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Goutaudier V, Danger R, Catar RA, Racapé M, Philippe A, Elias M, Raynaud M, Aubert O, Bouton D, Girardin F, Vicaut É, Yaiche S, Demotes J, Heidecke H, Taupin JL, Randoux-Lebrun C, Zaidan M, Papuchon E, Le Mai H, Nguyen TVH, Moreso F, Berney T, Villard J, Legendre C, Dragun D, Papalois V, Potena L, Giral M, Gourraud PA, Brouard S, Crespo E, Halleck F, Budde K, Bestard O, Loupy A, Lefaucheur C. Evaluation of non-invasive biomarkers of kidney allograft rejection in a prospective multicenter unselected cohort study (EU-TRAIN). Kidney Int 2024; 106:943-960. [PMID: 39197587 DOI: 10.1016/j.kint.2024.07.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 06/25/2024] [Accepted: 07/26/2024] [Indexed: 09/01/2024]
Abstract
Non-invasive biomarkers are promising tools for improving kidney allograft rejection monitoring, but their clinical adoption requires more evidence in specifically designed studies. To address this unmet need, we designed the EU-TRAIN study, a large prospective multicentric unselected cohort funded by the European Commission. Here, we included consecutive adult patients who received a kidney allograft in nine European transplant centers between November 2018 and June 2020. We prospectively assessed gene expression levels of 19 blood messenger RNAs, four antibodies targeting non-human leukocyte antigen (HLA) endothelial antigens, together with circulating anti-HLA donor-specific antibodies (DSA). The primary outcome was allograft rejection (antibody-mediated, T cell-mediated, or mixed) in the first year post-transplantation. Overall, 412 patients were included, with 812 biopsies paired with a blood sample. CD4 gene expression was significantly associated with rejection, while circulating anti-HLA DSA had a significant association with allograft rejection and a strong association with antibody-mediated rejection. All other tested biomarkers, including AKR1C3, CD3E, CD40, CD8A, CD9, CTLA4, ENTPD1, FOXP3, GZMB, ID3, IL7R, MS4A1, MZB1, POU2AF1, POU2F1, TCL1A, TLR4, and TRIB1, as well as antibodies against angiotensin II type 1 receptor, endothelin 1 type A receptor, C3a and C5a receptors, did not show significant associations with allograft rejection. The blood messenger RNAs and non-HLA antibodies did not show an additional value beyond standard of care monitoring parameters and circulating anti-HLA DSA to predict allograft rejection in the first year post-transplantation. Thus, our results open avenues for specifically designed studies to demonstrate the clinical relevance and implementation of other candidate non-invasive biomarkers in kidney transplantation practice.
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Affiliation(s)
- Valentin Goutaudier
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Richard Danger
- Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Rusan Ali Catar
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Maud Racapé
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Aurélie Philippe
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany; BIH Biomedical Innovation Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin (BIH), Berlin, Germany
| | - Michelle Elias
- Department of Kidney Transplantation, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Marc Raynaud
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Olivier Aubert
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Didier Bouton
- DRCI Direction of Clinical Research and Innovation, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - François Girardin
- Division of Clinical Pharmacology, Department of Medicine and Department of Laboratory Medicine and Pathology, Lausanne University Hospital, Faculty of Medicine, University of Lausanne, Lausanne, Switzerland
| | - Éric Vicaut
- Clinical Trial Unit Hospital, Lariboisière Saint-Louis Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Cité University, Paris, France
| | - Sarhan Yaiche
- ECRIN European Clinical Research Infrastructure Network, Paris, France
| | - Jacques Demotes
- ECRIN European Clinical Research Infrastructure Network, Paris, France
| | | | - Jean-Luc Taupin
- Immunology and Histocompatibility Laboratory, Medical Biology Department, Saint-Louis Hospital, Paris, France
| | | | - Mohamad Zaidan
- Department of Nephrology and Transplantation, Kremlin-Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
| | - Emmanuelle Papuchon
- Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Hoa Le Mai
- Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Thi-Van-Ha Nguyen
- Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Francesc Moreso
- Nephrology and Kidney Transplant Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Thierry Berney
- Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Jean Villard
- Department of Immunology and Allergy and Department of Laboratory Medicine, Geneva University Hospital, Geneva, Switzerland
| | - Christophe Legendre
- Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Duska Dragun
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Vassilios Papalois
- European Society for Organ Transplantation (ESOT); Imperial College Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Luciano Potena
- European Society for Organ Transplantation (ESOT); Cardiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Magali Giral
- Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France; Centre d'Investigation Clinique en Biothérapie, Centre de Ressources Biologiques (CRB), Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France
| | - Pierre-Antoine Gourraud
- Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France; Nantes Université, Centre Hospitalier Universitaire (CHU) Nantes, Pôle Hospitalo-Universitaire 11: Santé Publique, Clinique des données, INSERM, Centre d'Investigation Clinique (CIC) 1413, Nantes, France
| | - Sophie Brouard
- Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France; Centre d'Investigation Clinique en Biothérapie, Centre de Ressources Biologiques (CRB), Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France
| | - Elena Crespo
- Translational Nephrology and Kidney Transplant Research Laboratory, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
| | - Fabian Halleck
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Klemens Budde
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Oriol Bestard
- Nephrology and Kidney Transplant Department, Vall d'Hebron University Hospital, Barcelona, Spain; Translational Nephrology and Kidney Transplant Research Laboratory, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
| | - Alexandre Loupy
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
| | - Carmen Lefaucheur
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Department of Kidney Transplantation, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
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Baert L, Mahmudul HM, Stegall M, Joo H, Oh S. B Cell-mediated Immune Regulation and the Quest for Transplantation Tolerance. Transplantation 2024; 108:2021-2033. [PMID: 38389135 DOI: 10.1097/tp.0000000000004948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2024]
Abstract
Pathophysiologic function of B cells in graft rejection has been well recognized in transplantation. B cells promote alloantigen-specific T-cell response and secrete antibodies that can cause antibody-mediated graft failures and rejections. Therefore, strategies targeting B cells, for example, B-cell depletion, have been used for the prevention of both acute and chronic rejections. Interestingly, however, recent mounting evidence indicates that subsets of B cells yet to be further identified can display potent immune regulatory functions, and they contribute to transplantation tolerance and operational tolerance in both experimental and clinical settings, respectively. In this review, we integrate currently available information on B-cell subsets, including T-cell Ig domain and mucin domain 1-positive transitional and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive memory B cells, displaying immune regulatory functions, with a focus on transplantation tolerance, by analyzing their mechanisms of action. In addition, we will discuss potential T-cell Ig domain and mucin domain 1-positive and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive B cell-based strategies for the enhancement of operational tolerance in transplantation patients.
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Affiliation(s)
- Laurie Baert
- Department of Immunology, Mayo Clinic, Scottsdale, AZ
| | | | - Mark Stegall
- Department of Surgery, William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN
| | - HyeMee Joo
- Department of Immunology, Mayo Clinic, Scottsdale, AZ
| | - SangKon Oh
- Department of Immunology, Mayo Clinic, Scottsdale, AZ
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Elias C, Chen C, Cherukuri A. Regulatory B Cells in Solid Organ Transplantation: From Immune Monitoring to Immunotherapy. Transplantation 2024; 108:1080-1089. [PMID: 37779239 PMCID: PMC10985051 DOI: 10.1097/tp.0000000000004798] [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] [Indexed: 10/03/2023]
Abstract
Regulatory B cells (Breg) modulate the immune response in diverse disease settings including transplantation. Despite the lack of a specific phenotypic marker or transcription factor, their significance in transplantation is underscored by their ability to prolong experimental allograft survival, the possibility for their clinical use as immune monitoring tools, and the exciting prospect for them to form the basis for cell therapy. Interleukin (IL)-10 expression remains the most widely used marker for Breg. Several Breg subsets with distinct phenotypes that express this "signature Breg cytokine" have been described in mice and humans. Although T-cell immunoglobulin and mucin family-1 is the most inclusive and functional marker that accounts for murine Breg with disparate mechanisms of action, the significance of T-cell immunoglobulin and mucin family-1 as a marker for Breg in humans still needs to be explored. Although the primary focus of this review is the role of Breg in clinical transplantation, the net modulatory effect of B cells on the immune response and clinical outcomes is the result of the balancing functions of both Breg and effector B cells. Supporting this notion, B-cell IL-10/tumor necrosis factor α ratio is shown to predict immunologic reactivity and clinical outcomes in kidney and liver transplantation. Assessment of Breg:B effector balance using their IL-10/tumor necrosis factor α ratio may identify patients that require more immunosuppression and provide mechanistic insights into potential therapies. In summary, current advances in our understanding of murine and human Breg will pave way for future definitive clinical studies aiming to test them for immune monitoring and as therapeutic targets.
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Affiliation(s)
- Charbel Elias
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Chuxiao Chen
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Aravind Cherukuri
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Renal and Electrolyte Division, Department of Internal Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
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Hruba P, Klema J, Le AV, Girmanova E, Mrazova P, Massart A, Maixnerova D, Voska L, Piredda GB, Biancone L, Puga AR, Seyahi N, Sever MS, Weekers L, Muhfeld A, Budde K, Watschinger B, Miglinas M, Zahradka I, Abramowicz M, Abramowicz D, Viklicky O. Novel transcriptomic signatures associated with premature kidney allograft failure. EBioMedicine 2023; 96:104782. [PMID: 37660534 PMCID: PMC10480056 DOI: 10.1016/j.ebiom.2023.104782] [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: 04/25/2023] [Revised: 08/18/2023] [Accepted: 08/18/2023] [Indexed: 09/05/2023] Open
Abstract
BACKGROUND The power to predict kidney allograft outcomes based on non-invasive assays is limited. Assessment of operational tolerance (OT) patients allows us to identify transcriptomic signatures of true non-responders for construction of predictive models. METHODS In this observational retrospective study, RNA sequencing of peripheral blood was used in a derivation cohort to identify a protective set of transcripts by comparing 15 OT patients (40% females), from the TOMOGRAM Study (NCT05124444), 14 chronic active antibody-mediated rejection (CABMR) and 23 stable graft function patients ≥15 years (STA). The selected differentially expressed transcripts between OT and CABMR were used in a validation cohort (n = 396) to predict 3-year kidney allograft loss at 3 time-points using RT-qPCR. FINDINGS Archetypal analysis and classifier performance of RNA sequencing data showed that OT is clearly distinguishable from CABMR, but similar to STA. Based on significant transcripts from the validation cohort in univariable analysis, 2 multivariable Cox models were created. A 3-transcript (ADGRG3, ATG2A, and GNLY) model from POD 7 predicted graft loss with C-statistics (C) 0.727 (95% CI, 0.638-0.820). Another 3-transcript (IGHM, CD5, GNLY) model from M3 predicted graft loss with C 0.786 (95% CI, 0.785-0.865). Combining 3-transcripts models with eGFR at POD 7 and M3 improved C-statistics to 0.860 (95% CI, 0.778-0.944) and 0.868 (95% CI, 0.790-0.944), respectively. INTERPRETATION Identification of transcripts distinguishing OT from CABMR allowed us to construct models predicting premature graft loss. Identified transcripts reflect mechanisms of injury/repair and alloimmune response when assessed at day 7 or with a loss of protective phenotype when assessed at month 3. FUNDING Supported by the Ministry of Health of the Czech Republic under grant NV19-06-00031.
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Affiliation(s)
- Petra Hruba
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Jiri Klema
- Department of Computer Science, Czech Technical University, Prague, Czech Republic
| | - Anh Vu Le
- Department of Computer Science, Czech Technical University, Prague, Czech Republic
| | - Eva Girmanova
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Petra Mrazova
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Annick Massart
- Antwerp University Hospital and Antwerp University, Antwerp, Belgium
| | - Dita Maixnerova
- Department of Nephrology, 1st Faculty of Medicine and General Faculty Hospital, Prague, Czech Republic
| | - Ludek Voska
- Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Gian Benedetto Piredda
- Department of Kidney Disease Medicine of Renal Transplantation, G.Brotzu Hospital Cagliari, Italy
| | - Luigi Biancone
- Department of Medical Sciences, University of Torino, Torino, Italy
| | - Ana Ramirez Puga
- Hospital Universitario Insular de Gran Canaria, Servicio de nefrología, Spain
| | - Nurhan Seyahi
- Istanbul University, Cerrahpasa Medical Faculty, Nephrology, Istanbul, Turkey
| | - Mehmet Sukru Sever
- Istanbul University, Istanbul School of Medicine, Internal Medicine, Nephrology, Istanbul, Turkey
| | | | - Anja Muhfeld
- Department of Nephrology, Uniklinik RWTH Aachen, Aachen, Germany
| | - Klemens Budde
- Charité - Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Nephrologie und Internistische Intensivmedizin, Berlin, Germany
| | - Bruno Watschinger
- Department of Internal Medicine III, Nephrology, Medical University Vienna / AKH Wien, Vienna, Austria
| | - Marius Miglinas
- Faculty of Medicine, Nephrology Center, Vilnius University Hospital Santaros Klinikos, Vilnius University, Vilnius, Lithuania
| | - Ivan Zahradka
- Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Marc Abramowicz
- Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Rue Michel Servet 1, 1206 Geneva, Switzerland
| | - Daniel Abramowicz
- Antwerp University Hospital and Antwerp University, Antwerp, Belgium
| | - Ondrej Viklicky
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
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Novacescu D, Latcu SC, Bardan R, Daminescu L, Cumpanas AA. Contemporary Biomarkers for Renal Transplantation: A Narrative Overview. J Pers Med 2023; 13:1216. [PMID: 37623466 PMCID: PMC10456039 DOI: 10.3390/jpm13081216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/18/2023] [Accepted: 07/28/2023] [Indexed: 08/26/2023] Open
Abstract
Renal transplantation (RT) is the preferred treatment for end-stage renal disease. However, clinical challenges persist, i.e., early detection of graft dysfunction, timely identification of rejection episodes, personalization of immunosuppressive therapy, and prediction of long-term graft survival. Biomarkers have emerged as valuable tools to address these challenges and revolutionize RT patient care. Our review synthesizes the existing scientific literature to highlight promising biomarkers, their biological characteristics, and their potential roles in enhancing clinical decision-making and patient outcomes. Emerging non-invasive biomarkers seemingly provide valuable insights into the immunopathology of nephron injury and allograft rejection. Moreover, we analyzed biomarkers with intra-nephron specificities, i.e., glomerular vs. tubular (proximal vs. distal), which can localize an injury in different nephron areas. Additionally, this paper provides a comprehensive analysis of the potential clinical applications of biomarkers in the prediction, detection, differential diagnosis and assessment of post-RT non-surgical allograft complications. Lastly, we focus on the pursuit of immune tolerance biomarkers, which aims to reclassify transplant recipients based on immune risk thresholds, guide personalized immunosuppression strategies, and ultimately identify patients for whom immunosuppression may safely be reduced. Further research, validation, standardization, and prospective studies are necessary to fully harness the clinical utility of RT biomarkers and guide the development of targeted therapies.
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Affiliation(s)
- Dorin Novacescu
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Silviu Constantin Latcu
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania;
- Department of Urology, “Pius Brinzeu” Timisoara County Emergency Hospital, Liviu Rebreanu Boulevard, Nr. 156, 300723 Timisoara, Romania; (R.B.); (L.D.); (A.A.C.)
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Razvan Bardan
- Department of Urology, “Pius Brinzeu” Timisoara County Emergency Hospital, Liviu Rebreanu Boulevard, Nr. 156, 300723 Timisoara, Romania; (R.B.); (L.D.); (A.A.C.)
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Liviu Daminescu
- Department of Urology, “Pius Brinzeu” Timisoara County Emergency Hospital, Liviu Rebreanu Boulevard, Nr. 156, 300723 Timisoara, Romania; (R.B.); (L.D.); (A.A.C.)
| | - Alin Adrian Cumpanas
- Department of Urology, “Pius Brinzeu” Timisoara County Emergency Hospital, Liviu Rebreanu Boulevard, Nr. 156, 300723 Timisoara, Romania; (R.B.); (L.D.); (A.A.C.)
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
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Bae H, Lee H, Ko EJ, Kim CD, Lee SH, Yang CW, Oh EJ, Chung BH. Discovery of cellular and genetic signatures of immune tolerance in kidney transplant recipients through single cell RNA sequencing analysis. HLA 2023. [PMID: 37038287 DOI: 10.1111/tan.15061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 03/29/2023] [Accepted: 03/31/2023] [Indexed: 04/12/2023]
Abstract
The objective of this study was to uncover distinct cellular and genetic signatures of transplant operational tolerance (TOT) in kidney transplant recipients (KTRs) through single cell RNA sequencing (scRNA-seq) using peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from 12 KTRs, including those with TOT (TOT, n = 4), stable allograft function on maintenance immunosuppression (STA, n = 4) and biopsy-proven allograft rejection (BPAR, n = 4). ScRNA-seq of PBMCs was analyzed using 20 cell surface marker antibody sequencing to annotate clusters and 399 immune response panel to identify gene expression. Differences in cellular distribution and gene expression were compared among the three groups. Heatmap hierarchical clustering showed that overall cellular distribution pattern was distinct in TOT in comparison with those in the other two groups, with the proportion of B cells being higher in TOT, attributed to immature B cell fraction (TOT vs. STA vs. BPAR: 4.61% vs. 1.27% vs. 2.53%, p = 0.01). Transcript analysis of B cells revealed that genes involved in allo-immune pathway were downregulated in TOT. In T cell subset analysis, the proportion of naïve T cells and regulatory T cells (Tregs) was increased. In transcript analysis, genes associated with inflammation were decreased, while expression levels of CCR6 in Tregs were increased in TOT. Proportions of NKT and NK cells were increased in TOT than in the other two groups. This study showed that TOT has distinct cellular and genetic signatures such as increases of immature B cells, naïve T cells and Tregs and high expression levels of CCR6 in Tregs.
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Affiliation(s)
- Hyunjoo Bae
- Department of Biomedical Science, Graduated School, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hanbi Lee
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Transplantation Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Convergent Research Consortium for Immunologic disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun Jeong Ko
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Transplantation Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Convergent Research Consortium for Immunologic disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chan-Duck Kim
- Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Sang-Ho Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gandong, Seoul, Republic of Korea
| | - Chul Woo Yang
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Transplantation Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Convergent Research Consortium for Immunologic disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun-Jee Oh
- Department of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Byung Ha Chung
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Transplantation Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Convergent Research Consortium for Immunologic disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Danger R, Le Berre L, Cadoux M, Kerleau C, Papuchon E, Mai HL, Nguyen TVH, Guérif P, Morelon E, Thaunat O, Legendre C, Anglicheau D, Lefaucheur C, Couzi L, Del Bello A, Kamar N, Le Quintrec M, Goutaudier V, Renaudin K, Giral M, Brouard S. Subclinical rejection-free diagnostic after kidney transplantation using blood gene expression. Kidney Int 2023; 103:1167-1179. [PMID: 36990211 DOI: 10.1016/j.kint.2023.03.019] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 02/16/2023] [Accepted: 03/08/2023] [Indexed: 03/29/2023]
Abstract
We previously established a six-gene-based blood score associated with operational tolerance in kidney transplantation which was decreased in patients developing anti-HLA donor-specific antibodies (DSA). Herein, we aimed to confirm that this score is associated with immunological events and risk of rejection. We measured this using quantitative PCR (qPCR) and NanoString methods from an independent multicenter cohort of 588 kidney transplant recipients with paired blood samples and biopsies at one year after transplantation validating its association with pre-existing and de novo DSA. From 441 patients with protocol biopsy, there was a significant decrease of the score of tolerance in 45 patients with biopsy-proven subclinical rejection (SCR), a major threat associated with pejorative allograft outcomes that prompted an SCR score refinement. This refinement used only two genes, AKR1C3 and TCL1A, and four clinical parameters (previous experience of rejection, previous transplantation, sex of recipient and tacrolimus uptake). This refined SCR score was able to identify patients unlikely to develop SCR with a C-statistic of 0.864 and a negative predictive value of 98.3%. The SCR score was validated in an external laboratory, with two methods (qPCR and NanoString), and on 447 patients from an independent and multicenter cohort. Moreover, this score allowed reclassifying patients with discrepancies between the DSA presence and the histological diagnosis of antibody mediated rejection unlike kidney function. Thus, our refined SCR score could improve detection of SCR for closer and noninvasive monitoring, allowing early treatment of SCR lesions notably for patients DSA-positive and during lowering of immunosuppressive treatment.
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Affiliation(s)
- Richard Danger
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France.
| | - Ludmilla Le Berre
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Marion Cadoux
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Clarisse Kerleau
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Emmanuelle Papuchon
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France; Centre d'Investigation Clinique en Biothérapie, Centre de Ressources Biologiques (CRB), CHU Nantes, Nantes, France
| | - Hoa Le Mai
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Thi-Van-Ha Nguyen
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Pierrick Guérif
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France
| | - Emmanuel Morelon
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, INSERM Unit 1111, Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
| | - Olivier Thaunat
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, INSERM Unit 1111, Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
| | - Christophe Legendre
- Department of Nephrology and Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Necker-Enfants Malades Institute, INSERM, Paris University, Paris, France
| | - Dany Anglicheau
- Department of Nephrology and Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Necker-Enfants Malades Institute, INSERM, Paris University, Paris, France
| | - Carmen Lefaucheur
- Paris Translational Research Center for Organ Transplantation, INSERM UMR S970, Université Paris Cité, Kidney Transplant Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Lionel Couzi
- Department of Nephrology, Transplantation, Dialysis, and Apheresis, CHU Bordeaux, Bordeaux, France
| | - Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, Centre Hospitalier Universitaire de Toulouse, INSERM UMR1291 - Université Toulouse III, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, Centre Hospitalier Universitaire de Toulouse, INSERM UMR1291 - Université Toulouse III, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France
| | - Moglie Le Quintrec
- Department of Nephrology, Dialysis and Renal Transplantation, University Hospital of Lapeyronie, Montpellier, France
| | - Valentin Goutaudier
- Department of Nephrology and Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Necker-Enfants Malades Institute, INSERM, Paris University, Paris, France; Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Karine Renaudin
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France; CHU Nantes, Service d'Anatomie et Cytologie Pathologiques, Nantes, France
| | - Magali Giral
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France; Centre d'Investigation Clinique en Biothérapie, Centre de Ressources Biologiques (CRB), CHU Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes Université, Nantes, France
| | - Sophie Brouard
- CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, ITUN, Nantes, France; Centre d'Investigation Clinique en Biothérapie, Centre de Ressources Biologiques (CRB), CHU Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes Université, Nantes, France.
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8
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Li Z, Lu Z, Hu C, Zhang Y, Chen Y, Zhang J, Guo F, Wang J, Tang Z, Tang F, He Z. A Machine Learning Analysis of Prognostic Genes Associated With Allograft Tolerance After Renal Transplantation. Cell Transplant 2023; 32:9636897231195116. [PMID: 37650419 PMCID: PMC10475226 DOI: 10.1177/09636897231195116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 07/22/2023] [Accepted: 08/01/2023] [Indexed: 09/01/2023] Open
Abstract
In this study, we aimed to identify transplantation tolerance (TOL)-related gene signature and use it to predict the different types of renal allograft rejection performances in kidney transplantation. Gene expression data were obtained from the Gene Expression Omnibus (GEO) database, differently expressed genes (DEGs) were performed, and the gene ontology (GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were also conducted. The machine learning methods were combined to analyze the feature TOL-related genes and verify their predictive performance. Afterward, the gene expression levels and predictive performances of TOL-related genes were conducted in the context of acute rejection (AR), chronic rejection (CR), and graft loss through heatmap plots and the receiver operating characteristic (ROC) curves, and their respective immune infiltration results were also performed. Furthermore, the TOL-related gene signature for graft survival was conducted to discover gene immune cell enrichment. A total of 25 TOL-related DEGs were founded, and the GO and KEGG results indicated that DEGs mainly enriched in B cell-related functions and pathways. 7 TOL-related gene signature was constructed and performed delightedly in TOL groups and different types of allograft rejection. The immune infiltration analysis suggested that gene signature was correlated with different types of immune cells. The Kaplan-Meier (KM) survival analysis demonstrated that BLNK and MZB1 were the prognostic TOL-related genes. Our study proposed a novel gene signature that may influence TOL in kidney transplantation, providing possible guidance for immunosuppressive therapy in kidney transplant patients.
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Affiliation(s)
- Zhibiao Li
- Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Zechao Lu
- Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Chuxian Hu
- The Sixth Clinical College of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yixin Zhang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, China
| | - Yushu Chen
- Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Jiahao Zhang
- Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Feng Guo
- Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Jinjin Wang
- Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Zhicheng Tang
- Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Fucai Tang
- Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Zhaohui He
- Department of Urology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
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9
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Alfaro R, Lorente S, Jimenez-Coll V, Martínez-Banaclocha H, Galián JA, Botella C, Moya-Quiles MR, Muro-Pérez M, de la Peña-Moral J, Minguela A, Legaz I, Muro M. Evaluating the Link between BAFF System Gene Expression and Acute Rejection Development in Kidney Transplantation. J Clin Med 2022; 11:jcm11143956. [PMID: 35887720 PMCID: PMC9319040 DOI: 10.3390/jcm11143956] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 06/28/2022] [Accepted: 07/05/2022] [Indexed: 02/04/2023] Open
Abstract
B-cell activating factor (BAFF) system signaling is critical for B-cell homeostasis, effector functions, and tolerance maintenance in transplants, but it has not been studied in kidney transplant recipients (KTRs). The aim was to analyze the changes in BAFF system expression in KTRs with/without acute rejection (AR/NAR). The BAFF system expression was analyzed by qPCR in 40 KTRs. A meta-analysis of BAFF system expression and histological renal damage was identified by the Chronic Allograft Damage Index (CADI) and performed from the GEO database. Proliferation-inducing ligand (APRIL) expression increased at three- and six-months post-KT (p = 0.014 and p < 0.001). B-cell maturation antigen (BCMA) expression increased at six-months post-KT (p = 0.038). BAFF expression remained stable in NAR-KTRs, but was increased in CADI concerning the No-CADI group at one year (p = 0.008). BCMA expression increased in the CADI group at one- (p = 0.001) and six-years post-KT (p = 0.024). At three months, the transmembrane activator and calcium modulator interactor (TACI) gene significantly elevated KTRs with DSAs (donor-specific antibody; p = 0.034). KTRs with DSAs significantly increase the B-cell activating factor receptor (R-BAFF; p = 0.021) and TACI (p = 0.018) between pre- and three-month post-KT. Changes in the expression of the BAFF system increase during post-KTR in the development of AR and chronic allograft damage, and could be an important pathological tool to detect and prevent kidney graft outcomes.
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Affiliation(s)
- Rafael Alfaro
- Immunology Services, University Clinical Hospital, Virgen de la Arrixaca-Biomedical Research Institute of Murcia (IMIB), 30100 Murcia, Spain; (R.A.); (V.J.-C.); (H.M.-B.); (J.A.G.); (C.B.); (M.R.M.-Q.); (M.M.-P.); (A.M.)
| | - Santiago Lorente
- Nephrology Services, University Clinical Hospital, Virgen de la Arrixaca-Biomedical Research Institute of Murcia (IMIB), 30100 Murcia, Spain;
| | - Víctor Jimenez-Coll
- Immunology Services, University Clinical Hospital, Virgen de la Arrixaca-Biomedical Research Institute of Murcia (IMIB), 30100 Murcia, Spain; (R.A.); (V.J.-C.); (H.M.-B.); (J.A.G.); (C.B.); (M.R.M.-Q.); (M.M.-P.); (A.M.)
| | - Helios Martínez-Banaclocha
- Immunology Services, University Clinical Hospital, Virgen de la Arrixaca-Biomedical Research Institute of Murcia (IMIB), 30100 Murcia, Spain; (R.A.); (V.J.-C.); (H.M.-B.); (J.A.G.); (C.B.); (M.R.M.-Q.); (M.M.-P.); (A.M.)
| | - José Antonio Galián
- Immunology Services, University Clinical Hospital, Virgen de la Arrixaca-Biomedical Research Institute of Murcia (IMIB), 30100 Murcia, Spain; (R.A.); (V.J.-C.); (H.M.-B.); (J.A.G.); (C.B.); (M.R.M.-Q.); (M.M.-P.); (A.M.)
| | - Carmen Botella
- Immunology Services, University Clinical Hospital, Virgen de la Arrixaca-Biomedical Research Institute of Murcia (IMIB), 30100 Murcia, Spain; (R.A.); (V.J.-C.); (H.M.-B.); (J.A.G.); (C.B.); (M.R.M.-Q.); (M.M.-P.); (A.M.)
| | - María Rosa Moya-Quiles
- Immunology Services, University Clinical Hospital, Virgen de la Arrixaca-Biomedical Research Institute of Murcia (IMIB), 30100 Murcia, Spain; (R.A.); (V.J.-C.); (H.M.-B.); (J.A.G.); (C.B.); (M.R.M.-Q.); (M.M.-P.); (A.M.)
| | - Manuel Muro-Pérez
- Immunology Services, University Clinical Hospital, Virgen de la Arrixaca-Biomedical Research Institute of Murcia (IMIB), 30100 Murcia, Spain; (R.A.); (V.J.-C.); (H.M.-B.); (J.A.G.); (C.B.); (M.R.M.-Q.); (M.M.-P.); (A.M.)
| | - Jesús de la Peña-Moral
- Pathology Services, University Clinical Hospital, Virgen de la Arrixaca-Biomedical Research Institute of Murcia (IMIB), 30100 Murcia, Spain;
| | - Alfredo Minguela
- Immunology Services, University Clinical Hospital, Virgen de la Arrixaca-Biomedical Research Institute of Murcia (IMIB), 30100 Murcia, Spain; (R.A.); (V.J.-C.); (H.M.-B.); (J.A.G.); (C.B.); (M.R.M.-Q.); (M.M.-P.); (A.M.)
| | - Isabel Legaz
- Department of Legal and Forensic Medicine, Faculty of Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum”, University of Murcia, 30100 Murcia, Spain
- Correspondence: (I.L.); (M.M.)
| | - Manuel Muro
- Immunology Services, University Clinical Hospital, Virgen de la Arrixaca-Biomedical Research Institute of Murcia (IMIB), 30100 Murcia, Spain; (R.A.); (V.J.-C.); (H.M.-B.); (J.A.G.); (C.B.); (M.R.M.-Q.); (M.M.-P.); (A.M.)
- Correspondence: (I.L.); (M.M.)
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10
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Early prediction of renal graft function: Analysis of a multi-center, multi-level data set. Curr Res Transl Med 2022; 70:103334. [DOI: 10.1016/j.retram.2022.103334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 01/05/2022] [Accepted: 01/14/2022] [Indexed: 11/20/2022]
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11
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Jiang L, Yang Y, Liu F, Ma M, Gao J, Sun L, Chen Y, Shen Z, Wu D. A Potential Diagnostic and Prognostic Biomarker TMEM176B and Its Relationship With Immune Infiltration in Skin Cutaneous Melanoma. Front Cell Dev Biol 2022; 10:859958. [PMID: 35399535 PMCID: PMC8986129 DOI: 10.3389/fcell.2022.859958] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 03/04/2022] [Indexed: 12/22/2022] Open
Abstract
Background: Melanoma is a highly malignant and aggressive tumor. The search for new and effective biomarkers facilitates early diagnosis and treatment, ultimately improving the prognosis of melanoma patients. Although the transmembrane protein TMEM176B has been linked to a number of cancers, its role in cancer immunity remains unknown. Methods: Expression levels of TMEM176B in normal tissues and several cancers, including Skin Cutaneous Melanoma (SKCM), were collected from TCGA and GTEx. We used Receiver operating characteristic and Kaplan–Meier survival curves and performed regression analysis to elucidate the link between TMEM176B and clinicopathological features of SKCM in order to determine the prognostic significance of TMEM176B in SKCM. We then used the GEPIA and STRING websites to search for proteins and associated top genes that may interact with TMEM176B and enriched them for analysis. The link between TMEM176B and immune cells infiltration was then investigated using TIMER, CIBERSORT algorithm and GSVA package of R (v3.6.3). Finally, animal tests were conducted to confirm the expression of Tmem176b and its influence on T-cell immune infiltration. Results:TMEM176B expression was considerably elevated in SKCM compared to normal tissues. Particularly, TMEM176B expression was also linked to pathological stage, tumor ulceration and radiation therapy. Patients with elevated TMEM176B expression had a better prognosis, according to the survival analysis. The majority of tumor infiltrating lymphocytes (TILs) especially T cells in SKCM was positively linked with TMEM176B expression. Our animal experiments also verified that the T-cell infiltration was significantly inhibited in local melanoma tissue of Tmem176b knockout mice. At the same time deleting Tmem176b accelerated tumor progress and impaired T cells effector function. Conclusion: Upregulated expression of TMEM176B in SKCM is associated with a better prognosis and it has the potential to serve as a diagnostic and prognostic marker for the disease. It may serve as a target for SKCM immunotherapy by regulating CD8+ T cells although it requires more evidence.
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Affiliation(s)
- Linlan Jiang
- Department of Oncology, Affiliated Sixth People’s Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Yanyin Yang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Fudan University, Shanghai, China
| | - Fangming Liu
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mingyue Ma
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Fudan University, Shanghai, China
| | - Jie Gao
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lu Sun
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuwen Chen
- Jinshan Hospital Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China
| | - Zan Shen
- Department of Oncology, Affiliated Sixth People’s Hospital, Shanghai Jiaotong University, Shanghai, China
- *Correspondence: Duojiao Wu, ; Zan Shen,
| | - Duojiao Wu
- Jinshan Hospital Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- *Correspondence: Duojiao Wu, ; Zan Shen,
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12
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Steines L, Scharf M, Hoffmann P, Schuster A, Banas B, Bergler T. Monitoring B cell alloresponses in rats. J Immunol Methods 2022; 501:113212. [PMID: 34971633 DOI: 10.1016/j.jim.2021.113212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 12/01/2021] [Accepted: 12/23/2021] [Indexed: 11/24/2022]
Abstract
Antibody-mediated rejection is a major cause of graft failure in organ transplantation. For this reason, B cell responses are of particular interest to transplantation research. Rats are important model organisms for transplant studies, but B cell alloimmune assays and B cell subset markers are poorly established in rats. We alloimmunized rats by donor blood injection using the high responder rat strain combination Brown Norway (donor) and Lewis (recipient) rats. Using splenocytes from alloimmunized and control rats, we established assays to assess allospecific B cell proliferation and the capacity to generate allospecific B memory cells and alloantibody-secreting cells after antigenic rechallenge in vitro using a mixed lymphocyte reaction. Furthermore, we defined a simple gating and sorting strategy for pre- and post-germinal center follicular B cells, as well as non-switched and switched plasmablasts. Our protocols for assessing B cell alloresponses and B cell subsets in rats may help to accelerate research into the role of B cells and manipulation of humoral alloresponses in transplant research.
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Affiliation(s)
- Louisa Steines
- Department of Nephrology, University Hospital Regensburg, Germany.
| | - Mona Scharf
- Department of Nephrology, University Hospital Regensburg, Germany
| | - Petra Hoffmann
- Department of Internal Medicine III, University Hospital Regensburg, Germany; Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany
| | - Antonia Schuster
- Department of Nephrology, University Hospital Regensburg, Germany
| | - Bernhard Banas
- Department of Nephrology, University Hospital Regensburg, Germany
| | - Tobias Bergler
- Department of Nephrology, University Hospital Regensburg, Germany
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13
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Liu J, Tang T, Qu Z, Wang L, Si R, Wang H, Jiang Y. Elevated number of IL-21+ TFH and CD86+CD38+ B cells in blood of renal transplant recipients with AMR under conventional immuno-suppression. Int J Immunopathol Pharmacol 2022; 36:20587384211048027. [PMID: 35012395 PMCID: PMC8755922 DOI: 10.1177/20587384211048027] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 09/03/2021] [Indexed: 11/12/2022] Open
Abstract
The objective of this study is to detect the number of different subsets of TFH and B cells in renal transplant recipients (RTR) with antibody-mediated acute rejection (AMR), acute rejection (AR), chronic rejection (CR), or transplant stable (TS). The present study was a prospective study. The numbers of ICOS +, PD-1+ and IL-21+ TFH, CD86+, CD38+, CD27+, and IgD- B cells in 21 patients with end-stage renal disease (ESRD) and post-transplant times were measured by flow cytometry. The level of serum IL-21 was detected by ELISA. The numbers of circulating CD4+CXCR5+, CD4+CXCR5+ICOS+, CD4+CXCR5+PD-1+, CD4+CXCR5+IL-21+ TFH, CD19+CD86+, and CD19 +CD86+CD38+ B cells as well as the level of serum IL-21 in the AMR, AR, and CR groups at post-transplantation were significantly higher than those at pre-transplantation. In contrast, the number of circulating CD19+CD27+IgD B cells was significantly increased in the TS groups in respect to the other groups. Moreover, the numbers of circulating CD4+CXCR5+IL-21+ TFH cells, CD19+CD86+CD38+ B cells as well as the level of serum IL-21 were positive related to the level of serum Cr while showing negative correlated with the values of eGFR in the AMR groups at post-transplantation for 4 and 12 weeks. Circulating TFH cells may be a biomarker in RTR with AMR, which can promote the differentiation of B cells into plasma cells by activating B cells, thereby promoting disease progression.
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Affiliation(s)
- Jing Liu
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, China
| | - Tongyu Tang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, China
| | - Zhihui Qu
- Department of Nephrology, the First Hospital of Jilin University, Changchun, China
| | - Li Wang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, China
- Xu Zhou Central Hospital, Xuzhou, China
| | - Rui Si
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, China
| | - Haifeng Wang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, China
| | - Yanfang Jiang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, China
- Key Laboratory of Zoonoses Research, Ministry of Education, The First Hospital of Jilin University, Changchun, China
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14
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Fu Q, Agarwal D, Deng K, Matheson R, Yang H, Wei L, Ran Q, Deng S, Markmann JF. An Unbiased Machine Learning Exploration Reveals Gene Sets Predictive of Allograft Tolerance After Kidney Transplantation. Front Immunol 2021; 12:695806. [PMID: 34305931 PMCID: PMC8297499 DOI: 10.3389/fimmu.2021.695806] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/18/2021] [Indexed: 12/14/2022] Open
Abstract
Efforts at finding potential biomarkers of tolerance after kidney transplantation have been hindered by limited sample size, as well as the complicated mechanisms underlying tolerance and the potential risk of rejection after immunosuppressant withdrawal. In this work, three different publicly available genome-wide expression data sets of peripheral blood lymphocyte (PBL) from 63 tolerant patients were used to compare 14 different machine learning models for their ability to predict spontaneous kidney graft tolerance. We found that the Best Subset Selection (BSS) regression approach was the most powerful with a sensitivity of 91.7% and a specificity of 93.8% in the test group, and a specificity of 86.1% and a sensitivity of 80% in the validation group. A feature set with five genes (HLA-DOA, TCL1A, EBF1, CD79B, and PNOC) was identified using the BSS model. EBF1 downregulation was also an independent factor predictive of graft rejection and graft loss. An AUC value of 84.4% was achieved using the two-gene signature (EBF1 and HLA-DOA) as an input to our classifier. Overall, our systematic machine learning exploration suggests novel biological targets that might affect tolerance to renal allografts, and provides clinical insights that can potentially guide patient selection for immunosuppressant withdrawal.
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Affiliation(s)
- Qiang Fu
- Organ Transplantation Center, Sichuan Provincial People's Hospital and School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.,Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Divyansh Agarwal
- Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, United States
| | - Kevin Deng
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Rudy Matheson
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Hongji Yang
- Organ Transplantation Center, Sichuan Provincial People's Hospital and School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Liang Wei
- Organ Transplantation Center, Sichuan Provincial People's Hospital and School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Qing Ran
- Organ Transplantation Center, Sichuan Provincial People's Hospital and School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Shaoping Deng
- Organ Transplantation Center, Sichuan Provincial People's Hospital and School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - James F Markmann
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
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15
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Nagakawa S, Shiota M, Fujimoto N, Yamamoto Y, Blas L, Tsukahara S, Matsumoto T, Kashiwagi E, Takeuchi A, Inokuchi J, Uchiumi T, Matsuyama H, Eto M. The impact of single-nucleotide polymorphisms on intravesical recurrence after bacillus Calmette-Guérin therapy for non-muscle invasive bladder cancer in a genome-wide association study. Urol Oncol 2021; 39:733.e17-733.e24. [PMID: 34215507 DOI: 10.1016/j.urolonc.2021.05.034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/25/2021] [Accepted: 05/27/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVE Bacillus Calmette-Guérin (BCG) instillation therapy is widely used to reduce intravesical recurrence in non-muscle invasive bladder cancer (NMIBC). In this study, we aimed to reveal the genetic variations associated with intravesical recurrence after BCG therapy for NMIBC in a genome-wide association study (GWAS). MATERIALS AND METHODS This study included Japanese patients with NMIBC, in whom genomic DNA was obtained from whole blood samples. The association between genetic variation and treatment failure was analyzed by GWAS in 44 patients treated with BCG instillation as a discovery cohort. Candidate single-nucleotide polymorphisms (SNPs) were examined separately in 47 patients treated with BCG instillation and in 62 patients treated with chemotherapeutic agent instillation as validation studies. RESULTS Among the 44 patients in the discovery cohort, 14 cases experienced intravesical recurrent diseases. GWAS identified 12 candidate SNPs (rs9374832, rs35176001, rs363765, rs2127120, rs4277759, rs73664140, rs1607282, rs12141654, rs4541358, rs6986852, rs12373386, and rs17637903). In the validation study, a genetic risk stratification model using the number of risk alleles in rs363765 and rs6986852 discriminated the risk of intravesical recurrence after BCG therapy, but not after non-BCG therapy. CONCLUSION This study suggested that several SNPs were associated with intravesical recurrence after BCG therapy for NMIBC. A genetic risk model may be useful to predict intravesical recurrence after BCG therapy, warranting further research and development for clinical application.
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Affiliation(s)
- Shohei Nagakawa
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaki Shiota
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Naohiro Fujimoto
- Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Yoshiaki Yamamoto
- Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Japan
| | - Leandro Blas
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shigehiro Tsukahara
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takashi Matsumoto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Kashiwagi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ario Takeuchi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Junichi Inokuchi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Uchiumi
- Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hideyasu Matsuyama
- Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Japan
| | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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16
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TCL1A, B Cell Regulation and Tolerance in Renal Transplantation. Cells 2021; 10:cells10061367. [PMID: 34206047 PMCID: PMC8230170 DOI: 10.3390/cells10061367] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 05/25/2021] [Accepted: 05/29/2021] [Indexed: 12/31/2022] Open
Abstract
Despite much progress in the management of kidney transplantation, the need for life-long immunosuppressive therapies remains a major issue representing many risks for patients. Operational tolerance, defined as allograft acceptance without immunosuppression, has logically been subject to many investigations with the aim of a better understanding of post-transplantation mechanisms and potentially how it would be induced in patients. Among proposed biomarkers, T-cell Leukemia/Lymphoma protein 1A (TCL1A) has been observed as overexpressed in the peripheral blood of operational tolerant patients in several studies. TCL1A expression is restricted to early B cells, also increased in the blood of tolerant patients, and showing regulatory properties, notably through IL-10 secretion for some subsets. TCL1A has first been identified as an oncogene, overexpression of which is associated to the development of T and B cell cancer. TCL1A acts as a coactivator of the serine threonine kinase Akt and through other interactions favoring cell survival, growth, and proliferation. It has also been identified as interacting with others major actors involved in B cells differentiation and regulation, including IL-10 production. Herein, we reviewed known interactions and functions of TCL1A in B cells which could involve its potential role in the set up and maintenance of renal allograft tolerance.
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17
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Cahova M, Kveton M, Petr V, Funda D, Dankova H, Viklicky O, Hruba P. Local Angiotensin-Converting Enzyme 2 Gene Expression in Kidney Allografts Is Not Affected by Renin-Angiotensin-Aldosterone Inhibitors. Kidney Blood Press Res 2021; 46:245-249. [PMID: 33756485 PMCID: PMC8089425 DOI: 10.1159/000513710] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 12/10/2020] [Indexed: 12/21/2022] Open
Abstract
Background Preclinical studies suggested that pharmacological inhibition of the renin-angiotensin-aldosterone system (RAAS) by ACE inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) may increase local angiotensin-converting enzyme 2 (ACE2) expression. Methods In this study, we evaluated the effect of ACEi or ARB treatment on expression of ACE2, ACE, and AGTR1 in 3-month protocol kidney allograft biopsies of stable patients using RT-qPCR (n = 48). Protein ACE2 expression was assessed using immunohistochemistry from paraffin sections. Results The therapy with RAAS blockers was not associated with increased ACE2, ACE, or ATGR1 expression in kidney allografts and also ACE2 protein immunohistochemistry did not reveal differences among groups. Conclusions ACEis or ARBs in kidney transplant recipients do not affect local ACE2 expression. This observation supports long-term RAAS treatment in kidney transplant recipients, despite acute complications such as COVID-19 where ACE2 serves as the entry protein for infection.
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Affiliation(s)
- Monika Cahova
- Institute for Clinical and Experimental Medicine, Department of Experimental Endocrinology, Prague, Czechia
| | - Martin Kveton
- Institute for Clinical and Experimental Medicine, Department of Clinical and Transplant Pathology, Prague, Czechia
| | - Vojtech Petr
- Institute for Clinical and Experimental Medicine, Department of Nephrology, Transplant Center, Prague, Czechia
| | - David Funda
- Institute of Microbiology, Academy of Science, Prague, Czechia
| | - Helena Dankova
- Institute for Clinical and Experimental Medicine, Department of Experimental Endocrinology, Prague, Czechia
| | - Ondrej Viklicky
- Institute for Clinical and Experimental Medicine, Department of Nephrology, Transplant Center, Prague, Czechia.,Institute for Clinical and Experimental Medicine, Transplant Laboratory, Prague, Czechia
| | - Petra Hruba
- Institute for Clinical and Experimental Medicine, Transplant Laboratory, Prague, Czechia,
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18
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Suchanek O, Clatworthy MR. Novel strategies to target the humoral alloimmune response. HLA 2020; 96:667-680. [PMID: 33022883 DOI: 10.1111/tan.14092] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/02/2020] [Accepted: 10/03/2020] [Indexed: 12/24/2022]
Abstract
Antibody-mediated rejection (ABMR) represents a major cause of late allograft loss in solid organ transplantation worldwide. This process is driven by donor-specific antibodies (DSA), which develop either de-novo or, in sensitized patients, are preformed at the time of transplantation. Effective targeting of ABMR has been hampered by a lack of robust randomized controlled trials (RCT), required for the regulatory approval of new therapeutics. In this review, we discuss the evidence behind the present "standard" of care and recent progress in the development of novel strategies targeting different aspects of the alloimmune humoral response, including naïve and memory B-cell activation, the germinal centre reaction, plasma cell survival and antibody effector functions. In particular, we focus on co-stimulation blockade and its combination with next-generation proteasome inhibitors, new depleting monoclonal antibodies (anti-CD19, anti-BCMA, anti-CD38, anti-CD138), interleukin-6 blockade, complement inhibition and DSA degradation. These treatment modalities, when used in the appropriate clinical context and combination, have the potential to finally improve long-term allograft survival.
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Affiliation(s)
- Ondrej Suchanek
- Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | - Menna R Clatworthy
- Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, NIHR Cambridge Biomedical Research Centre, Cambridge, UK
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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19
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Abstract
B cells are typically characterized by their ability to produce antibodies, function as secondary antigen-present cells, and produce various immunoregulatory cytokines. The regulatory B (Breg)-cell population is now widely accepted as an important modulatory component of the immune system that suppresses inflammation. Recent studies indicate that Breg-cell populations are small under physiological conditions but expand substantially in both human patients and murine models of chronic inflammatory diseases, autoimmune diseases, infection, transplantation, and cancer. Almost all B-cell subsets can be induced to form Breg cells. In addition, there are unique Breg-cell subsets such as B10 and Tim-1+ B cells. Immunoregulatory function may be mediated by production of cytokines such as IL-10 and TGF-β and ensuing suppression of T cells, by direct cell-cell interactions, and (or) by altering the immune microenvironment. In this chapter, we describe in detail the discovery of Breg cells, their phenotypes, differentiation, function, contributions to disease, and therapeutic potential.
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Affiliation(s)
- Luman Wang
- Department of Immunology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, No. 138, Yi Xue Yuan Rd, 226, Shanghai, 200032, China
| | - Ying Fu
- Department of Immunology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, No. 138, Yi Xue Yuan Rd, 226, Shanghai, 200032, China
| | - Yiwei Chu
- Department of Immunology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, No. 138, Yi Xue Yuan Rd, 226, Shanghai, 200032, China.
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20
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Molecular Patterns Discriminate Accommodation and Subclinical Antibody-mediated Rejection in Kidney Transplantation. Transplantation 2019; 103:909-917. [PMID: 30801516 DOI: 10.1097/tp.0000000000002604] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Accommodation in ABO-incompatible (ABOi) transplantation and subclinical antibody-mediated rejection in HLA-incompatible (HLAi) transplantation share several morphological similarities. Because the clinical long-term outcomes differ, we hypothesized different molecular processes involved in ABOi transplantation and subclinical antibody-mediated rejection. METHODS Using Illumina Human HT-12 v4 Expression BeadChips, the whole transcriptome was evaluated based on 3-month protocol C4d+ biopsies in otherwise stable ABOi and HLAi kidney grafts, as well as in C4d-negative HLA-compatible grafts exhibiting normal histological findings. Top differently regulated genes were further validated using real-time quantitative polymerase chain reaction in another patient cohort and complement regulatory proteins by immunohistochemistry. RESULTS In the case of genes involved in immune response-related biological processes, ABOi and HLAi cohorts had similar transcriptomic profiles to C4d-negative controls. The majority of deregulated genes in the ABOi and HLAi groups consisted of metallothioneins and epithelial transporter genes. Increased expression of epithelial transporters (SLC4A1, SLC4A9, SLC17A3, SLC12A3, and SLC30A2) and class 1 metallothioneins (MT1F, MT1G, and MT1X) in HLAi transplantation was validated by real-time quantitative polymerase chain reaction. In comparison to controls, both incompatible cohorts were characterized by the upregulation of intrarenal complement regulatory genes. CD46 and CD59 transcripts were increased in the ABOi cohort, whereas CD46 solely in HLAi group, and CD59 protein expression was similar in both incompatible groups. CONCLUSIONS Several epithelial transporters and metallothioneins discriminate subclinical antibody-mediated rejection in HLAi transplantation from accommodation in ABOi transplantation, which suggest different involved downstream mechanisms and increased risk of injury in HLAi settings. Metallothioneins with their antioxidative properties may help to attenuate the inflammation response induced by donor-specific anti-HLA antibody binding.
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21
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Viklicky O. Are we ready to implement non-invasive tests to detect allograft rejection in a daily praxis? EBioMedicine 2019; 41:28-29. [PMID: 30850351 PMCID: PMC6444118 DOI: 10.1016/j.ebiom.2019.03.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 03/01/2019] [Indexed: 02/03/2023] Open
Affiliation(s)
- Ondrej Viklicky
- Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
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22
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Kidney Transplant Outcome Is Associated with Regulatory T Cell Population and Gene Expression Early after Transplantation. J Immunol Res 2019; 2019:7452019. [PMID: 30729139 PMCID: PMC6341262 DOI: 10.1155/2019/7452019] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 10/16/2018] [Accepted: 11/12/2018] [Indexed: 01/08/2023] Open
Abstract
Successful long-term kidney allograft survival with parallel reduction of complications resulting from prolonged immunosuppressive treatment is a goal in kidney transplantation. We studied the immune changes in cell phenotypes and gene expression induced by kidney transplantation. Our goal was to find a phenotypic and/or transcriptional pattern that might be considered prognostic for the kidney transplant outcome. The analysis was performed prospectively on 36 KTx recipients sampled during the first year and followed for five years after transplantation and on 40 long-term KTx recipients (7.9 ± 2.2 y. post-KTx). The research involved flow cytometry assessment of lymphocyte subpopulations (including Tregs and CD3+CD8+CD28− lymphocytes) and gene expression analysis of immune-related genes (CD4, CD8, CTLA4, GZMB, FOXP3, IL10, IL4, ILR2A, NOTCH, PDCD1, PRF1, TGFB, and TNFA). The analysis of patterns observed over the first post-KTx year was confronted with control, pretransplant, and long-term transplant results. Treg counts at months one and three post-KTx correlated positively with the current and future allograft function. FOXP3 gene expression at month one post-KTx was also associated with long-term allograft function. The KTx-induced CD3+CD8+CD28− population correlated with GZMB and PRF1 expression and suggested their cytotoxic properties. The size of the Treg population and regulatory FOXP3 gene expression in the early period after transplantation are associated with kidney transplant outcome. The outlined predictive power of the Treg population needs to be investigated further to be confirmed as one of the immune monitoring strategies that may help achieve the best long-term kidney allograft outcomes.
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23
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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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24
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Lee YH, Seo JW, Kim YG, Moon JY, Kim JS, Jeong KH, Kim BM, Kim KW, Yang CW, Kim CD, Park JB, Kim YH, Chung BH, Lee SH. Validation Study of an Operational Tolerance Signature in Korean Kidney Transplant Recipients. Immune Netw 2018; 18:e36. [PMID: 30402331 PMCID: PMC6215901 DOI: 10.4110/in.2018.18.e36] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/16/2018] [Accepted: 10/17/2018] [Indexed: 12/21/2022] Open
Abstract
Operational tolerance (OT), defined as maintaining stable graft function without immunosuppression after transplant surgery, is an ideal goal for kidney transplant recipients (KTRs). Recent investigations have demonstrated the distinctive features of B cells, T cells, and dendritic cell-related gene signatures and the distributions of circulating lymphocytes in these patients; nonetheless, substantial heterogeneities exist across studies. This study was conducted to determine whether previously reported candidate gene biomarkers and the profiles of lymphocyte subsets of OT could be applied in Korean KTRs. Peripheral blood samples were collected from 153 patients, including 7 operationally tolerant patients. Quantitative real-time PCR and flow cytometry were performed to evaluate gene expression and lymphocyte subsets, respectively. Patients with OT showed significantly higher levels of B cell-related gene signatures (IGKV1D-13 and IGKV4-1), while T cell-related genes (TOAG-1) and dendritic cell-related genes (BNC2, KLF6, and CYP1B1) were not differentially expressed across groups. Lymphocyte subset analyses also revealed a higher proportion of immature B cells in this group. In contrast, the distributions of CD4+ T cells, CD8+ T cells, mature B cells, and memory B cells showed no differences across diagnostic groups. An OT signature, generated by the integration of IGKV1D-13, IGKV4-1, and immature B cells, effectively discriminated patients with OT from those in other diagnostic groups. Finally, the OT signature was observed among 5.6% of patients who had stable graft function for more than 10 years while on immunosuppression. In conclusion, we validated an association of B cells and their related signature with OT in Korean KTRs.
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Affiliation(s)
- Yu Ho Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Jung-Woo Seo
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Yang Gyun Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Ju-Young Moon
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Jin Sug Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Kyung-Hwan Jeong
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Bo-Mi Kim
- Transplant Research Center, Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Kyoung Woon Kim
- Transplant Research Center, Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Chul Woo Yang
- Transplant Research Center, Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Chan-Duck Kim
- Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu 41404, Korea
| | - Jae Berm Park
- Department of Surgery, Samsung Medical Center, Seoul 06351, Korea
| | - Yeong Hoon Kim
- Division of Nephrology, Department of Internal Medicine, Inje University College of Medicine, Busan 47392, Korea
| | - Byung Ha Chung
- Transplant Research Center, Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Sang-Ho Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul 02447, Korea
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25
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Abstract
This review is focused on present and future biomarkers, along with pharmacogenomics used in clinical practice for kidney transplantation. It aims to highlight biomarkers that could potentially be used to improve kidney transplant early and long-term graft survival, but also potentially patient co-morbidity. Future directions for improving outcomes are discussed, which include immune tolerance and personalising immunosuppression regimens.
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26
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Yamamoto T, Iwasaki K, Murotani K, Takeda A, Futamura K, Okada M, Tsujita M, Hiramitsu T, Goto N, Narumi S, Watarai Y, Morozumi K, Uchida K, Kobayashi T. Peripheral blood immune response-related gene analysis for evaluating the potential risk of chronic antibody-mediated rejection. Hum Immunol 2018; 79:432-438. [PMID: 29614336 DOI: 10.1016/j.humimm.2018.03.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 03/24/2018] [Accepted: 03/28/2018] [Indexed: 12/15/2022]
Abstract
Noninvasive methods for the early diagnosis of chronic antibody-mediated rejection (cAMR) are desired for patients with de novo (dn) donor-specific HLA antibody (DSA). This study aimed to elucidate the clinical relevance of immune-related gene expression in peripheral blood of kidney transplant recipients. The expression levels of fourteen key molecules (Foxp3, CTLA-4, CCR7, TGF-β, IGLL-1, IL-10, ITCH, CBLB, Bcl-6, CXCR5, granzyme B, CIITA, Baff, TOAG-1/TCAIM) related to regulatory/cytotoxic function of immune cells were compared in 93 patients, which were divided into Groups A (clinical cAMR with dn DSA, n = 16), B (subclinical cAMR with dn DSA, n = 17), C (negative cAMR with dn DSA, n = 21) and D (stable function without dn DSA, n = 39). CIITA mRNA expression levels in groups B and C were significantly lower than those in group D (p < 0.01). Moreover, the CTLA-4 mRNA expression in group A was significantly higher than that in groups B and C (p < 0.01). ROC curve analysis suggested that CIITA (AUC = 0.902) and CTLA-4 (AUC = 0.785) may serve as valuable biomarkers of the stage of dn DSA production and clinical cAMR, respectively. In addition to dn DSA screening, monitoring of CIITA and CTLA-4 in peripheral blood could offer useful information on the time course of the development of cAMR.
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Affiliation(s)
- Takayuki Yamamoto
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan; Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, AL, USA
| | - Kenta Iwasaki
- Department of Kidney Disease and Transplant Immunology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Kenta Murotani
- Division of Biostatistics, Clinical Research Center, Aichi Medical University Hospital, Nagakute, Japan
| | - Asami Takeda
- Department of Nephrology, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Kenta Futamura
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Manabu Okada
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Makoto Tsujita
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Takahisa Hiramitsu
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Norihiko Goto
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Shunji Narumi
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Yoshihiko Watarai
- Department of Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Kunio Morozumi
- Department of Nephrology, Masuko Memorial Hospital, Nagoya, Japan
| | - Kazuharu Uchida
- Department of Kidney Disease and Transplant Immunology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Takaaki Kobayashi
- Department of Renal Transplant Surgery, Aichi Medical University School of Medicine, Nagakute, Japan.
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27
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Chesneau M, Danger R, Soulillou JP, Brouard S. B cells in operational tolerance. Hum Immunol 2018; 79:373-379. [PMID: 29458071 DOI: 10.1016/j.humimm.2018.02.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 02/02/2018] [Accepted: 02/12/2018] [Indexed: 12/17/2022]
Abstract
Transplantation is currently the therapy of choice for endstage organ failure even though it requires long-term immunosuppresive therapy, with its numerous side effects, for acceptance of the transplanted organ. In rare cases however, patients develop operational tolerance, that is, graft survival without immunosuppression. Studies conducted on these patients reveal genetic, phenotypic, and functional signatures. They provide a better understanding of the immunological mechanisms involved in operational tolerance and define biomarkers that could be used to adapt immunosuppressive treatment to the individual, safely reduce immunosuppression doses, and ideally and safely guide immunosuppression withdrawal. This review summarizes studies that suggest a role for B cells as biomarkers of operational tolerance and discusses the use of B cells as a predictive tool for immunologic risk.
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Affiliation(s)
- M Chesneau
- Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology," Nantes, France
| | - R Danger
- Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology," Nantes, France
| | - J-P Soulillou
- Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; Faculté de Médecine, Université de Nantes, Nantes, France
| | - S Brouard
- Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology," Nantes, France; Centre d'Investigation Clinique (CIC) Biothérapie, CHU Nantes, Nantes, France.
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28
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Chu Z, Zou W, Xu Y, Sun Q, Zhao Y. The regulatory roles of B cell subsets in transplantation. Expert Rev Clin Immunol 2018; 14:115-125. [PMID: 29338551 DOI: 10.1080/1744666x.2018.1426461] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Zhulang Chu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Department of Pathology, Beijing University of Chinese Medicine, Beijing, China
| | - Weilong Zou
- Surgery of Transplant and Hepatopancrobiliary, The General Hospital of Chinese People’s Armed Police Forces, Beijing, China
| | - Yanan Xu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Qiquan Sun
- Department of Renal Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
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29
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Sun Y, Zhang D, Sun G, Lv Y, Li Y, Li X, Song Y, Li J, Fan Z, Wang H. RNA-sequencing study of peripheral blood mononuclear cells in sporadic Ménière's disease patients: possible contribution of immunologic dysfunction to the development of this disorder. Clin Exp Immunol 2017; 192:33-45. [PMID: 29164594 DOI: 10.1111/cei.13083] [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: 11/09/2017] [Indexed: 12/13/2022] Open
Abstract
To date, the pathogenesis of Ménière's disease (MD) remains unclear. This study aims to investigate the possible relationship between potential immune system-related genes and sporadic MD. The whole RNA-sequencing (RNA-seq) technology was used to analyse the transcriptome of peripheral blood mononuclear cells of three MD patients and three control individuals. Of 366 differentially expressed genes (DEGs), 154 genes were up-regulated and 212 genes were down-regulated (|log2 fold change| > 1 and P < 0·05). Gene ontology (GO) enrichment analysis illustrated that immune relevant factors played a key role in the pathogenesis of MD. Of 366 DEGs, we focused upon analysing the possible immune-related genes, among which the significantly up-regulated genes [glutathione S-transferase mu 1 (GSTM1), transmembrane protein 176 (TMEM176)B, TMEM176A] and down-regulated genes [solute carrier family 4 member (SLC4A)10 and SLC4A1] especially drew our attention. The mRNA expression levels of GSTM1, TMEM176B, TMEM176A, SLC4A1 and SLC4A10 were analysed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The serum concentration of GSTM1, TMEM176B and SLC4A10 proteins were measured by enzyme-linked immunosorbent assay (ELISA). Considering the results of qRT-PCR and ELISA, it was noteworthy that GSTM1 exhibited the highest fold change between two groups, which was consistent with the deep sequencing results by RNA-seq. In conclusion, our study first offers a new perspective in MD development on the basis of RNA expression patterns, suggesting that immune factors might be involved in the MD pathogenesis. Remarkably, GSTM1 might be a possible candidate gene for the diagnostic biomarker of MD and provides the basis for further biological and functional investigations.
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Affiliation(s)
- Y Sun
- Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Otology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - D Zhang
- Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Otology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - G Sun
- Shandong Provincial Key Laboratory of Otology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Y Lv
- Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Y Li
- Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - X Li
- Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Y Song
- Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Otology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - J Li
- Shandong Provincial Key Laboratory of Otology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Z Fan
- Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Otology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - H Wang
- Otolaryngology-Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Otology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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30
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Tycová I, Hrubá P, Maixnerová D, Girmanová E, Mrázová P, Straňavová L, Zachoval R, Merta M, Slatinská J, Kollár M, Honsová E, Tesař V, Viklický O. Molecular profiling in IgA nephropathy and focal and segmental glomerulosclerosis. Physiol Res 2017; 67:93-105. [PMID: 29137483 DOI: 10.33549/physiolres.933670] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The aim of the study was to characterize by molecular profiling two glomerular diseases: IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS) and to identify potential molecular markers of IgAN and FSGS progression. The expressions of 90 immune-related genes were compared in biopsies of patients with IgAN (n=33), FSGS (n=17) and in controls (n=11) using RT-qPCR. To identify markers of disease progression, gene expression was compared between progressors and non-progressors in 1 year follow-up. The results were verified on validation cohort of patients with IgAN (n=8) and in controls (n=6) using laser-capture microdissection, that enables to analyze gene expression separately for glomeruli and interstitium. In comparison to controls, patients with both IgAN and FSGS, had lower expression of BAX (apoptotic molecule BCL2-associated protein) and HMOX-1 (heme oxygenase 1) and higher expression of SELP (selectin P). Furthermore, in IgAN higher expression of PTPRC (protein-tyrosine phosphatase, receptor-type C) and in FSGS higher expression of BCL2L1 (regulator of apoptosis BCL2-like 1) and IL18 compared to control was observed. Validation of differentially expressed genes between IgAN and controls on another cohort using laser-capture microdissection confirmed higher expression of PTPRC in glomeruli of patients with IgAN. The risk of progression in IgAN was associated with higher expression EDN1 (endothelin 1) (AUC=0.77) and FASLG (Fas ligand) (AUC=0.82) and lower expression of VEGF (vascular endothelial growth factor) (AUC=0.8) and in FSGS with lower expression of CCL19 (chemokine (C-C motif) ligand 19) (AUC=0.86). Higher expression of EDN1 and FASLG along with lower expression of VEGF in IgAN and lower expression of CCL19 in FSGS at the time of biopsy can help to identify patients at risk of future disease progression.
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Affiliation(s)
- I Tycová
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
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31
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Altered Th17 Pathway in Tolerant Kidney Transplant Patients: A "Chicken-or-the-Egg" Dilemma? Transplantation 2017; 102:9-10. [PMID: 28968352 DOI: 10.1097/tp.0000000000001968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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32
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Danger R, Sawitzki B, Brouard S. Immune monitoring in renal transplantation: The search for biomarkers. Eur J Immunol 2017; 46:2695-2704. [PMID: 27861809 DOI: 10.1002/eji.201545963] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 11/02/2016] [Accepted: 11/07/2016] [Indexed: 11/11/2022]
Abstract
It is now widely accepted that in order to improve long-term graft function and survival, a more personalized immunosuppressive treatment of transplant patients according to the individual anti-donor immune response status is needed. This applies to the identification of potentially "high-risk" patients likely to develop acute rejection episodes or display an accelerated decline of graft function, patients who might need immunosuppression intensification, and operationally tolerant patients suitable for immunosuppression minimization or weaning off. Such a patient stratification would benefit from biomarkers, which enable categorization into low and high risk or, ideally, identification of operational tolerant patients. Here, we report on recent developments regarding identification and performance analysis of noninvasive biomarkers such as mRNA and miRNA expression profiles, chemokines, or changes in immune cell subsets in either blood or urine of renal transplant patients. We will also discuss which future steps are needed to accelerate their clinical implementation.
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Affiliation(s)
- Richard Danger
- Inserm, , Center for Research in Transplantation and Immunology (CRTI) U1064, Nantes, France.,Université de Nantes, , UMR1064, Nantes, France.,CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), Nantes, France
| | - Birgit Sawitzki
- Institute of Medical Immunology, Charité University Berlin, Germany.,Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Berlin, Germany
| | - Sophie Brouard
- Inserm, , Center for Research in Transplantation and Immunology (CRTI) U1064, Nantes, France.,Université de Nantes, , UMR1064, Nantes, France.,CHU Nantes, Institut de Transplantation Urologie Néphrologie (ITUN), Nantes, France.,CIC Biotherapy, CHU Nantes, , 30 bd Jean-Monnet, Nantes, France
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33
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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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34
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Behnam Sani K, Sawitzki B. Immune monitoring as prerequisite for transplantation tolerance trials. Clin Exp Immunol 2017; 189:158-170. [PMID: 28518214 DOI: 10.1111/cei.12988] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2017] [Indexed: 02/06/2023] Open
Abstract
Ever since its first application in clinical medicine, scientists have been urged to induce tolerance towards foreign allogeneic transplants and thus avoid rejection by the recipient's immune system. This would circumvent chronic use of immunosuppressive drugs (IS) and thus avoid development of IS-induced side effects, which are contributing to the still unsatisfactory long-term graft and patient survival after solid organ transplantation. Although manifold strategies of tolerance induction have been described in preclinical models, only three therapeutic approaches have been utilized successfully in a still small number of patients. These approaches are based on (i) IS withdrawal in spontaneous operational tolerant (SOT) patients, (ii) induction of a mixed chimerism and (iii) adoptive transfer of regulatory cells. Results of clinical trials utilizing these approaches show that tolerance induction does not work in all patients. Thus, there is a need for reliable biomarkers, which can be used for patient selection and post-therapeutic immune monitoring of safety, success and failure. In this review, we summarize recent achievements in the identification and validation of such immunological assays and biomarkers, focusing mainly on kidney and liver transplantation. From the published findings so far, it has become clear that indicative biomarkers may vary between different therapeutic approaches applied and organs transplanted. Also, patient numbers studied so far are very small. This is the main reason why nearly all described parameters lack validation and reproducibility testing in large clinical trials, and are therefore not yet suitable for clinical practice.
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Affiliation(s)
- K Behnam Sani
- Institute of Medical Immunology, Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - B Sawitzki
- Institute of Medical Immunology, Charité Universitaetsmedizin Berlin, Berlin, Germany
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35
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Danger R, Chesneau M, Paul C, Guérif P, Durand M, Newell KA, Kanaparthi S, Turka LA, Soulillou JP, Houlgatte R, Giral M, Ramstein G, Brouard S. A composite score associated with spontaneous operational tolerance in kidney transplant recipients. Kidney Int 2017; 91:1473-1481. [PMID: 28242033 PMCID: PMC5432017 DOI: 10.1016/j.kint.2016.12.020] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Revised: 11/29/2016] [Accepted: 12/22/2016] [Indexed: 11/16/2022]
Abstract
New challenges in renal transplantation include using biological information to devise a useful clinical test for discerning high- and low-risk patients for individual therapy and ascertaining the best combination and appropriate dosages of drugs. Based on a 20-gene signature from a microarray meta-analysis performed on 46 operationally tolerant patients and 266 renal transplant recipients with stable function, we applied the sparse Bolasso methodology to identify a minimal and robust combination of six genes and two demographic parameters associated with operational tolerance. This composite score of operational tolerance discriminated operationally tolerant patients with an area under the curve of 0.97 (95% confidence interval 0.94-1.00). The score was not influenced by immunosuppressive treatment, center of origin, donor type, or post-transplant lymphoproliferative disorder history of the patients. This composite score of operational tolerance was significantly associated with both de novo anti-HLA antibodies and tolerance loss. It was validated by quantitative polymerase chain reaction using independent samples and demonstrated specificity toward a model of tolerance induction. Thus, our score would allow clinicians to improve follow-up of patients, paving the way for individual therapy.
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Affiliation(s)
- Richard Danger
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Mélanie Chesneau
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Chloé Paul
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Pierrick Guérif
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Maxim Durand
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | | | | | - Laurence A Turka
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jean-Paul Soulillou
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Rémi Houlgatte
- INSERM UMR 954, Nancy, France; CHU de Nancy, DRCI, Nancy, France
| | - Magali Giral
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; Université de Nantes, Faculté de Médecine, Nantes, France; CIC Biotherapy, CHU Nantes, Nantes, France
| | - Gérard Ramstein
- LINA DUKe, UMR 6241, Université de Nantes, Ecole des Mines de Nantes and CNRS, Nantes, France
| | - Sophie Brouard
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France; CIC Biotherapy, CHU Nantes, Nantes, France.
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36
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Massart A, Ghisdal L, Abramowicz M, Abramowicz D. Operational tolerance in kidney transplantation and associated biomarkers. Clin Exp Immunol 2017; 189:138-157. [PMID: 28449211 DOI: 10.1111/cei.12981] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2017] [Indexed: 12/30/2022] Open
Abstract
In the 1960s, our predecessors won a historical battle against acute rejection and ensured that transplantation became a common life-saving treatment. In parallel with this success, or perhaps because of it, we lost the battle for long-lived transplants, being overwhelmed with chronic immune insults and the toxicities of immunosuppression. It is likely that current powerful treatments block acute rejection, but at the same time condemn the few circulating donor cells that would have been able to elicit immunoregulatory host responses towards the allograft. Under these conditions, spontaneously tolerant kidney recipients - i.e. patients who maintain allograft function in the absence of immunosuppression - are merely accidents; they are scarce, mysterious and precious. Several teams pursue the goal of finding a biomarker that would guide us towards the 'just right' level of immunosuppression that avoids rejection while leaving some space for donor immune cells. Some cellular assays are attractive because they are antigen-specific, and provide a comprehensive view of immune responses toward the graft. These seem to closely follow patient regulatory capacities. However, these tests are cumbersome, and require abundant cellular material from both donor and recipient. The latest newcomers, non-antigen-specific recipient blood transcriptomic biomarkers, offer the promise that a practicable and simple signature may be found that overcomes the complexity of a system in which an infinite number of individual cell combinations can lead possibly to graft acceptance. Biomarker studies are as much an objective - identifying tolerant patients, enabling tolerance trials - as a means to deciphering the underlying mechanisms of one of the most important current issues in transplantation.
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Affiliation(s)
- A Massart
- Department of Nephrology, Dialysis, and Transplantation, CUB Hôpital Erasme and Institute of Interdisciplinary Research in Molecular and Human Biology (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium
| | - L Ghisdal
- Department of Nephrology, Centre Hospitalier EpiCURA, Baudour, Belgium
| | - M Abramowicz
- Department of Human Genetics, CUB Hôpital Erasme and Institute of Interdisciplinary Research in Molecular and Human Biology (IRIBHM), Université Libre de Bruxelles, Brussels, Belgium
| | - D Abramowicz
- Department of Nephrology, Universitair Ziekenhuis Antwerpen and Antwerp University, Antwerp, Belgium
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37
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Hruba P, Tycova I, Krepsova E, Girmanova E, Sekerkova A, Slatinska J, Striz I, Honsova E, Viklicky O. Steroid free immunosuppression is associated with enhanced Th1 transcripts in kidney transplantation. Transpl Immunol 2017; 42:18-23. [PMID: 28366698 DOI: 10.1016/j.trim.2017.03.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Revised: 03/26/2017] [Accepted: 03/28/2017] [Indexed: 10/19/2022]
Abstract
BACKGROUND Steroid avoidance in immunosuppression in kidney transplantation offers several metabolic advantages, however it is associated with higher early acute rejection rate. Cellular and molecular mechanisms of this phenomenon remain poorly understood. METHODS In this single center observational study, low-risk kidney transplant recipients randomized into large multicenter prospective ADVANCE trial with steroid avoidance/early withdrawal and center standard of care treated patients were monitored for 12months. The expressions of 28 transcripts, associated with alloimmune response and operational tolerance, were evaluated in the peripheral blood using RT-qPCR at 0, 7, 14, 90 and 365 postoperative days (POD) and in the protocol graft biopsy at 3months while lymphocyte subpopulations were analyzed by flow-cytometry within the follow-up. RESULTS Both steroid avoidance and withdrawal regimens were associated with significantly higher granzyme B (GZMB) transcript at POD 14 and perforin 1 (PRF1) transcript at POD 7. The higher interleukin 2 (IL-2) expression at POD 7 was detected only in the steroid avoidance group. Initial steroids decreased the expression SH2D1B transcript at POD14 and there were no further differences in other operational tolerance transcripts among groups. The statistically significant decrease in absolute numbers of peripheral NK cells in the first 14days was observed in the standard of care group only. There were no differences in analyzed intrarenal transcripts in 3-month biopsies among groups. CONCLUSIONS The enhanced expression of some of Th1 associated transcripts and limited effects on NK cells of steroid avoidance immunosuppression suggest higher susceptibility for early acute rejection.
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Affiliation(s)
- Petra Hruba
- Transplant Laboratory, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Irena Tycova
- Transplant Laboratory, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Eva Krepsova
- Transplant Laboratory, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Eva Girmanova
- Transplant Laboratory, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Alena Sekerkova
- Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Janka Slatinska
- Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Ilja Striz
- Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Eva Honsova
- Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Ondrej Viklicky
- Transplant Laboratory, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
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38
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Wortel CM, Heidt S. Regulatory B cells: Phenotype, function and role in transplantation. Transpl Immunol 2017; 41:1-9. [PMID: 28257995 DOI: 10.1016/j.trim.2017.02.004] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 02/27/2017] [Accepted: 02/27/2017] [Indexed: 12/20/2022]
Abstract
While B cells are traditionally known for their roles in antibody production, antigen presentation and cytokine production, recent studies have highlighted the existence of B cells with regulatory properties, which have been termed Bregs, analogous to regulatory T cells (Tregs). Bregs have been found to play a role in autoimmune disease, malignancies, infections, and may also be involved in solid organ transplantation. Their main mechanism of action is by promoting the development of Tregs while suppressing effector CD4+ and CD8+ T cells, primarily by IL-10 secretion. In the field of transplantation evidence for an active role of Bregs is scarce. While the presence of Bregs has been associated with improved graft survival and operational tolerance in kidney transplant recipients, these findings are not without controversy. Since the majority of fundamental research on Bregs has been performed in the fields in autoimmunity and infectious diseases, we will first focus on what these fields taught us on basic Breg biology, after which the relevance for the transplant setting is discussed.
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Affiliation(s)
- C M Wortel
- Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, The Netherlands
| | - S Heidt
- Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, The Netherlands.
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39
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Viklicky O, Hruba P, Tomiuk S, Schmitz S, Gerstmayer B, Sawitzki B, Miqueu P, Mrazova P, Tycova I, Svobodova E, Honsova E, Janssen U, Volk HD, Reinke P. Sequential Targeting of CD52 and TNF Allows Early Minimization Therapy in Kidney Transplantation: From a Biomarker to Targeting in a Proof-Of-Concept Trial. PLoS One 2017; 12:e0169624. [PMID: 28085915 PMCID: PMC5234822 DOI: 10.1371/journal.pone.0169624] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Accepted: 12/11/2016] [Indexed: 01/04/2023] Open
Abstract
Background There is high medical need for safe long-term immunosuppression monotherapy in kidney transplantation. Selective targeting of post-transplant alloantigen-(re)activated effector-T cells by anti-TNF antibodies after global T cell depletion may allow safe drug minimization, however, it is unsolved what might be the best maintenance monotherapy. Methods In this open, prospective observational single-centre trial, 20 primary deceased donor kidney transplant recipients received 2x20 mg Alemtuzumab (d0/d1) followed by 5 mg/kg Infliximab (d2). For 14 days all patients received only tacrolimus, then they were allocated to either receive tacrolimus (TAC, n = 13) or sirolimus (SIR, n = 7) monotherapy, respectively. Protocol biopsies and extensive immune monitoring were performed and patients were followed-up for 60 months. Results TAC-monotherapy resulted in excellent graft survival (5yr 92%, 95%CI: 56.6–98.9) and function, normal histology, and no proteinuria. Immune monitoring revealed low intragraft inflammation (urinary IP-10) and hints for the development of operational tolerance signature in the TAC- but not SIR-group. Remarkably, the TAC-monotherapy was successful in all five presensitized (ELISPOT+) patients. However, recruitment into SIR-arm was stopped (after n = 7) because of high incidence of proteinuria and acute/chronic rejection in biopsies. No opportunistic infections occurred during follow-up. Conclusions In conclusion, our novel fast-track TAC-monotherapy protocol is likely to be safe and preliminary results indicated an excellent 5-year outcome, however, a full–scale study will be needed to confirm our findings. Trial Registration EudraCT Number: 2006-003110-18
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Affiliation(s)
- Ondrej Viklicky
- Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- * E-mail:
| | - Petra Hruba
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | | | | | | | - Birgit Sawitzki
- Institute of Medical Immunology, Charité University Medicine Berlin, Germany
- Berlin-Brandenburg Center for Regenerative Medicine (BCRT), Charité University Medicine Berlin, Germany
| | - Patrick Miqueu
- Institut National de la Santé et de la Recherche Médicale INSERM U1064, France
- Institut de Transplantation Urologie Néphrologie du Centre Hospitalier Universitaire Hôtel Dieu, Nantes, France
| | - Petra Mrazova
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Irena Tycova
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Eva Svobodova
- Department of Immunogenetics, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Eva Honsova
- Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Uwe Janssen
- Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
| | - Hans-Dieter Volk
- Institute of Medical Immunology, Charité University Medicine Berlin, Germany
- Berlin-Brandenburg Center for Regenerative Medicine (BCRT), Charité University Medicine Berlin, Germany
| | - Petra Reinke
- Berlin-Brandenburg Center for Regenerative Medicine (BCRT), Charité University Medicine Berlin, Germany
- Department of Nephrology and Intensive Care Medicine, Charité University Medicine Berlin, Germany
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40
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Karahan GE, Claas FHJ, Heidt S. B Cell Immunity in Solid Organ Transplantation. Front Immunol 2017; 7:686. [PMID: 28119695 PMCID: PMC5222792 DOI: 10.3389/fimmu.2016.00686] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 12/22/2016] [Indexed: 01/03/2023] Open
Abstract
The contribution of B cells to alloimmune responses is gradually being understood in more detail. We now know that B cells can perpetuate alloimmune responses in multiple ways: (i) differentiation into antibody-producing plasma cells; (ii) sustaining long-term humoral immune memory; (iii) serving as antigen-presenting cells; (iv) organizing the formation of tertiary lymphoid organs; and (v) secreting pro- as well as anti-inflammatory cytokines. The cross-talk between B cells and T cells in the course of immune responses forms the basis of these diverse functions. In the setting of organ transplantation, focus has gradually shifted from T cells to B cells, with an increased notion that B cells are more than mere precursors of antibody-producing plasma cells. In this review, we discuss the various roles of B cells in the generation of alloimmune responses beyond antibody production, as well as possibilities to specifically interfere with B cell activation.
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Affiliation(s)
- Gonca E Karahan
- Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center , Leiden , Netherlands
| | - Frans H J Claas
- Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center , Leiden , Netherlands
| | - Sebastiaan Heidt
- Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center , Leiden , Netherlands
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41
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Kamińska D, Kościelska-Kasprzak K, Krajewska M, Chełmoński A, Jabłecki J, Żabińska M, Myszka M, Banasik M, Boratyńska M, Gomółkiewicz A, Dzięgiel P, Klinger M. Immune activation- and regulation-related patterns in stable hand transplant recipients. Transpl Int 2016; 30:144-152. [DOI: 10.1111/tri.12883] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 06/06/2016] [Accepted: 11/02/2016] [Indexed: 11/26/2022]
Affiliation(s)
- Dorota Kamińska
- Department of Nephrology and Transplantation Medicine; Wroclaw Medical University; Wroclaw Poland
| | | | - Magdalena Krajewska
- Department of Nephrology and Transplantation Medicine; Wroclaw Medical University; Wroclaw Poland
| | - Adam Chełmoński
- Subdepartment of Replantation of Limbs; St. Hedwig of Silesia Hospital; Trzebnica Poland
| | - Jerzy Jabłecki
- Subdepartment of Replantation of Limbs; St. Hedwig of Silesia Hospital; Trzebnica Poland
| | - Marcelina Żabińska
- Department of Nephrology and Transplantation Medicine; Wroclaw Medical University; Wroclaw Poland
| | - Marta Myszka
- Department of Nephrology and Transplantation Medicine; Wroclaw Medical University; Wroclaw Poland
| | - Mirosław Banasik
- Department of Nephrology and Transplantation Medicine; Wroclaw Medical University; Wroclaw Poland
| | - Maria Boratyńska
- Department of Nephrology and Transplantation Medicine; Wroclaw Medical University; Wroclaw Poland
| | | | - Piotr Dzięgiel
- Department of Histology and Embryology; Wroclaw Medical University; Wroclaw Poland
| | - Marian Klinger
- Department of Nephrology and Transplantation Medicine; Wroclaw Medical University; Wroclaw Poland
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Chapman JR. Progress in Transplantation: Will It Be Achieved in Big Steps or by Marginal Gains? Am J Kidney Dis 2016; 69:287-295. [PMID: 27823818 DOI: 10.1053/j.ajkd.2016.08.024] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 08/06/2016] [Indexed: 12/29/2022]
Abstract
A wish for progress in transplantation assumes that there are needs not met by the currently available therapy and that the barriers to resolving the problems can be surmounted. There are 5 major unmet needs: the potential to avoid transplantation either by prevention of disease or provision of an alternative to natural biological organ replacement; geographic heterogeneity of access to, and quality of, transplantation; availability of transplantation to those in need of it; survival of the patient and the transplant; and the avoidance of adverse effects of immunosuppression. During the past 50 years, there have been advances on at least 4 of these 5 fronts that illustrate the interplay of "big steps" and "marginal gains" in the following areas: surgical technique, testing the immunologic barriers, introduction of chemical and biological immunosuppression, and prophylaxis for microbial infections. The potential for further improvement comes in 5 major areas: blood biomarkers for monitoring of rejection, drug-free transplantation through the development of stable tolerance, eliminating the impact of ischemia-reperfusion injury, xenotransplantation of porcine kidneys, and finally, the possibility of autologous regeneration of functioning kidney tissue to treat advanced kidney disease.
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Affiliation(s)
- Jeremy R Chapman
- Centre for Transplant and Renal Research, University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia.
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43
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Novel immunotherapeutic strategies to target alloantibody-producing B and plasma cells in transplantation. Curr Opin Organ Transplant 2016; 21:419-26. [DOI: 10.1097/mot.0000000000000338] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Svachova V, Sekerkova A, Hruba P, Tycova I, Rodova M, Cecrdlova E, Slatinska J, Honsova E, Striz I, Viklicky O. Dynamic changes of B-cell compartments in kidney transplantation: lack of transitional B cells is associated with allograft rejection. Transpl Int 2016; 29:540-8. [PMID: 26839984 DOI: 10.1111/tri.12751] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 11/25/2015] [Accepted: 01/22/2016] [Indexed: 01/11/2023]
Abstract
B cells play an important role in the immune responses which affect the outcomes of kidney allografts. Dynamic changes of B-cell compartments in clinical kidney transplantation are still poorly understood. B-cell subsets were prospectively monitored using flow cytometry for 1 year in 98 kidney transplant recipients. Data were correlated with immunosuppression and clinical outcomes. An increase in the total population of B lymphocytes was observed during the first week after transplantation. The level of IgM(high) CD38(high) CD24(high) transitional B cells reduced significantly up until the third month, with partial repopulation in the first year. Lower numbers of transitional B cells in the third month were associated with higher risk of graft rejection. IgM(+) IgD(+) CD27(-) naive B cells did not change within follow-up. IgM(+) CD27(+) nonswitched memory B cells and IgM(-) CD27(+) switched memory B cells increased on post-operative day 7. IgM(-) CD38(high) CD27(high) plasmablasts showed similar kinetics during the first post-transplant year, similar to transitional B cells. In conclusion, sensitized kidney transplant recipients as well as those with either acute or chronic rejection within the first post-transplant year exhibited lower levels of transitional B cells. Therefore, these data further support the hypothesis that transitional B cells have a protective role in kidney transplantation.
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Affiliation(s)
- Veronika Svachova
- Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Alena Sekerkova
- Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Petra Hruba
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Irena Tycova
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Marketa Rodova
- Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Eva Cecrdlova
- Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Janka Slatinska
- Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Eva Honsova
- Department of Clinical and Transplant Pathology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Ilja Striz
- Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Ondrej Viklicky
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.,Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
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45
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Vallin P, Désy O, Béland S, Wagner E, De Serres SA. Clinical relevance of circulating antibodies and B lymphocyte markers in allograft rejection. Clin Biochem 2016; 49:385-93. [PMID: 26721422 DOI: 10.1016/j.clinbiochem.2015.12.008] [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: 09/01/2015] [Revised: 11/27/2015] [Accepted: 12/06/2015] [Indexed: 01/08/2023]
Abstract
The main challenge in solid organ transplantation remains to tackle antibody-mediated rejection. Our understanding of the antibody-mediated response and the capacity to detect it has improved in the last decade. However, the sensitivity and specificity of the current clinical tools to monitor B cell activation are perfectible. New strategies, including the refinement in the characterization of HLA and non-HLA antibodies, as well as a better understanding of the circulating B cell phenotype will hopefully help to non-invasively identify patients at risk or undergoing antibody-mediated allograft damage. The current review discusses the current knowledge of the B cell biomarkers in solid organ transplantation, with a focus on circulating antibodies and peripheral B cells.
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Affiliation(s)
- Patrice Vallin
- Transplantation Unit, Renal Division, Department of Medicine, CHU de Québec, Faculty of Medicine, Laval University, Québec, QC, Canada
| | - Olivier Désy
- Transplantation Unit, Renal Division, Department of Medicine, CHU de Québec, Faculty of Medicine, Laval University, Québec, QC, Canada
| | - Stéphanie Béland
- Transplantation Unit, Renal Division, Department of Medicine, CHU de Québec, Faculty of Medicine, Laval University, Québec, QC, Canada
| | - Eric Wagner
- Immunology and Histocompatibility Laboratory, CHU de Québec, Faculty of Medicine, Laval University, Québec, QC, Canada
| | - Sacha A De Serres
- Transplantation Unit, Renal Division, Department of Medicine, CHU de Québec, Faculty of Medicine, Laval University, Québec, QC, Canada.
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46
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Molecular diagnostics identifies risks for graft dysfunction despite borderline histologic changes. Kidney Int 2015; 88:785-95. [DOI: 10.1038/ki.2015.211] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 05/06/2015] [Accepted: 05/07/2015] [Indexed: 11/09/2022]
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47
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Abstract
PURPOSE OF REVIEW B cells are known to play a central role in humoral immunity and to boost cellular immunity, however, in a variety of experimental models, B-cell subsets ameliorate inflammation and autoimmune disease, indicating that they can also play a regulatory role. Here, we highlight the advances in regulatory B-cell (Breg) biology of the past year with an emphasis on findings pertinent to transplantation. Several recent observations highlight the relevance to clinical transplantation. Data from at least three independent groups demonstrated that spontaneously tolerant renal transplant recipients exhibit a peripheral blood B-cell signature although the significance of these data remains unclear. Moreover, new data suggest that regulatory B cells may serve as a biomarker for long-term allograft outcomes. Finally, recent evidence suggesting that plasma cells may be an essential component of Bregs raises new concerns about targeting antibody producing cells. RECENT FINDINGS We describe new information on Breg mechanisms of action to suppress the alloresponse, signals to expand Bregs in vitro, and more functional evidence of Breg involvement in operationally tolerant kidney patients and in maintaining stable allograft function. SUMMARY Although lymphocyte depletion remains central to tolerance induction therapy, the sparing or expansion of regulatory B cells may be an additional strategy to preempt graft rejection.
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Affiliation(s)
- James I. Kim
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Thier 8, Boston, MA 02114
| | - David M. Rothstein
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical School, 200 Lothrop Street, E1555 Biomedical Science Tower, Pittsburgh, PA 15261
| | - James F. Markmann
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Thier 8, Boston, MA 02114
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48
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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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49
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Affiliation(s)
- M R Clatworthy
- Department of Medicine, Addenbrooke's Hospital and Pembroke College, University of Cambridge, Cambridge, UK
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50
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Jordan SC, Glotz D. 7th International Immunoglobulin Conference: Transplantation. Clin Exp Immunol 2015; 178 Suppl 1:46-7. [PMID: 25546758 DOI: 10.1111/cei.12507] [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] [Indexed: 11/27/2022] Open
Abstract
In transplantation, harnessing the immune system is essential for allograft survival and function. This session explores different aspects of the immune system during transplantation, including the effect of donor-specific anti-human leucocyte antigen (HLA) antibodies (DSAs), antibody-mediated rejection (AMR), B cell modulation and the role of immunoglobulin (Ig) therapy. It is well known that DSAs play a key role in the failure of allografts. Identifying and characterizing DSAs provides information that can aid in risk stratification of transplant recipients. The ability to bind complement provides additional information regarding the cytotoxic potential of these antibodies and can therefore potentially guide individualized treatment strategies. AMR presents as several phenotypes, which vary in severity. As such, potentially different treatment strategies are required, emphasizing the importance of accurate diagnosis. In patients with elevated anti-HLA antibodies, waiting times for a compatible organ are often prolonged. Desensitization protocols using intravenous immunoglobulin (IVIg), in combination with other therapies, have been developed to enhance the availability of compatible donors. Another important aspect of transplantation is the role of B cells. While B cells may be involved in AMR and forms of cellular rejection, there is evidence to suggest that regulatory B cells may also have a positive impact upon long-term graft survival. Hypogammaglobulinaemia (HGG) has been reported after solid organ transplantation and is associated with an increased risk of infections. Monitoring immunoglobulin G (IgG) levels post-transplantation may identify patients at risk for infections who could potentially benefit from pre-emptive treatment with IVIg.
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Affiliation(s)
- S C Jordan
- Cedars-Sinai Medical Center, Los Angeles, CA, USA
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