep after transplantation. Renal allografts and peripheral blood were collected on day 5 after transplantation for histological examination and mechanism investigation. We found that inhibition of EZH2 by DZNep after transplantation significantly ameliorated acute rejection (AR), with decreased histological injury and reduced inflammatory infiltration in renal allografts. Attenuation of AR was due to the prohibited activation of alloreactive T cells, the subsequent impaired production of inflammatory cytokines, and also the elevated apoptosis of alloreactive T cells in both renal allografts and periphery. However, inhibition of EZH2 did not increase the regulatory T cells during the AR. CONCLUSIONS Disruption of EZH2 by DZNep suppressed the immune responses of alloreactive T cells and ameliorated AR of renal allografts. This suggests a therapeutic potential of targeting histone methyltransferases EZH2 in treating allograft rejection after solid organ transplantation.
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Affiliation(s)
- Long Li
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China
| | - Yi Zhang
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.,Biomedical Research Center, Institute for Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Ming Xu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China
| | - Ruiming Rong
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China
| | - Jina Wang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. .,Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.
| | - Tongyu Zhu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. .,Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.
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13
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Zhao W, Zhang Z, Zhao Q, Liu M, Wang Y. Inhibition of Interferon Regulatory Factor 4 Attenuates Acute Liver Allograft Rejection in Mice. Scand J Immunol 2015; 82:262-8. [PMID: 26095713 DOI: 10.1111/sji.12318] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 05/17/2015] [Indexed: 11/28/2022]
Affiliation(s)
- W. Zhao
- Department of Anesthesiology; Shandong Provincial Qianfoshan hospital; Shandong University. Jinan; Shandong 250014 China
| | - Z. Zhang
- Department of Anesthesiology; The People's Hospital of Zhangqiu.Jinan; Shandong 250200 China
| | - Q. Zhao
- Department of Anesthesiology; The People's Hospital of Zhangqiu.Jinan; Shandong 250200 China
| | - M. Liu
- Department of Anesthesiology; Shandong Provincial Qianfoshan hospital; Shandong University. Jinan; Shandong 250014 China
| | - Y. Wang
- Department of Anesthesiology; Shandong Provincial Qianfoshan hospital; Shandong University. Jinan; Shandong 250014 China
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14
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Li X, Zhuang S. Recent advances in renal interstitial fibrosis and tubular atrophy after kidney transplantation. FIBROGENESIS & TISSUE REPAIR 2014; 7:15. [PMID: 25285155 PMCID: PMC4185272 DOI: 10.1186/1755-1536-7-15] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Accepted: 08/29/2014] [Indexed: 01/05/2023]
Abstract
Although kidney transplantation has been an important means for the treatment of patients with end stage of renal disease, the long-term survival rate of the renal allograft remains a challenge. The cause of late renal allograft loss, once known as chronic allograft nephropathy, has been renamed “interstitial fibrosis and tubular atrophy” (IF/TA) to reflect the histologic pattern seen on biopsy. The mechanisms leading to IF/TA in the transplanted kidney include inflammation, activation of renal fibroblasts, and deposition of extracellular matrix proteins. Identifying the mediators and factors that trigger IF/TA may be useful in early diagnosis and development of novel therapeutic strategies for improving long-term renal allograft survival and patient outcomes. In this review, we highlight the recent advances in our understanding of IF/TA from three aspects: pathogenesis, diagnosis, and treatment.
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Affiliation(s)
- Xiaojun Li
- Department of Nephrology, Tongji University School of Medicine, Shanghai East Hospital, Shanghai, China
| | - Shougang Zhuang
- Department of Nephrology, Tongji University School of Medicine, Shanghai East Hospital, Shanghai, China ; Department of Medicine, Alpert Medical School of Brown University, Rhode Island Hospital, Middle House 301, 593 Eddy Street, Providence, RI 02903, USA
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Guillén-Gómez E, Guirado L, Belmonte X, Maderuelo A, Santín S, Juarez C, Ars E, Facundo C, Ballarín JA, Vidal S, Díaz-Encarnación MM. Monocyte implication in renal allograft dysfunction. Clin Exp Immunol 2014; 175:323-331. [PMID: 24134783 PMCID: PMC3892423 DOI: 10.1111/cei.12228] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2013] [Indexed: 01/05/2023] Open
Abstract
Macrophages are involved in the development and progression of kidney fibrosis. The aim of this study was to analyse the phenotype of circulating monocytes and their ability to predict kidney allograft dysfunction in living kidney transplant recipients. Whole blood samples from 25 kidney recipients and 17 donors were collected at five time-points. Monocyte phenotype was analysed by flow cytometry, and interleukin (IL)-10 and soluble CD163 by enzyme-linked immunosorbent assay. One week after transplantation, surface CD163 and IL-10 levels increased significantly from baseline [2·99 ± 1·38 mean fluorescence intensity (MFI) to 5·18 ± 2·42 MFI for CD163; 4·5 ± 1·46 pg/ml to 6·7 ± 2·5 pg/ml for IL-10]. This CD163 increase correlated with 4-month creatinine levels (r = 0·4394, P = 0·04). However, soluble CD163 decreased significantly from baseline at 1 week (797·11 ± 340·45 ng/ml to 576·50 ± 293·60 ng/ml). CD14(+) CD16(-) monocytes increased at 4 months and correlated positively with creatinine levels at 12 and 24 months (r = 0·6348, P = 0·002 and r = 0·467, P = 0·028, respectively) and negatively with Modification of Diet in Renal Disease (MDRD) at 12 months (r = 0·6056, P = 0·003). At 4 months, IL-10 decreased significantly (P = 0·008) and correlated positively with creatinine at 2 years (r = 0·68, P = 0·010) and with CD14(+) CD16(-) monocytes at 4 months (r = 0·732, P = 0·004). At 24 h, levels of human leucocyte antigen D-related declined from 12·12 ± 5·99 to 5·21 ± 3·84 and CD86 expression decreased from 2·76 ± 1·08 to 1·87 ± 0·95. Both markers recovered progressively until 12 months, when they decreased again. These results indicate that monitoring monocytes could be a promising new prognostic tool of graft dysfunction in renal transplant patients.
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Affiliation(s)
- E Guillén-Gómez
- Laboratori de Biologia Molecular, Fundació Puigvert, Universitat Autònoma de Barcelona, REDinREN, Institut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Barcelona, Spain
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Sinuani I, Beberashvili I, Averbukh Z, Sandbank J. Role of IL-10 in the progression of kidney disease. World J Transplant 2013; 3:91-98. [PMID: 24392313 PMCID: PMC3879528 DOI: 10.5500/wjt.v3.i4.91] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Revised: 07/11/2013] [Accepted: 10/12/2013] [Indexed: 02/05/2023] Open
Abstract
Interleukin-10 (IL-10), a cytokine with anti-inflammatory and immunomodulatory functions, regulates the biology of B and T cells. The present review describes the role of IL-10 in normal renal physiology, during acute kidney injury and in the development of chronic renal failure. We further discuss IL-10-induced cellular and molecular pathways and their link to the progression of kidney injury.
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Williams WW, Taheri D, Tolkoff-Rubin N, Colvin RB. Clinical role of the renal transplant biopsy. Nat Rev Nephrol 2012; 8:110-21. [PMID: 22231130 DOI: 10.1038/nrneph.2011.213] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Percutaneous needle core biopsy is the definitive procedure by which essential diagnostic and prognostic information on acute and chronic renal allograft dysfunction is obtained. The diagnostic value of the information so obtained has endured for over three decades and has proven crucially important in shaping strategies for therapeutic intervention. This Review provides a broad outline of the utility of performing kidney graft biopsies after transplantation, highlighting the relevance of biopsy findings in the immediate and early post-transplant period (from days to weeks after implantation), the first post-transplant year, and the late period (beyond the first year). We focus on how biopsy findings change over time, and the wide variety of pathological features that characterize the major clinical diagnoses facing the clinician. This article also includes a discussion of acute cellular and humoral rejection, the toxic effects of calcineurin inhibitors, and the widely varying etiologies and characteristics of chronic lesions. Emerging technologies based on gene expression analyses and proteomics, the in situ detection of functionally relevant molecules, and new bioinformatic approaches that hold the promise of improving diagnostic precision and developing new, refined molecular pathways for therapeutic intervention are also presented.
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Affiliation(s)
- Winfred W Williams
- Transplant Center, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. wwwilliams@ partners.org
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Gene expression changes are associated with loss of kidney graft function and interstitial fibrosis and tubular atrophy: diagnosis versus prediction. Transplantation 2011; 91:657-65. [PMID: 21242883 DOI: 10.1097/tp.0b013e3182094a5a] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Loss of kidney graft function due to interstitial fibrosis (IF) and tubular atrophy (TA) is the most common cause of kidney allograft loss. METHODS One hundred one allograft tissues (26 samples with IF/TA, 17 normal allografts, and an independent biopsy group collected at 3 month [n=34] posttransplantation) underwent microarray analysis to identify early detection/diagnostic biomarkers of IF/TA. Profiling of 24 allograft biopsies collected at or after 9-month posttransplantation (range 9-18 months) was used for validation. Three-month posttransplantation biopsies were classified as IF/TA nonprogressors (group 1) or progressors (group 2) using graft function and histology at 9-month posttransplantation. RESULTS We identified 2223 differentially expressed probe sets between IF/TA and normal allograft biopsies using a Bonferroni correction. Genes up-regulated in IF/TA were primarily involved in pathways related to T-cell activation, natural killer cell-mediated cytotoxicity, and programmed cell death. A least absolute shrinkage and selection operator model was derived from the differentially expressed probe sets, resulting in a final model that included 10 probe sets and had 100% training set accuracy. The N-fold crossvalidated error was 2.4% (sensitivity 95.8% and specificity 100%). When 3-month biopsies were tested using the model, all the samples were classified as normal. However, evaluating gene expression of the 3-month biopsies and fitting a new penalized model, 100% sensitivity was observed in classifying the samples as group1 or 2. This model was evaluated in the sample set collected at or after 9-month posttransplantation. CONCLUSIONS An IF/TA gene expression signature was identified, and it was useful for diagnosis but not prediction. However, gene expression profiles at 3 months might predict IF/TA progression.
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