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1
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Mayer KA, Budde K, Diebold M, Halloran PF, Böhmig GA. Targeting CD38 in Antibody-Mediated Rejection. Transpl Int 2025; 38:14343. [PMID: 40444214 PMCID: PMC12119314 DOI: 10.3389/ti.2025.14343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 05/06/2025] [Indexed: 06/02/2025]
Abstract
Antibody-mediated rejection (AMR) remains a major challenge in clinical transplantation. Current therapies have yielded inconsistent outcomes, highlighting the need for innovative approaches. CD38, a multifunctional glycoprotein, is highly expressed on plasma cells and natural killer (NK) cells, potentially offering a dual mechanism of action that could intervene in the pathophysiologic course of AMR: depleting alloantibody-producing plasma cells and NK cells. This review focuses on recent results from CD38-targeted therapies, with felzartamab emerging as a promising option. Previous case reports and series suggested that off-label daratumumab treatment could effectively reverse AMR. Felzartamab has now demonstrated safety and efficacy in a phase 2 trial for late AMR. Reductions in microvascular inflammation, downregulation of rejection-associated transcripts, and decreases in donor-derived cell-free DNA paralleled a substantial decrease in NK cell counts. However, felzartamab did not significantly affect donor-specific antibodies, which may reflect its distinct mechanism of action, primarily involving antibody-dependent cellular cytotoxicity and phagocytosis. The effects on rejection activity may have a rapid onset, but are transient. The potential benefits of prolonged therapy are currently being investigated in a recently launched phase III trial. Future studies may expand the applications of CD38 targeting to early AMR or broader indications, such as DSA-negative microvascular inflammation.
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Affiliation(s)
- Katharina A. Mayer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Klemens Budde
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Matthias Diebold
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Philip F. Halloran
- Alberta Transplant Applied Genomics Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Georg A. Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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2
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Stomberski CT, Colvin MM. Cardiac Allograft Vasculopathy: A Focus on Advances in Diagnosis and Management. Methodist Debakey Cardiovasc J 2025; 21:58-71. [PMID: 40384732 PMCID: PMC12082475 DOI: 10.14797/mdcvj.1580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 04/12/2025] [Indexed: 05/20/2025] Open
Abstract
Cardiac allograft vasculopathy (CAV) is a type of coronary artery disease unique to heart transplant recipients that can result from chronic rejection of the transplanted heart. CAV is a major cause of morbidity and mortality after the first year of transplantation. Both immune and nonimmune mechanisms contribute to the initiation and progression of CAV and result in intimal thickening, fibrosis with luminal stenosis, chronic myocardial ischemia and eventual graft failure. Recent advances in imaging modalities-including invasive intracoronary imaging and noninvasive imaging with cardiac positron emission tomography-have improved the early detection of CAV and may allow for optimization of CAV-targeted therapies to reduce CAV progression and ultimately preserve graft function.
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3
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Diebold M, Vietzen H, Schatzl M, Mayer KA, Haindl S, Heinzel A, Hittmeyer P, Herz CT, Hopfer H, Menter T, Kühner LM, Berger SM, Puchhammer-Stöckl E, Doberer K, Steiger J, Schaub S, Böhmig GA. Functional Natural Killer-cell Genetics and Microvascular Inflammation After Kidney Transplantation: An Observational Cohort Study. Transplantation 2025; 109:860-870. [PMID: 39402708 PMCID: PMC12011434 DOI: 10.1097/tp.0000000000005228] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 08/13/2024] [Accepted: 08/26/2024] [Indexed: 04/23/2025]
Abstract
BACKGROUND Recent evidence highlights the pivotal role of natural killer (NK) cells in allograft rejection. METHODS We explored associations of missing self and gene polymorphisms determining the phenotype and/or functionality of NK cells with microvascular inflammation (MVI) in a single-center cohort of 507 consecutive kidney transplant recipients. Patients were genotyped for killer cell Ig-like receptors and polymorphisms in 4 selected genes ( FCGR3AV/F158 [rs396991], KLRC2wt/del , KLRK1HNK/LNK [rs1049174], and rs9916629-C/T). RESULTS MVI was detected in 69 patients (13.6%). In a proportional odds model, the KLRC2del/del variant reduced MVI risk (odds ratio [OR] 0.26; 95% confidence interval [CI], 0.05-0.93; P = 0.037) independent of donor-specific antibodies, HLA class II eplet mismatch, and number of biopsies. Conversely, missing self (OR 1.40; 95% CI, 1.08-1.80; P = 0.011) and the rs9916629 T/T gene variant increased the risk (OR 1.70; 95% CI, 1.08-2.68; P = 0.021). Graft loss tended to be more frequent among patients with missing self ≥2 (hazard ratio 1.97; 95% CI, 0.89-4.37; P = 0.097), without influence on estimated glomerular filtration trajectories. FCGR3A variants were associated with MVI only in patients with preformed and/or de novo donor-specific antibodies (OR 4.14; 95% CI, 0.99-17.47; P = 0.052). CONCLUSIONS Missing self and NK-cell genetics may contribute to MVI, underscoring the important role of NK cells in transplant rejection.
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Affiliation(s)
- Matthias Diebold
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Hannes Vietzen
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Martina Schatzl
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Katharina A. Mayer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Susanne Haindl
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Andreas Heinzel
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Philip Hittmeyer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Carsten T. Herz
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Helmut Hopfer
- Department of Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Thomas Menter
- Department of Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Laura M. Kühner
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Sarah M. Berger
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | | | - Konstantin Doberer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Jürg Steiger
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Stefan Schaub
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Georg A. Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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Thorp EB, Ananthakrishnan A, Lantz CW. Decoding immune cell interactions during cardiac allograft vasculopathy: insights derived from bioinformatic strategies. Front Cardiovasc Med 2025; 12:1568528. [PMID: 40342971 PMCID: PMC12058854 DOI: 10.3389/fcvm.2025.1568528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 04/04/2025] [Indexed: 05/11/2025] Open
Abstract
Chronic allograft vasculopathy (CAV) is a major cause of late graft failure in heart transplant recipients, characterized by progressive intimal thickening and diffuse narrowing of the coronary arteries. Unlike atherosclerosis, CAV exhibits a distinct cellular composition and lesion distribution, yet its pathogenesis remains incompletely understood. A major challenge in CAV research has been the limited application of advanced "-omics" technologies, which have revolutionized the study of other vascular diseases. Recent advancements in single-cell and spatial transcriptomics, proteomics, and metabolomics have begun to uncover the complex immune-endothelial-stromal interactions driving CAV progression. Notably, single-cell RNA sequencing has identified previously unrecognized immune cell populations and signaling pathways implicated in endothelial injury and vascular remodeling after heart transplantation. Despite these breakthroughs, studies applying these technologies to CAV remain sparse, limiting the translation of these insights into clinical practice. This review aims to bridge this gap by summarizing recent findings from single-cell and multi-omic approaches, highlighting key discoveries, and discussing their implications for understanding CAV pathogenesis.
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Affiliation(s)
- Edward B. Thorp
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Aparnaa Ananthakrishnan
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Connor W. Lantz
- Department of Surgery, Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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5
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Diebold M, Mayer KA, Hidalgo L, Kozakowski N, Budde K, Böhmig GA. Chronic Rejection After Kidney Transplantation. Transplantation 2025; 109:610-621. [PMID: 39192468 PMCID: PMC11927446 DOI: 10.1097/tp.0000000000005187] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/16/2024] [Accepted: 07/18/2024] [Indexed: 08/29/2024]
Abstract
In kidney transplantation, ongoing alloimmune processes-commonly triggered by HLA incompatibilities-can trigger chronic transplant rejection, affecting the microcirculation and the tubulointerstitium. Continuous inflammation may lead to progressive, irreversible graft injury, culminating in graft dysfunction and accelerated transplant failure. Numerous experimental and translational studies have delineated a complex interplay of different immune mechanisms driving rejection, with antibody-mediated rejection (AMR) being an extensively studied rejection variant. In microvascular inflammation, a hallmark lesion of AMR, natural killer (NK) cells have emerged as pivotal effector cells. Their essential role is supported by immunohistologic evidence, bulk and spatial transcriptomics, and functional genetics. Despite significant research efforts, a substantial unmet need for approved rejection therapies persists, with many trials yielding negative outcomes. However, several promising therapies are currently under investigation, including felzartamab, a monoclonal antibody targeting the surface molecule CD38, which is highly expressed in NK cells and antibody-producing plasma cells. In an exploratory phase 2 trial in late AMR, this compound has demonstrated potential in resolving molecular and morphologic rejection activity and injury, predominantly by targeting NK cell effector function. These findings inspire hope for effective treatments and emphasize the necessity of further pivotal trials focusing on chronic transplant rejection.
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Affiliation(s)
- Matthias Diebold
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Katharina A. Mayer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Luis Hidalgo
- HLA Laboratory, Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | | | - Klemens Budde
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Georg A. Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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San Segundo D, Comins-Boo A, López-Hoyos M. Anti-Human Leukocyte Antigen Antibody Detection from Terasaki's Humoral Theory to Delisting Strategies in 2024. Int J Mol Sci 2025; 26:630. [PMID: 39859344 PMCID: PMC11766285 DOI: 10.3390/ijms26020630] [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: 12/05/2024] [Revised: 01/03/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
The human leukocyte antigen (HLA) system plays a critical role in transplant immunology, influencing outcomes through various immune-mediated rejection mechanisms. Hyperacute rejection is driven by preformed donor-specific antibodies (DSAs) targeting HLAs, leading to complement activation and graft loss within hours to days. Acute rejection typically occurs within six months post-transplantation, involving cellular and humoral responses, including the formation of de novo DSAs. Chronic rejection, a key factor in long-term graft failure, often involves class II DSAs and complex interactions between the innate and adaptive immune systems. Advancements in HLA antibody detection, particularly single antigen bead (SAB) assays, have improved the sensitivity and characterization of DSAs. However, these assays face challenges like false positives from denatured antigens and false negatives due to low antibody titers or complement competition. Furthermore, molecular mismatch (MM) analysis has emerged as a potential tool for refining donor-recipient compatibility but faces some issues such as a lack of standardization. Highly sensitized patients with calculated panel-reactive antibodies (cPRA) of 100% face barriers to transplantation. Strategies like serum dilution, novel therapies (e.g., Imlifidase), and delisting approaches could refine immunological risk assessment and delisting strategies are essential to expand transplant opportunities for these patients.
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Affiliation(s)
- David San Segundo
- Immunology Department, University Hospital Marqués de Valdecilla, 39008 Santander, Spain; (D.S.S.); (A.C.-B.)
- Institute for Research Marqués de Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Alejandra Comins-Boo
- Immunology Department, University Hospital Marqués de Valdecilla, 39008 Santander, Spain; (D.S.S.); (A.C.-B.)
- Institute for Research Marqués de Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Marcos López-Hoyos
- Immunology Department, University Hospital Marqués de Valdecilla, 39008 Santander, Spain; (D.S.S.); (A.C.-B.)
- Institute for Research Marqués de Valdecilla (IDIVAL), 39011 Santander, Spain
- Departamento de Biología Molecular, Universidad de Cantabria, 39011 Santander, Spain
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Cucchiari D, Podestà MA, Ponticelli C. Pathophysiology of rejection in kidney transplantation. Expert Rev Clin Immunol 2024; 20:1471-1481. [PMID: 39467249 DOI: 10.1080/1744666x.2024.2421310] [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: 02/04/2024] [Accepted: 10/04/2024] [Indexed: 10/30/2024]
Abstract
INTRODUCTION Rejection remains a major obstacle to successful kidney transplantation. The complex pathophysiology of rejection depends on a fine-tuned interplay between the innate and adaptive immune systems. AREAS COVERED This review provides a comprehensive analysis of the pathophysiology of rejection of kidney grafts, performed through careful selection of most relevant papers available on the topic in the PubMed database. The two types of rejection usually observed at the kidney biopsy, i.e. cellular and humoral rejection, are described with an accurate outline of the biological processes that lead to their development. EXPERT OPINION The incidence of T-cell-mediated rejection is decreasing, and most cases promptly respond to appropriate immunosuppression. However, late diagnosis or incomplete response to treatment may have deleterious consequences in the long term. The main issue is represented by antibody-mediated rejection, which unsatisfactorily responds to aggressive immunosuppression, especially when diagnosed late. Prevention of acute ABMR rests on HLA-specific antibody detection prior to transplantation, adequate immunosuppression, and optimal patients' compliance. Late diagnosis and poor response to treatment inevitably lead to chronic ABMR, for which no therapies are currently available.
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Affiliation(s)
- David Cucchiari
- Department of Nephrology and Kidney Transplantation, Hospital Clínic, Barcelona, Spain
| | - Manuel Alfredo Podestà
- Transplantation Research Center, Renal Division, Brigham and Women's Hopsital, Harvard Medical School, Boston, MA, USA
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8
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Chambon M, Koenig A. NK Cells: Not Just Followers But Also Initiators of Chronic Vascular Rejection. Transpl Int 2024; 37:13318. [PMID: 39479216 PMCID: PMC11521863 DOI: 10.3389/ti.2024.13318] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 09/23/2024] [Indexed: 11/02/2024]
Abstract
Chronic graft rejection represents a significant threat to long-term graft survival. Early diagnosis, understanding of the immunological mechanisms and appropriate therapeutic management are essential to improve graft survival and quality of life for transplant patients. Knowing which immune cells are responsible for chronic vascular rejection would allow us to provide effective and appropriate treatment for these patients. It is now widely accepted that natural killer (NK) cells play an important role in chronic vascular rejection. They can either initiate chronic vascular rejection by recognizing missing self on the graft or be recruited by donor-specific antibodies to destroy the graft during antibody-mediated rejection. Whatever the mechanisms of activation of NK cells, they need to be primed to become fully activated and damaging to the graft. A better understanding of the signaling pathways involved in NK cell priming and activation would pave the way for the development of new therapeutic strategies to cure chronic vascular rejection. This review examines the critical role of NK cells in the complex context of chronic vascular rejection.
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Affiliation(s)
- Mathilde Chambon
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France
| | - Alice Koenig
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France
- Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology, Lyon, France
- Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
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9
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Thaunat O. Natural killer cell-mediated innate microvascular rejection. Nat Rev Nephrol 2024; 20:489-490. [PMID: 38898355 DOI: 10.1038/s41581-024-00862-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Affiliation(s)
- Olivier Thaunat
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, Lyon, France.
- Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology, Lyon, France.
- Claude Bernard University (Lyon 1), Villeurbanne, France.
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10
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Fuhrmann B, Jiang J, Mcleod P, Huang X, Balaji S, Arp J, Diao H, Ma S, Peng T, Haig A, Gunaratnam L, Zhang ZX, Jevnikar AM. Inhibition of NK cell cytotoxicity by tubular epithelial cell expression of Clr-b and Clr-f. CURRENT RESEARCH IN IMMUNOLOGY 2024; 5:100081. [PMID: 39113760 PMCID: PMC11303997 DOI: 10.1016/j.crimmu.2024.100081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 06/21/2024] [Accepted: 07/03/2024] [Indexed: 08/10/2024] Open
Abstract
NK cells participate in ischemia reperfusion injury (IRI) and transplant rejection. Endogenous regulatory systems may exist to attenuate NK cell activation and cytotoxicity in IRI associated with kidney transplantation. A greater understanding of NK regulation will provide insights in transplant outcomes and could direct new therapeutic strategies. Kidney tubular epithelial cells (TECs) may negatively regulate NK cell activation by their surface expression of a complex family of C-type lectin-related proteins (Clrs). We have found that Clr-b and Clr-f were expressed by TECs. Clr-b was upregulated by inflammatory cytokines TNFα and IFNγ in vitro. Silencing of both Clr-b and Clr-f expression using siRNA resulted in increased NK cell killing of TECs compared to silencing of either Clr-b or Clr-f alone (p < 0.01) and when compared to control TECs (p < 0.001). NK cells treated in vitro with soluble Clr-b and Clr-f proteins reduced their capacity to kill TECs (p < 0.05). Hence, NK cell cytotoxicity can be inhibited by Clr proteins on the surface of TECs. Our study suggests a synergistic effect of Clr molecules in regulating NK cell function in renal cells and this may represent an important endogenous regulatory system to limit NK cell-mediated organ injury during inflammation.
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Affiliation(s)
- Benjamin Fuhrmann
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - Jifu Jiang
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada
| | - Patrick Mcleod
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada
| | - Xuyan Huang
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada
| | - Shilpa Balaji
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - Jaqueline Arp
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada
| | - Hong Diao
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada
| | - Shengwu Ma
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - Tianqing Peng
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Aaron Haig
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Lakshman Gunaratnam
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
- Multi-Organ Transplantation Program, London Health Sciences Centre, London, Ontario, Canada
- Division of Nephrology, Department of Medicine, Western University, London, Ontario, Canada
| | - Zhu-Xu Zhang
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
- Multi-Organ Transplantation Program, London Health Sciences Centre, London, Ontario, Canada
- Division of Nephrology, Department of Medicine, Western University, London, Ontario, Canada
| | - Anthony M. Jevnikar
- Matthew Mailing Centre for Translational Transplant Studies, Lawson Health Research Institute, London, Ontario, Canada
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
- Multi-Organ Transplantation Program, London Health Sciences Centre, London, Ontario, Canada
- Division of Nephrology, Department of Medicine, Western University, London, Ontario, Canada
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Alessandrini A, Rosales IA. Down to the coronary arteries: When spatial multiomics open up a narrow path. Am J Transplant 2024; 24:1102-1104. [PMID: 38508320 DOI: 10.1016/j.ajt.2024.02.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 02/22/2024] [Accepted: 02/28/2024] [Indexed: 03/22/2024]
Affiliation(s)
- Alessandro Alessandrini
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ivy A Rosales
- Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Pathology, Immunopathology Research Laboratory, Massachusetts General Hospital, Boston, Massachusetts, USA.
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12
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Diebold M, Farkash EA, Barnes J, Regele H, Kozakowski N, Schatzl M, Mayer KA, Haindl S, Vietzen H, Hidalgo LG, Halloran PF, Eskandary F, Böhmig GA. Natural Killer Cell Presence in Antibody-Mediated Rejection. Transpl Int 2024; 37:13209. [PMID: 38979120 PMCID: PMC11228143 DOI: 10.3389/ti.2024.13209] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 06/12/2024] [Indexed: 07/10/2024]
Abstract
Transcript analyses highlight an important contribution of natural killer (NK) cells to microvascular inflammation (MVI) in antibody-mediated rejection (ABMR), but only few immunohistologic studies have quantified their spatial distribution within graft tissue. This study included 86 kidney transplant recipients who underwent allograft biopsies for a positive donor-specific antibody (DSA) result. NK cells were visualized and quantified within glomeruli and peritubular capillaries (PTC), using immunohistochemistry for CD34 alongside CD16/T-bet double-staining. Staining results were analyzed in relation to histomorphology, microarray analysis utilizing the Molecular Microscope Diagnostic System, functional NK cell genetics, and clinical outcomes. The number of NK cells in glomeruli per mm2 glomerular area (NKglom) and PTC per mm2 cortical area (NKPTC) was substantially higher in biopsies with ABMR compared to those without rejection, and correlated with MVI scores (NKglom Spearman's correlation coefficient [SCC] = 0.55, p < 0.001, NKPTC 0.69, p < 0.001). In parallel, NK cell counts correlated with molecular classifiers reflecting ABMR activity (ABMRprob: NKglom 0.59, NKPTC 0.75) and showed a trend towards higher levels in association with high functional FCGR3A and KLRC2 gene variants. Only NKPTC showed a marginally significant association with allograft function and survival. Our immunohistochemical results support the abundance of NK cells in DSA-positive ABMR.
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Affiliation(s)
- Matthias Diebold
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Evan A Farkash
- Department of Pathology, University of Michigan, Ann Arbor, MI, United States
| | - Jenna Barnes
- Department of Pathology, University of Michigan, Ann Arbor, MI, United States
| | - Heinz Regele
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | | | - Martina Schatzl
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Katharina A Mayer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Susanne Haindl
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Hannes Vietzen
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Luis G Hidalgo
- Department of Surgery, University of Wisconsin, Madison, WI, United States
| | - Philip F Halloran
- Alberta Transplant Applied Genomics Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Farsad Eskandary
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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Diebold M, Vietzen H, Heinzel A, Haindl S, Herz CT, Mayer K, Doberer K, Kainz A, Faé I, Wenda S, Kühner LM, Berger SM, Puchhammer-Stöckl E, Kozakowski N, Schaub S, Halloran PF, Böhmig GA. Natural killer cell functional genetics and donor-specific antibody-triggered microvascular inflammation. Am J Transplant 2024; 24:743-754. [PMID: 38097018 DOI: 10.1016/j.ajt.2023.12.005] [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: 08/16/2023] [Revised: 10/28/2023] [Accepted: 12/02/2023] [Indexed: 12/31/2023]
Abstract
Antibody-mediated rejection (ABMR) is a leading cause of graft failure. Emerging evidence suggests a significant contribution of natural killer (NK) cells to microvascular inflammation (MVI). We investigated the influence of genetically determined NK cell functionality on ABMR development and activity. The study included 86 kidney transplant recipients subjected to systematic biopsies triggered by donor-specific antibody detection. We performed killer immunoglobulin-like receptor typing to predict missing self and genotyped polymorphisms determining NK cell functionality (FCGR3AV/F158 [rs396991], KLRC2wt/del, KLRK1HNK/LNK [rs1049174], rs9916629-C/T). Fifty patients had ABMR with considerable MVI and elevated NK cell transcripts. Missing self was not related to MVI. Only KLRC2wt/wt showed an association (MVI score: 2 [median; interquartile range: 0-3] vs 0 [0-1] in KLRC2wt/del recipients; P = .001) and remained significant in a proportional odds multivariable model (odds ratio, 7.84; 95% confidence interval, 2.37-30.47; P = .001). A sum score incorporating all polymorphisms and missing self did not outperform a score including only KLRC2 and FCGR3A variants, which were predictive in univariable analysis. NK cell genetics did not affect graft functional decline and survival. In conclusion, a functional KLRC2 polymorphism emerged as an independent determinant of ABMR activity, without a considerable contribution of missing self and other NK cell gene polymorphisms.
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Affiliation(s)
- Matthias Diebold
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Hannes Vietzen
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Andreas Heinzel
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Susanne Haindl
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Carsten T Herz
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Katharina Mayer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Konstantin Doberer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Alexander Kainz
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Ingrid Faé
- Department of Blood Group Serology and Transfusion Medicine, Medical University Vienna, Vienna, Austria
| | - Sabine Wenda
- Department of Blood Group Serology and Transfusion Medicine, Medical University Vienna, Vienna, Austria
| | - Laura M Kühner
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Sarah M Berger
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | | | | | - Stefan Schaub
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Philip F Halloran
- Alberta Transplant Applied Genomics Centre, ATAGC, University of Alberta, Edmonton, Alberta, Canada
| | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
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14
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Lunardi F, Vedovelli L, Pezzuto F, Le Pavec J, Dorfmuller P, Ivanovic M, Pena T, Wassilew K, Perch M, Hirschi S, Chenard MP, Sosa RA, Goddard M, Neil D, Montero-Fernandez A, Rice A, Cozzi E, Rea F, Levine DJ, Roux A, Fishbein GA, Calabrese F. Assessing the role of phosphorylated S6 ribosomal protein in the pathological diagnosis of pulmonary antibody-mediated rejection. J Heart Lung Transplant 2024; 43:403-413. [PMID: 37806601 DOI: 10.1016/j.healun.2023.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 09/27/2023] [Accepted: 10/02/2023] [Indexed: 10/10/2023] Open
Abstract
BACKGROUND Pulmonary antibody-mediated rejection is still a challenging diagnosis as C4d immunostaining has poor sensitivity. Previous studies have indicated that the phosphorylated S6 ribosomal protein, a component of the mammalian target of rapamycin (mTOR) pathway, is correlated with de novo donor-specific antibodies in lung transplantation. The objective of this study was to evaluate the phosphorylation of S6 ribosomal protein as a surrogate for antibody-mediated rejection diagnosis in lung transplant patients. METHODS This multicentre retrospective study analyzed transbronchial biopsies from 216 lung transplanted patients, 114 with antibody-mediated rejection and 102 without (19 with acute cellular rejection, 17 with ischemia/reperfusion injury, 18 with infection, and 48 without post-transplant complications). Immunohistochemistry was used to quantify phosphorylated S6 ribosomal protein expression in macrophages, endothelium, epithelium, and inter-pathologist agreement was assessed. RESULTS Median phosphorylated S6 ribosomal protein expression values were higher in antibody-mediated rejection cases than in controls for all cell components, with the highest sensitivity in macrophages (0.9) and the highest specificity in endothelial expression (0.8). The difference was mainly significant in macrophages compared to other post-lung transplantation complications. Inter-pathologist agreement was moderate for macrophages and endothelium, with higher agreement when phosphorylated S6 ribosomal protein expression was dichotomized into positive/negative. The inclusion of phosphorylated S6 ribosomal protein in the diagnostic algorithm could have increased antibody-mediated rejection certainty levels by 25%. CONCLUSIONS The study supports the role of the mTOR pathway in antibody-mediated rejection-related graft injury and suggests that tissue phosphorylation of S6 ribosomal protein could be a useful surrogate for a more accurate pathological diagnosis of lung antibody-mediated rejection.
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Affiliation(s)
- Francesca Lunardi
- Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Luca Vedovelli
- Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Federica Pezzuto
- Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Jerome Le Pavec
- Service de Pneumologie et de Transplantation Pulmonaire, Groupe Hospitalier Marie-Lannelongue-Paris Saint Joseph, Le Plessis-Robinson, France; Faculty of Medicine, Université Paris-Saclay, Le Kremlin Bicêtre, France; UMR_S 999, Université Paris-Sud, INSERM, Groupe hospitalier Marie-Lannelongue-Saint Joseph, Le Plessis-Robinson, France
| | - Peter Dorfmuller
- UMR_S 999, Université Paris-Sud, INSERM, Groupe hospitalier Marie-Lannelongue-Saint Joseph, Le Plessis-Robinson, France
| | - Marina Ivanovic
- Department of Pathology, Loyola University Medical Center, Chicago, Illinois
| | - Tahuanty Pena
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | | | - Michael Perch
- Department of Cardiology, Section for Lung Transplantation, Righospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Sandrine Hirschi
- Department of Respiratory Medicine, University Hospital of Strasbourg, Strasbourg, France
| | | | - Rebecca A Sosa
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Martin Goddard
- Department of Histopathology, Papworth Hospital NHS Trust, Cambridge, UK
| | - Desley Neil
- Department of Histopathology, Queen Elizabeth Hospital, Birmingham, UK
| | | | - Alexandra Rice
- Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Emanuele Cozzi
- Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Federico Rea
- Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy
| | - Deborah J Levine
- Department of Medicine, University of Texas Health Science Center San Antonio, San Antonio, Texas
| | - Antoine Roux
- Department of Pneumology, Hôpital Foch, Suresnes, France and Université Versailles-Saint-Quentin-en-Yvelines, Versailles, France
| | - Gregory A Fishbein
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Fiorella Calabrese
- Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padova, Italy.
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15
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Shah Y, Yang H, Mueller FB, Li C, Gul Rahim SE, Varma E, Salinas T, Dadhania DM, Salvatore SP, Seshan SV, Sharma VK, Elemento O, Suthanthiran M, Muthukumar T. Transcriptomic signatures of chronic active antibody-mediated rejection deciphered by RNA sequencing of human kidney allografts. Kidney Int 2024; 105:347-363. [PMID: 38040290 PMCID: PMC10841597 DOI: 10.1016/j.kint.2023.11.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/27/2023] [Accepted: 11/10/2023] [Indexed: 12/03/2023]
Abstract
Natural killer (NK) cells mediate spontaneous cell-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity. This dual functionality could enable their participation in chronic active antibody-mediated rejection (CA-ABMR). Earlier microarray profiling studies have not subcategorized antibody-mediated rejection into CA-ABMR and active-ABMR, and the gene expression pattern of CA-ABMR has not been compared with that of T cell-mediated rejection (TCMR). To fill these gaps, we RNA sequenced human kidney allograft biopsies categorized as CA-ABMR, active-ABMR, TCMR, or No Rejection (NR). Among the 15,910 genes identified in the biopsies, 60, 114, and 231 genes were uniquely overexpressed in CA-ABMR, TCMR, and active-ABMR, respectively; compared to NR, 50 genes were shared between CA-ABMR and active-ABMR, and 164 genes between CA-ABMR and TCMR. The overexpressed genes were annotated to NK cells and T cells in CA-ABMR and TCMR, and to neutrophils and monocytes in active-ABMR. The NK cell cytotoxicity and allograft rejection pathways were enriched in CA-ABMR. Genes encoding perforin, granzymes, and death receptor were overexpressed in CA-ABMR versus active-ABMR but not compared to TCMR. NK cell cytotoxicity pathway gene set variation analysis score was higher in CA-ABMR compared to active-ABMR but not in TCMR. Principal component analysis of the deconvolved immune cellular transcriptomes separated CA-ABMR and TCMR from active-ABMR and NR. Immunohistochemistry of kidney allograft biopsies validated a higher proportion of CD56+ NK cells in CA-ABMR than in active-ABMR. Thus, CA-ABMR was exemplified by the overexpression of the NK cell cytotoxicity pathway gene set and, surprisingly, molecularly more like TCMR than active-ABMR.
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Affiliation(s)
- Yajas Shah
- Department of Physiology and Biophysics, Caryl and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA; Graduate Program in Biophysics and Systems Biology, Weill Cornell Medical College, New York, New York, USA
| | - Hua Yang
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Franco B Mueller
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Carol Li
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Shab E Gul Rahim
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Elly Varma
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Thalia Salinas
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Department of Transplantation Medicine, NewYork-Presbyterian/Weill Cornell Medical Center, New York, New York, USA
| | - Darshana M Dadhania
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Department of Transplantation Medicine, NewYork-Presbyterian/Weill Cornell Medical Center, New York, New York, USA
| | - Steven P Salvatore
- Division of Renal Pathology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Surya V Seshan
- Division of Renal Pathology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Vijay K Sharma
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Olivier Elemento
- Department of Physiology and Biophysics, Caryl and Israel Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, USA; Graduate Program in Biophysics and Systems Biology, Weill Cornell Medical College, New York, New York, USA
| | - Manikkam Suthanthiran
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Department of Transplantation Medicine, NewYork-Presbyterian/Weill Cornell Medical Center, New York, New York, USA
| | - Thangamani Muthukumar
- Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Department of Transplantation Medicine, NewYork-Presbyterian/Weill Cornell Medical Center, New York, New York, USA.
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16
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Marco I, López-Azor García JC, González Martín J, Severo Sánchez A, García-Cosío Carmena MD, Mancebo Sierra E, de Juan Bagudá J, Castrodeza Calvo J, Hernández Pérez FJ, Delgado JF. De Novo Donor-Specific Antibodies after Heart Transplantation: A Comprehensive Guide for Clinicians. J Clin Med 2023; 12:7474. [PMID: 38068526 PMCID: PMC10707043 DOI: 10.3390/jcm12237474] [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: 09/24/2023] [Revised: 11/28/2023] [Accepted: 11/30/2023] [Indexed: 04/12/2024] Open
Abstract
Antibodies directed against donor-specific human leukocyte antigens (HLAs) can be detected de novo after heart transplantation and play a key role in long-term survival. De novo donor-specific antibodies (dnDSAs) have been associated with cardiac allograft vasculopathy, antibody-mediated rejection, and mortality. Advances in detection methods and international guideline recommendations have encouraged the adoption of screening protocols among heart transplant units. However, there is still a lack of consensus about the correct course of action after dnDSA detection. Treatment is usually started when antibody-mediated rejection is present; however, some dnDSAs appear years before graft failure is detected, and at this point, damage may be irreversible. In particular, class II, anti-HLA-DQ, complement binding, and persistent dnDSAs have been associated with worse outcomes. Growing evidence points towards a more aggressive management of dnDSA. For that purpose, better diagnostic tools are needed in order to identify subclinical graft injury. Cardiac magnetic resonance, strain techniques, or coronary physiology parameters could provide valuable information to identify patients at risk. Treatment of dnDSA usually involves plasmapheresis, intravenous immunoglobulin, immunoadsorption, and ritxumab, but the benefit of these therapies is still controversial. Future efforts should focus on establishing effective treatment protocols in order to improve long-term survival of heart transplant recipients.
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Affiliation(s)
- Irene Marco
- Cardiology Department, Hospital Universitario La Paz, 28046 Madrid, Spain;
| | - Juan Carlos López-Azor García
- Cardiology Department, Hospital Universitario Puerta de Hierro, 28222 Madrid, Spain; (J.C.L.-A.G.); (F.J.H.P.)
- Centro Nacional de Investigaciones Biomédicas en Red de Enfermedades CardioVasculares (CIBERCV), 28029 Madrid, Spain; (J.G.M.); (M.D.G.-C.C.); (J.d.J.B.); (J.C.C.)
- School of Medicine, Universidad Europea de Madrid, 28670 Madrid, Spain
| | - Javier González Martín
- Centro Nacional de Investigaciones Biomédicas en Red de Enfermedades CardioVasculares (CIBERCV), 28029 Madrid, Spain; (J.G.M.); (M.D.G.-C.C.); (J.d.J.B.); (J.C.C.)
- Cardiology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain;
| | - Andrea Severo Sánchez
- Cardiology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain;
| | - María Dolores García-Cosío Carmena
- Centro Nacional de Investigaciones Biomédicas en Red de Enfermedades CardioVasculares (CIBERCV), 28029 Madrid, Spain; (J.G.M.); (M.D.G.-C.C.); (J.d.J.B.); (J.C.C.)
- Cardiology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain;
| | - Esther Mancebo Sierra
- Immunology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain;
| | - Javier de Juan Bagudá
- Centro Nacional de Investigaciones Biomédicas en Red de Enfermedades CardioVasculares (CIBERCV), 28029 Madrid, Spain; (J.G.M.); (M.D.G.-C.C.); (J.d.J.B.); (J.C.C.)
- School of Medicine, Universidad Europea de Madrid, 28670 Madrid, Spain
- Cardiology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain;
| | - Javier Castrodeza Calvo
- Centro Nacional de Investigaciones Biomédicas en Red de Enfermedades CardioVasculares (CIBERCV), 28029 Madrid, Spain; (J.G.M.); (M.D.G.-C.C.); (J.d.J.B.); (J.C.C.)
- Cardiology Department, Hospital Universitario Gregorio Marañón, 28007 Madrid, Spain
| | | | - Juan Francisco Delgado
- Centro Nacional de Investigaciones Biomédicas en Red de Enfermedades CardioVasculares (CIBERCV), 28029 Madrid, Spain; (J.G.M.); (M.D.G.-C.C.); (J.d.J.B.); (J.C.C.)
- Cardiology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain;
- School of Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain
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17
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Farhana S, Kai YC, Kadir R, Sulaiman WAW, Nordin NA, Nasir NAM. The fate of adipose tissue and adipose-derived stem cells in allograft. Cell Tissue Res 2023; 394:269-292. [PMID: 37624425 DOI: 10.1007/s00441-023-03827-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/15/2023] [Indexed: 08/26/2023]
Abstract
Utilizing adipose tissue and adipose-derived stem cells (ADSCs) turned into a promising field of allograft in recent years. The therapeutic potential of adipose tissue and ADSCs is governed by their molecular secretions, ability to sustain multi-differentiation and self-renewal which are pivotal in reconstructive, genetic diseases, and cosmetic goals. However, revisiting the existing functional capacity of adipose tissue and ADSCs and their intricate relationship with allograft is crucial to figure out the remarkable question of safety to use in allograft due to the growing evidence of interactions between tumor microenvironment and ADSCs. For instance, the molecular secretions of adipose tissue and ADSCs induce angiogenesis, create growth factors, and control the inflammatory response; it has now been well determined. Though the existing preclinical allograft studies gave positive feedback, ADSCs and adipose tissue are attracted by some factors of tumor stroma. Moreover, allorecognition is pivotal to allograft rejection which is carried out by costimulation in a complement-dependent way and leads to the destruction of the donor cells. However, extensive preclinical trials of adipose tissue and ADSCs in allograft at molecular level are still limited. Hence, comprehensive immunomodulatory analysis could ensure the successful allograft of adipose tissue and ADSCs avoiding the oncological risk.
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Affiliation(s)
- Sadia Farhana
- Reconstructive Sciences Unit, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
| | - Yew Chun Kai
- Reconstructive Sciences Unit, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
- Hospital Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
| | - Ramlah Kadir
- Department of Immunology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
| | - Wan Azman Wan Sulaiman
- Reconstructive Sciences Unit, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
- Hospital Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
| | - Nor Asyikin Nordin
- Department of Immunology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
| | - Nur Azida Mohd Nasir
- Reconstructive Sciences Unit, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia.
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18
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Hug MN, Keller S, Marty T, Gygax D, Meinel D, Spies P, Handschin J, Kleiser M, Vazquez N, Linnik J, Buchli R, Claas F, Heidt S, Kramer CSM, Bezstarosti S, Lee JH, Schaub S, Hönger G. HLA antibody affinity determination: From HLA-specific monoclonal antibodies to donor HLA specific antibodies (DSA) in patient serum. HLA 2023. [PMID: 37191252 DOI: 10.1111/tan.15047] [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: 12/30/2022] [Revised: 03/08/2023] [Accepted: 03/20/2023] [Indexed: 05/17/2023]
Abstract
Organs transplanted across donor-specific HLA antibodies (DSA) are associated with a variety of clinical outcomes, including a high risk of acute kidney graft rejection. Unfortunately, the currently available assays to determine DSA characteristics are insufficient to clearly discriminate between potentially harmless and harmful DSA. To further explore the hazard potential of DSA, their concentration and binding strength to their natural target, using soluble HLA, may be informative. There are currently a number of biophysical technologies available that allow the assessment of antibody binding strength. However, these methods require prior knowledge of antibody concentrations. Our objective within this study was to develop a novel approach that combines the determination of DSA-affinity as well as DSA-concentration for patient sample evaluation within one assay. We initially tested the reproducibility of previously reported affinities of human HLA-specific monoclonal antibodies and assessed the technology-specific precision of the obtained results on multiple platforms, including surface plasmon resonance (SPR), bio-layer interferometry (BLI), Luminex (single antigen beads; SAB), and flow-induced dispersion analysis (FIDA). While the first three (solid-phase) technologies revealed comparable high binding-strengths, suggesting measurement of avidity, the latter (in-solution) approach revealed slightly lower binding-strengths, presumably indicating measurement of affinity. We believe that our newly developed in-solution FIDA-assay is particularly suitable to provide useful clinical information by not just measuring DSA-affinities in patient serum samples but simultaneously delivering a particular DSA-concentration. Here, we investigated DSA from 20 pre-transplant patients, all of whom showed negative CDC-crossmatch results with donor cells and SAB signals ranging between 571 and 14899 mean fluorescence intensity (MFI). DSA-concentrations were found in the range between 11.2 and 1223 nM (median 81.1 nM), and their measured affinities fall between 0.055 and 24.7 nM (median 5.34 nM; 449-fold difference). In 13 of 20 sera (65%), DSA accounted for more than 0.1% of total serum antibodies, and 4/20 sera (20%) revealed a proportion of DSA even higher than 1%. To conclude, this study strengthens the presumption that pre-transplant patient DSA consists of various concentrations and different net affinities. Validation of these results in a larger patient cohort with clinical outcomes will be essential in a further step to assess the clinical relevance of DSA-concentration and DSA-affinity.
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Affiliation(s)
- Melanie N Hug
- University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences Muttenz, Muttenz, Switzerland
| | - Sabrina Keller
- University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences Muttenz, Muttenz, Switzerland
| | - Talea Marty
- University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences Muttenz, Muttenz, Switzerland
| | - Daniel Gygax
- University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences Muttenz, Muttenz, Switzerland
| | - Dominik Meinel
- University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences Muttenz, Muttenz, Switzerland
| | - Peter Spies
- University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences Muttenz, Muttenz, Switzerland
| | - Joëlle Handschin
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Marc Kleiser
- Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | - Noemi Vazquez
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Janina Linnik
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
- Swiss Institute for Bioinformatics, Basel, Switzerland
| | - Rico Buchli
- Department of Research and Development, PureProtein LLC, Oklahoma City, Oklahoma, USA
| | - Frans Claas
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Sebastiaan Heidt
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Cynthia S M Kramer
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Suzanne Bezstarosti
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Jar-How Lee
- Research Department, Terasaki Innovation Center (TIC), Glendale, California, USA
| | - Stefan Schaub
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Gideon Hönger
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
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19
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Tseng HT, Lin YW, Huang CY, Shih CM, Tsai YT, Liu CW, Tsai CS, Lin FY. Animal Models for Heart Transplantation Focusing on the Pathological Conditions. Biomedicines 2023; 11:biomedicines11051414. [PMID: 37239085 DOI: 10.3390/biomedicines11051414] [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: 03/30/2023] [Revised: 04/29/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
Cardiac transplant recipients face many complications due to transplant rejection. Scientists must conduct animal experiments to study disease onset mechanisms and develop countermeasures. Therefore, many animal models have been developed for research topics including immunopathology of graft rejection, immunosuppressive therapies, anastomotic techniques, and graft preservation techniques. Small experimental animals include rodents, rabbits, and guinea pigs. They have a high metabolic rate, high reproductive rate, small size for easy handling, and low cost. Additionally, they have genetically modified strains for pathological mechanisms research; however, there is a lacuna, as these research results rarely translate directly to clinical applications. Large animals, including canines, pigs, and non-human primates, have anatomical structures and physiological states that are similar to those of humans; therefore, they are often used to validate the results obtained from small animal studies and directly speculate on the feasibility of applying these results in clinical practice. Before 2023, PubMed Central® at the United States National Institute of Health's National Library of Medicine was used for literature searches on the animal models for heart transplantation focusing on the pathological conditions. Unpublished reports and abstracts from conferences were excluded from this review article. We discussed the applications of small- and large-animal models in heart transplantation-related studies. This review article aimed to provide researchers with a complete understanding of animal models for heart transplantation by focusing on the pathological conditions created by each model.
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Affiliation(s)
- Horng-Ta Tseng
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Departments of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yi-Wen Lin
- Institute of Oral Biology, National Yang Ming Chiao Tung University (Yangming Campus), Taipei 112304, Taiwan
| | - Chun-Yao Huang
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Departments of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Chun-Ming Shih
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Departments of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yi-Ting Tsai
- Division of Cardiovascular Surgery, Tri-Service General Hospital, Defense Medical Center, Taipei 11490, Taiwan
| | - Chen-Wei Liu
- Department of Basic Medical Science, College of Medicine, University of Arizona, Phoenix, AZ 85721, USA
| | - Chien-Sung Tsai
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiovascular Surgery, Tri-Service General Hospital, Defense Medical Center, Taipei 11490, Taiwan
- Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei 11490, Taiwan
| | - Feng-Yen Lin
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Departments of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
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20
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Unraveling complexity of antibody-mediated rejections, the mandatory way towards an accurate diagnosis and a personalized treatment. Presse Med 2022; 51:104141. [PMID: 36209931 DOI: 10.1016/j.lpm.2022.104141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 09/29/2022] [Indexed: 11/09/2022] Open
Abstract
Antibody-mediated rejection (ABMR) remains one of the most challenging issues after organ transplantation and particularly after kidney transplantation. Despite many progresses during the last decade, ABMR is still the main cause of kidney graft loss and this all over the post- transplant period. In this review, we describe the recent knowledge about molecular and cellular mechanisms involved in ABMR. We focused our report on the role of the complement pathway in the process of ABMR and we give some insights into the role of inflammatory cells, NK lymphocytes and the role of endothelial cells. We further describe the potential role of non-HLA antibodies, of which the importance has been increasingly emphasized in recent years. Overall, this report could be of interest for all physicians who are working in the field of organ transplantation or who are working in the field of immunology. It gives essential information to understand new diagnosis advances and further therapeutic approaches. Antibody-mediated rejection (ABMR) is the leading cause of graft failure ([1,2]). In contrast to T-cell mediated rejection usually sensitive to steroids, active ABMR remains a therapeutic challenge. ABMR diagnosis relies on the presence of renal injuries and donor-specific antibodies (DSA) (HLA and non HLA antibodies) with sometimes the evidence of interaction between DSA and graft endothelium. Regularly revised during expert conferences, ABMR definition is currently categorized as active or chronic active. [3] The emergence of validated molecular assays targeting a better phenotyping of ABMR and the recent advances regarding the detrimental effect of DSA directed against minor antigens open the way to a better assessment of the heterogeneity of ABMR. In this review, we will address new aspects of ABMR regarding its mechanisms, diagnosis and treatments.
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21
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Rosales IA, Mahowald GK, Tomaszewski K, Hotta K, Iwahara N, Otsuka T, Tsuji T, Takada Y, Acheampong E, Araujo-Medina M, Bruce A, Rios A, Cosimi AB, Elias N, Kawai T, Gilligan H, Safa K, Riella LV, Tolkoff-Rubin NE, Williams WW, Smith RN, Colvin RB. Banff Human Organ Transplant Transcripts Correlate with Renal Allograft Pathology and Outcome: Importance of Capillaritis and Subpathologic Rejection. J Am Soc Nephrol 2022; 33:2306-2319. [PMID: 36450597 PMCID: PMC9731628 DOI: 10.1681/asn.2022040444] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 07/19/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND To seek insights into the pathogenesis of chronic active antibody-mediated rejection (CAMR), we performed mRNA analysis and correlated transcripts with pathologic component scores and graft outcomes. METHODS We utilized the NanoString nCounter platform and the Banff Human Organ Transplant gene panel to quantify transcripts on 326 archived renal allograft biopsy samples. This system allowed correlation of transcripts with Banff pathology scores from the same tissue block and correlation with long-term outcomes. RESULTS The only pathology score that correlated with AMR pathways in CAMR was peritubular capillaritis (ptc). C4d, cg, g, v, i, t, or ci scores did not correlate. DSA-negative CAMR had lower AMR pathway scores than DSA-positive CAMR. Transcript analysis in non-CAMR biopsies yielded evidence of increased risk of later CAMR. Among 108 patients without histologic CAMR, 23 developed overt biopsy-documented CAMR within 5 years and as a group had higher AMR pathway scores (P=3.4 × 10-5). Random forest analysis correlated 3-year graft loss with elevated damage, innate immunity, and macrophage pathway scores in CAMR and TCMR. Graft failure in CAMR was associated with TCMR transcripts but not with AMR transcripts, and graft failure in TCMR was associated with AMR transcripts but not with TCMR transcripts. CONCLUSIONS Peritubular capillary inflammation and DSA are the primary drivers of AMR transcript elevation. Transcripts revealed subpathological evidence of AMR, which often preceded histologic CAMR and subpathological evidence of TCMR that predicted graft loss in CAMR.
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Affiliation(s)
- Ivy A. Rosales
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Grace K. Mahowald
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kristen Tomaszewski
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kiyohiko Hotta
- Department of Urology, Hokkaido University Hospital, Hokkaido, Japan
| | - Naoya Iwahara
- Department of Urology, Hokkaido University Hospital, Hokkaido, Japan
| | - Takuya Otsuka
- Department of Surgical Pathology, Hokkaido University Hospital, Hokkaido, Japan
| | - Takahiro Tsuji
- Department of Pathology, Sapporo City General Hospital, Hokkaido, Japan
| | - Yusuke Takada
- Department of Kidney Transplant Surgery, Sapporo City General Hospital, Hokkaido, Japan
| | - Ellen Acheampong
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Milagros Araujo-Medina
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Amy Bruce
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Andrea Rios
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Anthony Benedict Cosimi
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Nahel Elias
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Tatsuo Kawai
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Hannah Gilligan
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kassem Safa
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Leonardo V. Riella
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Nina E. Tolkoff-Rubin
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Winfred W. Williams
- Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Rex Neal Smith
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Robert B. Colvin
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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22
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Charmetant X, Chen CC, Hamada S, Goncalves D, Saison C, Rabeyrin M, Rabant M, Duong van Huyen JP, Koenig A, Mathias V, Barba T, Lacaille F, le Pavec J, Brugière O, Taupin JL, Chalabreysse L, Mornex JF, Couzi L, Graff-Dubois S, Jeger-Madiot R, Tran-Dinh A, Mordant P, Paidassi H, Defrance T, Morelon E, Badet L, Nicoletti A, Dubois V, Thaunat O. Inverted direct allorecognition triggers early donor-specific antibody responses after transplantation. Sci Transl Med 2022; 14:eabg1046. [PMID: 36130013 DOI: 10.1126/scitranslmed.abg1046] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The generation of antibodies against donor-specific major histocompatibility complex (MHC) antigens, a type of donor-specific antibodies (DSAs), after transplantation requires that recipient's allospecific B cells receive help from T cells. The current dogma holds that this help is exclusively provided by the recipient's CD4+ T cells that recognize complexes of recipient's MHC II molecules and peptides derived from donor-specific MHC alloantigens, a process called indirect allorecognition. Here, we demonstrated that, after allogeneic heart transplantation, CD3ε knockout recipient mice lacking T cells generate a rapid, transient wave of switched alloantibodies, predominantly directed against MHC I molecules. This is due to the presence of donor CD4+ T cells within the graft that recognize intact recipient's MHC II molecules expressed by B cell receptor-activated allospecific B cells. Indirect evidence suggests that this inverted direct pathway is also operant in patients after transplantation. Resident memory donor CD4+ T cells were observed in perfusion liquids of human renal and lung grafts and acquired B cell helper functions upon in vitro stimulation. Furthermore, T follicular helper cells, specialized in helping B cells, were abundant in mucosa-associated lymphoid tissue of lung and intestinal grafts. In the latter, more graft-derived passenger T cells correlated with the detection of donor T cells in recipient's circulation; this, in turn, was associated with an early transient anti-MHC I DSA response and worse transplantation outcomes. We conclude that this inverted direct allorecognition is a possible explanation for the early transient anti-MHC DSA responses frequently observed after lung or intestinal transplantations.
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Affiliation(s)
- Xavier Charmetant
- CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France
| | - Chien-Chia Chen
- Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Sarah Hamada
- French National Blood Service (EFS), HLA Laboratory, 69150 Décines, France
| | - David Goncalves
- CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France
| | - Carole Saison
- French National Blood Service (EFS), HLA Laboratory, 69150 Décines, France
| | - Maud Rabeyrin
- Department of Pathology, Hospices Civils de Lyon, Groupement Hospitalier Est, 69500 Bron, France
| | - Marion Rabant
- Pathology Department, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, 75015 Paris, France
| | | | - Alice Koenig
- CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France
- Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), 69008 Lyon, France
- Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, 69003 Lyon, France
| | - Virginie Mathias
- French National Blood Service (EFS), HLA Laboratory, 69150 Décines, France
| | - Thomas Barba
- CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France
| | - Florence Lacaille
- Pediatric Gastroenterology-Hepatology-Nutrition Unit, Hôpital Universitaire Necker-Enfants malades, 75015 Paris, France
| | - Jérôme le Pavec
- Department of Pulmonology and Lung Transplantation, Marie Lannelongue Hospital, 92350 Le Plessis Robinson, France
| | - Olivier Brugière
- Pulmonology Department, Adult Cystic Fibrosis Centre and Lung Transplantation Department, Foch Hospital, 92150 Suresnes, France
| | - Jean-Luc Taupin
- Laboratory of Immunology and Histocompatibility, Hôpital Saint-Louis APHP, 75010 Paris, France
- INSERM U976 Institut de Recherche Saint-Louis, Université Paris Diderot, 75010 Paris, France
| | - Lara Chalabreysse
- Department of Pathology, Hospices Civils de Lyon, Groupement Hospitalier Est, 69500 Bron, France
| | - Jean-François Mornex
- Université de Lyon, Université Lyon 1, INRAE, IVPC, UMR754, 69000 Lyon, France
- Department of Pneumology, GHE, Hospices Civils de Lyon, 69000 Lyon, France
| | - Lionel Couzi
- Department of Nephrology, Transplantation, Dialysis, Apheresis, Pellegrin Hospital, 33000 Bordeaux, France
| | - Stéphanie Graff-Dubois
- Sorbonne Université, INSERM, Immunology-Immunopathology-Immunotherapy (i3), 75013 Paris, France
| | - Raphaël Jeger-Madiot
- Sorbonne Université, INSERM, Immunology-Immunopathology-Immunotherapy (i3), 75013 Paris, France
| | - Alexy Tran-Dinh
- Université de Paris, LVTS, INSERM U1148, 75018 Paris, France
| | - Pierre Mordant
- Department of Vascular and Thoracic Surgery, Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard Hospital, 75018 Paris, France
| | - Helena Paidassi
- CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France
| | - Thierry Defrance
- CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France
| | - Emmanuel Morelon
- CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France
- Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), 69008 Lyon, France
- Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, 69003 Lyon, France
| | - Lionel Badet
- Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), 69008 Lyon, France
- Department of Urology and Transplantation Surgery, Hospices Civils de Lyon, Edouard Herriot Hospital, 69003 Lyon, France
| | | | - Valérie Dubois
- French National Blood Service (EFS), HLA Laboratory, 69150 Décines, France
| | - Olivier Thaunat
- CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France
- Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), 69008 Lyon, France
- Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, 69003 Lyon, France
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23
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Zamir MR, Shahi A, Salehi S, Amirzargar A. Natural killer cells and killer cell immunoglobulin-like receptors in solid organ transplantation: Protectors or opponents? Transplant Rev (Orlando) 2022; 36:100723. [DOI: 10.1016/j.trre.2022.100723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 07/20/2022] [Accepted: 07/25/2022] [Indexed: 10/16/2022]
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24
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Gill RG. Bringing Clarity to the Murky Problem of Cardiac Allograft Vasculopathy. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:986-989. [PMID: 35577009 PMCID: PMC9253909 DOI: 10.1016/j.ajpath.2022.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 05/09/2022] [Indexed: 06/15/2023]
Affiliation(s)
- Ronald G Gill
- Department of Surgery, University of Colorado Denver, Aurora, Colorado.
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25
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Van Loon E, Lamarthée B, Barba T, Claes S, Coemans M, de Loor H, Emonds MP, Koshy P, Kuypers D, Proost P, Senev A, Sprangers B, Tinel C, Thaunat O, Van Craenenbroeck AH, Schols D, Naesens M. Circulating Donor-Specific Anti-HLA Antibodies Associate With Immune Activation Independent of Kidney Transplant Histopathological Findings. Front Immunol 2022; 13:818569. [PMID: 35281018 PMCID: PMC8904423 DOI: 10.3389/fimmu.2022.818569] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 01/10/2022] [Indexed: 12/17/2022] Open
Abstract
Despite the critical role of cytokines in allograft rejection, the relation of peripheral blood cytokine profiles to clinical kidney transplant rejection has not been fully elucidated. We assessed 28 cytokines through multiplex assay in 293 blood samples from kidney transplant recipients at time of graft dysfunction. Unsupervised hierarchical clustering identified a subset of patients with increased pro-inflammatory cytokine levels. This patient subset was hallmarked by a high prevalence (75%) of donor-specific anti-human leukocyte antigen antibodies (HLA-DSA) and histological rejection (70%) and had worse graft survival compared to the group with low cytokine levels (HLA-DSA in 1.7% and rejection in 33.7%). Thirty percent of patients with high pro-inflammatory cytokine levels and HLA-DSA did not have histological rejection. Exploring the cellular origin of these cytokines, we found a corresponding expression in endothelial cells, monocytes, and natural killer cells in single-cell RNASeq data from kidney transplant biopsies. Finally, we confirmed secretion of these cytokines in HLA-DSA-mediated cross talk between endothelial cells, NK cells, and monocytes. In conclusion, blood pro-inflammatory cytokines are increased in kidney transplant patients with HLA-DSA, even in the absence of histology of rejection. These observations challenge the concept that histology is the gold standard for identification of ongoing allo-immune activation after transplantation.
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Affiliation(s)
- Elisabet Van Loon
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Baptiste Lamarthée
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Thomas Barba
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital Lyon, Hospices Civils de Lyon, Lyon, France
| | - Sandra Claes
- Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Maarten Coemans
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Leuven Biostatistics and Statistical Bioinformatics Centre, Department of Public Health and Primary Care, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Henriette de Loor
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Marie-Paule Emonds
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Histocompatibility and Immunogenetics Laboratory, Red Cross-Flanders, Mechelen, Belgium
| | - Priyanka Koshy
- Department of Imaging and Pathology, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Dirk Kuypers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Aleksandar Senev
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Histocompatibility and Immunogenetics Laboratory, Red Cross-Flanders, Mechelen, Belgium
| | - Ben Sprangers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium.,Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Claire Tinel
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Olivier Thaunat
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital Lyon, Hospices Civils de Lyon, Lyon, France
| | - Amaryllis H Van Craenenbroeck
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Dominique Schols
- Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
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26
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Sazpinar O, Gaspert A, Sidler D, Rechsteiner M, Mueller TF. Histologic and Molecular Patterns in Responders and Non-responders With Chronic-Active Antibody-Mediated Rejection in Kidney Transplants. Front Med (Lausanne) 2022; 9:820085. [PMID: 35573002 PMCID: PMC9099145 DOI: 10.3389/fmed.2022.820085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 04/05/2022] [Indexed: 11/13/2022] Open
Abstract
IntroductionThere is no proven therapy for chronic-active antibody-mediated rejection (caABMR), the major cause of late kidney allograft failure. Histological and molecular patterns associated with possible therapy responsiveness are not known.MethodsBased on rigorous selection criteria this single center, retrospective study identified 16 out of 1027 consecutive kidney transplant biopsies taken between 2008 and 2016 with pure, unquestionable caABMR, without other pathologic features. The change in estimated GFR pre- and post-biopsy/treatment were utilized to differentiate subjects into responders and non-responders. Gene sets reflecting active immune processes of caABMR were defined a priori, including endothelial, inflammatory, cellular, interferon gamma (IFNg) and calcineurin inhibitor (CNI) related-genes based on the literature. Transcript measurements were performed in RNA extracted from stored, formalin-fixed, paraffin-embedded (FFPE) samples using NanoString™ technology. Histology and gene expression patterns of responders and non-responders were compared.ResultsA reductionist approach applying very tight criteria to identify caABMR and treatment response excluded the vast majority of clinical ABMR cases. Only 16 out of 139 cases with a written diagnosis of chronic rejection fulfilled the caABMR criteria. Histological associations with therapy response included a lower peritubular capillaritis score (p = 0.028) along with less glomerulitis. In contrast, no single gene discriminated responders from non-responders. Activated genes associated with NK cells and endothelial cells suggested lack of treatment response.ConclusionIn caABMR active microvascular injury, in particular peritubular capillaritis, differentiates treatment responders from non-responders. Transcriptome changes in NK cell and endothelial cell associated genes may further help to identify treatment response. Future prospective studies will be needed which include more subjects, who receive standardized treatment protocols to identify biomarkers for treatment response.Clinical Trial Registration[ClinicalTrials.gov], identifier [NCT03430414].
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Affiliation(s)
- Onur Sazpinar
- Clinic of Nephrology, Department of Medicine, University Hospital Zürich, Zurich, Switzerland
| | - Ariana Gaspert
- Department of Pathology and Molecular Pathology, University Hospital Zürich, Zurich, Switzerland
| | - Daniel Sidler
- Department of Nephrology and Hypertension, University Hospital Bern, Bern, Switzerland
| | - Markus Rechsteiner
- Department of Pathology and Molecular Pathology, University Hospital Zürich, Zurich, Switzerland
| | - Thomas F. Mueller
- Clinic of Nephrology, Department of Medicine, University Hospital Zürich, Zurich, Switzerland
- *Correspondence: Thomas F. Mueller,
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27
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Perrin S, Magill M. The Inhibition of CD40/CD154 Costimulatory Signaling in the Prevention of Renal Transplant Rejection in Nonhuman Primates: A Systematic Review and Meta Analysis. Front Immunol 2022; 13:861471. [PMID: 35464470 PMCID: PMC9022482 DOI: 10.3389/fimmu.2022.861471] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/15/2022] [Indexed: 11/29/2022] Open
Abstract
The prevention of allograft transplant rejection by inhibition of the CD40/CD40L costimulatory pathway has been described in several species. We searched pubmed for studies reporting the prevention of kidney transplant rejection in nonhuman primates utilizing either anti CD40 or anti CD40L (CD154) treatment. Inclusion of data required treatment with anti CD40 or anti CD154 as monotherapy treatment arms, full text available, studies conducted in nonhuman primate species, the transplant was renal transplantation, sufficient duration of treatment to assess long term rejection, and the reporting of individual graft survival or survival duration. Eleven publications were included in the study. Rejection free survival was calculated using the Kaplan-Meier (KM) life test methods to estimate the survival functions. The 95% CI for the medians was also calculated. A log-rank test was used to test the equality of the survival curves between control and treatment arms (CD40 and CD154). The hazard ratio for CD154 compared to CD40 and 95% CI was calculated using a Cox proportional-hazards model including treatment as the covariate to assess the magnitude of the treatment effect. Both anti CD40 and anti CD154 treatments prevented acute and long term graft rejection. The median (95% CI) rejection free survival was 131 days (84,169 days) in the anti CD40 treated animals and 352 days (173,710 days) in the anti CD154 treated animals. Median survival in the untreated animals was 6 days. The inhibition of transplant rejection was more durable in the anti CD154 group compared to the anti CD40 group after cessation of treatment. The median (95% CI) rejection free survival after cessation of treatment was 60 days (21,80 days) in the anti CD40 treated animals and 230 days (84,552 days) in the anti CD154 treated animals.
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28
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Fueyo-González F, McGinty M, Ningoo M, Anderson L, Cantarelli C, Andrea Angeletti, Demir M, Llaudó I, Purroy C, Marjanovic N, Heja D, Sealfon SC, Heeger PS, Cravedi P, Fribourg M. Interferon-β acts directly on T cells to prolong allograft survival by enhancing regulatory T cell induction through Foxp3 acetylation. Immunity 2022; 55:459-474.e7. [PMID: 35148827 PMCID: PMC8917088 DOI: 10.1016/j.immuni.2022.01.011] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 06/18/2021] [Accepted: 01/13/2022] [Indexed: 12/19/2022]
Abstract
Type I interferons (IFNs) are pleiotropic cytokines with potent antiviral properties that also promote protective T cell and humoral immunity. Paradoxically, type I IFNs, including the widely expressed IFNβ, also have immunosuppressive properties, including promoting persistent viral infections and treating T-cell-driven, remitting-relapsing multiple sclerosis. Although associative evidence suggests that IFNβ mediates these immunosuppressive effects by impacting regulatory T (Treg) cells, mechanistic links remain elusive. Here, we found that IFNβ enhanced graft survival in a Treg-cell-dependent murine transplant model. Genetic conditional deletion models revealed that the extended allograft survival was Treg cell-mediated and required IFNβ signaling on T cells. Using an in silico computational model and analysis of human immune cells, we found that IFNβ directly promoted Treg cell induction via STAT1- and P300-dependent Foxp3 acetylation. These findings identify a mechanistic connection between the immunosuppressive effects of IFNβ and Treg cells, with therapeutic implications for transplantation, autoimmunity, and malignancy.
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Affiliation(s)
- Francisco Fueyo-González
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Mitchell McGinty
- Carter Immunology Center, University of Virginia, Charlottesville, VA 22903, USA
| | - Mehek Ningoo
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Lisa Anderson
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Chiara Cantarelli
- UO Nefrologia, Azienda Ospedaliero-Universitaria Parma, Parma, Italy
| | - Andrea Angeletti
- Division of Nephrology, Dialysis, Transplantation, IRCCS Giannina Gaslini, Genoa, Italy
| | - Markus Demir
- Department of Anesthesiology, University of Cologne, Cologne, Germany
| | - Inés Llaudó
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Carolina Purroy
- Department of Nephrology, Complejo Hospitalario de Navarra, Navarra, Spain
| | - Nada Marjanovic
- Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - David Heja
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Stuart C Sealfon
- Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Peter S Heeger
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Paolo Cravedi
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - Miguel Fribourg
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York City, NY, USA; Immunology Institute Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
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29
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Rodriguez ER, Santos-Martins C, Tan CD. Pathology of cardiac transplantation. Cardiovasc Pathol 2022. [DOI: 10.1016/b978-0-12-822224-9.00023-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
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30
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Failing Heart Transplants and Rejection-A Cellular Perspective. J Cardiovasc Dev Dis 2021; 8:jcdd8120180. [PMID: 34940535 PMCID: PMC8708043 DOI: 10.3390/jcdd8120180] [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: 11/15/2021] [Revised: 12/05/2021] [Accepted: 12/09/2021] [Indexed: 11/17/2022] Open
Abstract
The median survival of patients with heart transplants is relatively limited, implying one of the most relevant questions in the field—how to expand the lifespan of a heart allograft? Despite optimal transplantation conditions, we do not anticipate a rise in long-term patient survival in near future. In order to develop novel strategies for patient monitoring and specific therapies, it is critical to understand the underlying pathological mechanisms at cellular and molecular levels. These events are driven by innate immune response and allorecognition driven inflammation, which controls both tissue damage and repair in a spatiotemporal context. In addition to immune cells, also structural cells of the heart participate in this process. Novel single cell methods have opened new avenues for understanding the dynamics driving the events leading to allograft failure. Here, we review current knowledge on the cellular composition of a normal heart, and cellular mechanisms of ischemia-reperfusion injury (IRI), acute rejection and cardiac allograft vasculopathy (CAV) in the transplanted hearts. We highlight gaps in current knowledge and suggest future directions, in order to improve cellular and molecular understanding of failing heart allografts.
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31
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Charmetant X, Bachelet T, Déchanet-Merville J, Walzer T, Thaunat O. Innate (and Innate-like) Lymphoid Cells: Emerging Immune Subsets With Multiple Roles Along Transplant Life. Transplantation 2021; 105:e322-e336. [PMID: 33859152 DOI: 10.1097/tp.0000000000003782] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Transplant immunology is currently largely focused on conventional adaptive immunity, particularly T and B lymphocytes, which have long been considered as the only cells capable of allorecognition. In this vision, except for the initial phase of ischemia/reperfusion, during which the role of innate immune effectors is well established, the latter are largely considered as "passive" players, recruited secondarily to amplify graft destruction processes during rejection. Challenging this prevalent dogma, the recent progresses in basic immunology have unraveled the complexity of the innate immune system and identified different subsets of innate (and innate-like) lymphoid cells. As most of these cells are tissue-resident, they are overrepresented among passenger leukocytes. Beyond their role in ischemia/reperfusion, some of these subsets have been shown to be capable of allorecognition and/or of regulating alloreactive adaptive responses, suggesting that these emerging immune players are actively involved in most of the life phases of the grafts and their recipients. Drawing upon the inventory of the literature, this review synthesizes the current state of knowledge of the role of the different innate (and innate-like) lymphoid cell subsets during ischemia/reperfusion, allorecognition, and graft rejection. How these subsets also contribute to graft tolerance and the protection of chronically immunosuppressed patients against infectious and cancerous complications is also examined.
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Affiliation(s)
- Xavier Charmetant
- CIRI, INSERM U1111, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon I, Lyon, France
| | - Thomas Bachelet
- Clinique Saint-Augustin-CTMR, ELSAN, Bordeaux, France
- Department of Nephrology, Transplantation, Dialysis and Apheresis, Bordeaux University Hospital, Bordeaux, France
| | | | - Thierry Walzer
- CIRI, INSERM U1111, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon I, Lyon, France
| | - Olivier Thaunat
- CIRI, INSERM U1111, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon I, Lyon, France
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
- Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
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32
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Ravindranath MH, El Hilali F, Filippone EJ. The Impact of Inflammation on the Immune Responses to Transplantation: Tolerance or Rejection? Front Immunol 2021; 12:667834. [PMID: 34880853 PMCID: PMC8647190 DOI: 10.3389/fimmu.2021.667834] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 10/11/2021] [Indexed: 12/21/2022] Open
Abstract
Transplantation (Tx) remains the optimal therapy for end-stage disease (ESD) of various solid organs. Although alloimmune events remain the leading cause of long-term allograft loss, many patients develop innate and adaptive immune responses leading to graft tolerance. The focus of this review is to provide an overview of selected aspects of the effects of inflammation on this delicate balance following solid organ transplantation. Initially, we discuss the inflammatory mediators detectable in an ESD patient. Then, the specific inflammatory mediators found post-Tx are elucidated. We examine the reciprocal relationship between donor-derived passenger leukocytes (PLs) and those of the recipient, with additional emphasis on extracellular vesicles, specifically exosomes, and we examine their role in determining the balance between tolerance and rejection. The concept of recipient antigen-presenting cell "cross-dressing" by donor exosomes is detailed. Immunological consequences of the changes undergone by cell surface antigens, including HLA molecules in donor and host immune cells activated by proinflammatory cytokines, are examined. Inflammation-mediated donor endothelial cell (EC) activation is discussed along with the effect of donor-recipient EC chimerism. Finally, as an example of a specific inflammatory mediator, a detailed analysis is provided on the dynamic role of Interleukin-6 (IL-6) and its receptor post-Tx, especially given the potential for therapeutic interdiction of this axis with monoclonal antibodies. We aim to provide a holistic as well as a reductionist perspective of the inflammation-impacted immune events that precede and follow Tx. The objective is to differentiate tolerogenic inflammation from that enhancing rejection, for potential therapeutic modifications. (Words 247).
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Affiliation(s)
- Mepur H. Ravindranath
- Department of Hematology and Oncology, Children’s Hospital, Los Angeles, CA, United States
- Terasaki Foundation Laboratory, Santa Monica, CA, United States
| | | | - Edward J. Filippone
- Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
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Pober JS, Chih S, Kobashigawa J, Madsen JC, Tellides G. Cardiac allograft vasculopathy: current review and future research directions. Cardiovasc Res 2021; 117:2624-2638. [PMID: 34343276 PMCID: PMC8783389 DOI: 10.1093/cvr/cvab259] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/02/2021] [Accepted: 07/29/2021] [Indexed: 12/25/2022] Open
Abstract
Cardiac allograft vasculopathy (CAV) is a pathologic immune-mediated remodelling of the vasculature in transplanted hearts and, by impairing perfusion, is the major cause of late graft loss. Although best understood following cardiac transplantation, similar forms of allograft vasculopathy occur in other vascularized organ grafts and some features of CAV may be shared with other immune-mediated vasculopathies. Here, we describe the incidence and diagnosis, the nature of the vascular remodelling, immune and non-immune contributions to pathogenesis, current therapies, and future areas of research in CAV.
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MESH Headings
- Adaptive Immunity
- Animals
- Coronary Artery Disease/epidemiology
- Coronary Artery Disease/immunology
- Coronary Artery Disease/metabolism
- Coronary Artery Disease/pathology
- Coronary Vessels/immunology
- Coronary Vessels/metabolism
- Coronary Vessels/pathology
- Endothelial Cells/immunology
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- Graft Rejection/epidemiology
- Graft Rejection/immunology
- Graft Rejection/metabolism
- Graft Rejection/pathology
- Graft Survival
- Heart Transplantation/adverse effects
- Humans
- Immunity, Innate
- Muscle, Smooth, Vascular/immunology
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/immunology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Risk Factors
- Signal Transduction
- Treatment Outcome
- Vascular Remodeling
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Affiliation(s)
- Jordan S Pober
- Department of Immunobiology, Pathology and Dermatology, Yale School of Medicine, 10 Amistad Street, New Haven CT 06520-8089, USA
| | - Sharon Chih
- Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada
| | - Jon Kobashigawa
- Department of Medicine, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA
| | - Joren C Madsen
- Division of Cardiac Surgery and Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - George Tellides
- Department of Surgery (Cardiac Surgery), Yale School of Medicine, New Haven, CT, USA
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34
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Gołębiewska JE, Wardowska A, Pietrowska M, Wojakowska A, Dębska-Ślizień A. Small Extracellular Vesicles in Transplant Rejection. Cells 2021; 10:2989. [PMID: 34831212 PMCID: PMC8616261 DOI: 10.3390/cells10112989] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 10/31/2021] [Accepted: 10/31/2021] [Indexed: 12/28/2022] Open
Abstract
Small extracellular vesicles (sEV), which are released to body fluids (e.g., serum, urine) by all types of human cells, may stimulate or inhibit the innate and adaptive immune response through multiple mechanisms. Exosomes or sEV have on their surface many key receptors of immune response, including major histocompatibility complex (MHC) components, identical to their cellular origin. They also exhibit an ability to carry antigen and target leukocytes either via interaction with cell surface receptors or intracellular delivery of inflammatory mediators, receptors, enzymes, mRNAs, and noncoding RNAs. By the transfer of donor MHC antigens to recipient antigen presenting cells sEV may also contribute to T cell allorecognition and alloresponse. Here, we review the influence of sEV on the development of rejection or tolerance in the setting of solid organ and tissue allotransplantation. We also summarize and discuss potential applications of plasma and urinary sEV as biomarkers in the context of transplantation. We focus on the attempts to use sEV as a noninvasive approach to detecting allograft rejection. Preliminary studies show that both sEV total levels and a set of specific molecules included in their cargo may be an evidence of ongoing allograft rejection.
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Affiliation(s)
- Justyna E. Gołębiewska
- Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, 80-210 Gdańsk, Poland;
| | - Anna Wardowska
- Department of Physiopathology, Medical University of Gdańsk, 80-210 Gdańsk, Poland;
| | - Monika Pietrowska
- Centre for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, 44-102 Gliwice, Poland;
| | - Anna Wojakowska
- Institute of Bioorganic Chemistry Polish Academy of Sciences, 61-704 Poznań, Poland;
| | - Alicja Dębska-Ślizień
- Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, 80-210 Gdańsk, Poland;
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35
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Lin CM, Gill RG, Mehrad B. The natural killer cell activating receptor, NKG2D, is critical to antibody-dependent chronic rejection in heart transplantation. Am J Transplant 2021; 21:3550-3560. [PMID: 34014614 PMCID: PMC9036609 DOI: 10.1111/ajt.16690] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 04/26/2021] [Accepted: 05/04/2021] [Indexed: 01/25/2023]
Abstract
Chronic rejection is among the most pressing clinical challenges in solid organ transplantation. Interestingly, in a mouse model of heterotopic heart transplantation, antibody-dependent, natural killer (NK) cell-mediated chronic cardiac allograft vasculopathy occurs in some donor-recipient strain combinations, but not others. In this study, we sought to identify the mechanism underlying this unexplained phenomenon. Cardiac allografts from major histocompatibility complex (MHC) mismatched donors were transplanted into immune-deficient C57Bl/6.rag-/- recipients, followed by administration of a monoclonal antibody against the donor MHC class I antigen. We found marked allograft vasculopathy in hearts from C3H donors, but near-complete protection of BALB/c allografts from injury. We found no difference in recipient NK cell phenotype or intrinsic responsiveness to activating signals between recipients of C3H versus BALB/c allografts. However, cardiac endothelial cells from C3H allografts showed an approximately twofold higher expression of Rae-1, an activating ligand of the NK cell receptor natural killer group 2D (NKG2D). Importantly, the administration of a neutralizing antibody against NKG2D abrogated the development of allograft vasculopathy in recipients of C3H allografts, even in the presence of donor-specific antibodies. Therefore, the activating NK cell receptor NKG2D is necessary in this model of chronic cardiac allograft vasculopathy, and strain-dependent expression of NK activating ligands correlates with the development of this disease.
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Affiliation(s)
- Christine M. Lin
- University of Florida. Department of Medicine (Gainesville, FL, USA)
| | - Ronald G. Gill
- University of Colorado, Anschutz Medical Campus. Department of Surgery (Aurora, CO, USA)
| | - Borna Mehrad
- University of Florida. Department of Medicine (Gainesville, FL, USA)
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36
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Hamada S, Dubois V, Koenig A, Thaunat O. Allograft recognition by recipient's natural killer cells: Molecular mechanisms and role in transplant rejection. HLA 2021; 98:191-199. [PMID: 34050618 DOI: 10.1111/tan.14332] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 05/24/2021] [Indexed: 12/24/2022]
Abstract
The current transplant immunology dogma defends that allograft rejection is initiated by recipient's adaptive immune system. In this prevalent model, innate immune cells in general, and natural killer (NK) cells in particular, are merely considered as downstream effectors which participate in the destruction of the graft only upon recruitment by adaptive effectors: alloreactive T cells or donor-specific antibodies (DSA). Challenging this vision, recent data demonstrated that recipients' NK cells are capable of a form of allorecognition because they can sense the absence of self HLA class I molecules on the surface of graft endothelial cells. Missing-self triggers mTORC1-dependent activation of NK cells, which in turn promote the development of graft microvascular inflammation and detrimentally impact graft survival. The fact that some patients develop chronic vascular rejection in absence of DSA or genetically-predicted missing self suggests that other molecular mechanisms could underly NK cell allorecognition. This review provides an overview of these proven and putative molecular mechanisms and discusses future research directions in this emerging field in organ transplant immunology.
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Affiliation(s)
- Sarah Hamada
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, Lyon, France.,Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France
| | - Valérie Dubois
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, Lyon, France.,HLA Laboratory, French National Blood Service (EFS), Décines-Charpieu, France
| | - Alice Koenig
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, Lyon, France.,Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France.,Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
| | - Olivier Thaunat
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, Lyon, France.,Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France.,Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
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37
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Lai X, Zheng X, Mathew JM, Gallon L, Leventhal JR, Zhang ZJ. Tackling Chronic Kidney Transplant Rejection: Challenges and Promises. Front Immunol 2021; 12:661643. [PMID: 34093552 PMCID: PMC8173220 DOI: 10.3389/fimmu.2021.661643] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 04/27/2021] [Indexed: 01/09/2023] Open
Abstract
Despite advances in post-transplant management, the long-term survival rate of kidney grafts and patients has not improved as approximately forty percent of transplants fails within ten years after transplantation. Both immunologic and non-immunologic factors contribute to late allograft loss. Chronic kidney transplant rejection (CKTR) is often clinically silent yet progressive allogeneic immune process that leads to cumulative graft injury, deterioration of graft function. Chronic active T cell mediated rejection (TCMR) and chronic active antibody-mediated rejection (ABMR) are classified as two principal subtypes of CKTR. While significant improvements have been made towards a better understanding of cellular and molecular mechanisms and diagnostic classifications of CKTR, lack of early detection, differential diagnosis and effective therapies continue to pose major challenges for long-term management. Recent development of high throughput cellular and molecular biotechnologies has allowed rapid development of new biomarkers associated with chronic renal injury, which not only provide insight into pathogenesis of chronic rejection but also allow for early detection. In parallel, several novel therapeutic strategies have emerged which may hold great promise for improvement of long-term graft and patient survival. With a brief overview of current understanding of pathogenesis, standard diagnosis and challenges in the context of CKTR, this mini-review aims to provide updates and insights into the latest development of promising novel biomarkers for diagnosis and novel therapeutic interventions to prevent and treat CKTR.
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Affiliation(s)
- Xingqiang Lai
- Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Organ Transplant Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xin Zheng
- Department of Urology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - James M. Mathew
- Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Lorenzo Gallon
- Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Department of Medicine, Nephrology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Joseph R. Leventhal
- Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Zheng Jenny Zhang
- Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
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38
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Kim MY, Brennan DC. Therapies for Chronic Allograft Rejection. Front Pharmacol 2021; 12:651222. [PMID: 33935762 PMCID: PMC8082459 DOI: 10.3389/fphar.2021.651222] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/10/2021] [Indexed: 12/14/2022] Open
Abstract
Remarkable advances have been made in the pathophysiology, diagnosis, and treatment of antibody-mediated rejection (ABMR) over the past decades, leading to improved graft outcomes. However, long-term failure is still high and effective treatment for chronic ABMR, an important cause of graft failure, has not yet been identified. Chronic ABMR has a relatively different phenotype from active ABMR and is a slowly progressive disease in which graft injury is mainly caused by de novo donor specific antibodies (DSA). Since most trials of current immunosuppressive therapies for rejection have focused on active ABMR, treatment strategies based on those data might be less effective in chronic ABMR. A better understanding of chronic ABMR may serve as a bridge in establishing treatment strategies to improve graft outcomes. In this in-depth review, we focus on the pathophysiology and characteristics of chronic ABMR along with the newly revised Banff criteria in 2017. In addition, in terms of chronic ABMR, we identify the reasons for the resistance of current immunosuppressive therapies and look at ongoing research that could play a role in setting better treatment strategies in the future. Finally, we review non-invasive biomarkers as tools to monitor for rejection.
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Affiliation(s)
| | - Daniel C. Brennan
- Department of Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States
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39
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Lu J, Zhang Y, Sun J, Huang S, Wu W, Tan J. The Immune Cell Landscape in Renal Allografts. Cell Transplant 2021; 30:963689721995458. [PMID: 33593079 PMCID: PMC7894583 DOI: 10.1177/0963689721995458] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Immune cell infiltration plays an important role in the pathophysiology of kidney grafts, but the composition of immune cells is ill-defined. Here, we aimed at evaluating the levels and composition of infiltrating immune cells in kidney grafts. We used CIBERSORT, an established algorithm, to estimate the proportions of 22 immune cell types based on gene expression profiles. We found that non-rejecting kidney grafts were characteristic with high rates of M2 macrophages and resting mast cells. The proportion of M1 macrophages and activated NK cells were increased in antibody-mediated rejection (ABMR). In T cell-mediated rejection (TCMR), a significant increase in CD8 T cell and γδT cell infiltration was observed. CD8 positive T cells were dramatically increased in mixed-ABMR/TCMR. Then, the function of ABMR and TCMR prognostic molecular biomarkers were identified. Finally, we described the gene expression of molecular markers for ABMR diagnosis was elevated and related to the ratio of monocytes and M1 macrophages in ABMR biopsies, while the expression of TCMR diagnosis markers was increased too and positively correlated with γδT cells and activated CD4 memory T cells in TCMR biopsies. Our data suggest that CIBERSORT’s deconvolution analysis of gene expression data provides valuable information on the composition of immune cells in renal allografts.
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Affiliation(s)
- Jun Lu
- Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, China.,Laboratory of Basic Medicine, Fuzhou General Clinical College, Fujian Medical University, China
| | - Yi Zhang
- Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, China
| | - Jingjing Sun
- Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, China
| | | | - Weizhen Wu
- Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, China.,Department of Urology, 900th Hospital of the Joint Logistics Team, Fujian, China
| | - Jianming Tan
- Fujian Provincial Key Laboratory of Transplant Biology, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, China.,Department of Urology, 900th Hospital of the Joint Logistics Team, Fujian, China
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40
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Koenig A, Mezaache S, Callemeyn J, Barba T, Mathias V, Sicard A, Charreau B, Rabeyrin M, Dijoud F, Picard C, Meas-Yedid V, Olivo-Marin JC, Morelon E, Naesens M, Dubois V, Thaunat O. Missing Self-Induced Activation of NK Cells Combines with Non-Complement-Fixing Donor-Specific Antibodies to Accelerate Kidney Transplant Loss in Chronic Antibody-Mediated Rejection. J Am Soc Nephrol 2021; 32:479-494. [PMID: 33239394 PMCID: PMC8054908 DOI: 10.1681/asn.2020040433] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Accepted: 10/06/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Binding of donor-specific antibodies (DSAs) to kidney allograft endothelial cells that does not activate the classic complement cascade can trigger the recruitment of innate immune effectors, including NK cells. Activated NK cells contribute to microvascular inflammation leading to chronic antibody-mediated rejection (AMR). Recipient NK cells can also trigger antibody-independent microvascular inflammation by sensing the absence of self HLA class I molecules ("missing self") on allograft endothelial cells. This translational study investigated whether the condition of missing self amplifies DSA-dependent NK cell activation to worsen chronic AMR. METHODS AND RESULTS Among 1682 kidney transplant recipients who underwent an allograft biopsy at Lyon University Hospital between 2004 and 2017, 135 fulfilled the diagnostic criteria for AMR and were enrolled in the study. Patients with complement-fixing DSAs identified by a positive C3d binding assay (n=73, 54%) had a higher risk of transplant failure (P=0.002). Among the remaining patients with complement-independent chronic AMR (n=62, 46%), those in whom missing self was identified through donor and recipient genotyping exhibited worse allograft survival (P=0.02). In multivariable analysis, only proteinuria (HR: 7.24; P=0.01) and the presence of missing self (HR: 3.57; P=0.04) were independent predictors for transplant failure following diagnosis of chronic AMR. Cocultures of human NK cells and endothelial cells confirmed that addition of missing self to DSA-induced NK cell activation increased endothelial damage. CONCLUSIONS The assessment of missing self at the time of diagnosis of chronic AMR identifies patients at higher risk for kidney transplant failure.
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Affiliation(s)
- Alice Koenig
- International Center of Infectiology research (CIRI), French Institute of Health and Medical Research (INSERM) Unit 1111, Claude Bernard University Lyon I, National Center for Scientific Research (CNRS) Mixed University Unit (UMR) 5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France,Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France,Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
| | - Sarah Mezaache
- Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France
| | - Jasper Callemeyn
- Department of Microbiology, Immunology and Transplantation, Catholic University (KU) Leuven, University of Leuven, Leuven, Belgium,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Thomas Barba
- International Center of Infectiology research (CIRI), French Institute of Health and Medical Research (INSERM) Unit 1111, Claude Bernard University Lyon I, National Center for Scientific Research (CNRS) Mixed University Unit (UMR) 5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France,Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France,Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
| | - Virginie Mathias
- International Center of Infectiology research (CIRI), French Institute of Health and Medical Research (INSERM) Unit 1111, Claude Bernard University Lyon I, National Center for Scientific Research (CNRS) Mixed University Unit (UMR) 5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France,Human Leukocyte Antigen (HLA) Laboratory, French National Blood Service (EFS), Décines-Charpieu, France
| | - Antoine Sicard
- International Center of Infectiology research (CIRI), French Institute of Health and Medical Research (INSERM) Unit 1111, Claude Bernard University Lyon I, National Center for Scientific Research (CNRS) Mixed University Unit (UMR) 5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France,Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France,Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
| | - Béatrice Charreau
- Centre de Recherche en Transplantation et Immunologie (CRTI), University Hospital Center (CHU) Nantes, Université de Nantes, National Institute for Health and Medical Research (INSERM), Mixed University Unit (UMR) 1064, Transplantation Urology Nephrology Institute (ITUN), Nantes, France
| | - Maud Rabeyrin
- Department of Pathology, Hospices Civils de Lyon, Bron, France
| | | | - Cécile Picard
- Department of Pathology, Hospices Civils de Lyon, Bron, France
| | | | | | - Emmanuel Morelon
- International Center of Infectiology research (CIRI), French Institute of Health and Medical Research (INSERM) Unit 1111, Claude Bernard University Lyon I, National Center for Scientific Research (CNRS) Mixed University Unit (UMR) 5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France,Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France,Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, Catholic University (KU) Leuven, University of Leuven, Leuven, Belgium,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Valérie Dubois
- International Center of Infectiology research (CIRI), French Institute of Health and Medical Research (INSERM) Unit 1111, Claude Bernard University Lyon I, National Center for Scientific Research (CNRS) Mixed University Unit (UMR) 5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France,Human Leukocyte Antigen (HLA) Laboratory, French National Blood Service (EFS), Décines-Charpieu, France
| | - Olivier Thaunat
- International Center of Infectiology research (CIRI), French Institute of Health and Medical Research (INSERM) Unit 1111, Claude Bernard University Lyon I, National Center for Scientific Research (CNRS) Mixed University Unit (UMR) 5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France,Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France,Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
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41
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[Pathology of heart transplantation: Where are we now?]. Ann Pathol 2021; 41:38-49. [PMID: 33413972 DOI: 10.1016/j.annpat.2020.12.001] [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: 11/07/2020] [Revised: 12/03/2020] [Accepted: 12/04/2020] [Indexed: 11/23/2022]
Abstract
Pathology is still the gold standard for the diagnosis of rejection in heart transplantation. During the last decade, molecular pathology has emerged as a powerful tool for the understanding of the processes implicated in allograft rejection. Transcriptomic analysis of the allograft may also help the pathologist for diagnosis and accurate classification of rejection. This review will describe the recent advances and perspectives of molecular pathology in the field of heart transplantation.
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Hamada S, Thaunat O, Koenig A. [Missing self-induced NK cell activation promotes "innate" chronic vascular rejection of transplanted organs]. Med Sci (Paris) 2020; 36:984-987. [PMID: 33151859 DOI: 10.1051/medsci/2020183] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Affiliation(s)
- Sarah Hamada
- CIRI, Inserm U1111, Université Claude Bernard Lyon I, CNRS UMR5308, École normale supérieure de Lyon, Univ. Lyon, 21 avenue Tony-Garnier, 69007 Lyon, France
| | - Olivier Thaunat
- CIRI, Inserm U1111, Université Claude Bernard Lyon I, CNRS UMR5308, École normale supérieure de Lyon, Univ. Lyon, 21 avenue Tony-Garnier, 69007 Lyon, France. - Hospices civils de Lyon, Hôpital Edouard Herriot, Service de transplantation, néphrologie et immunologie clinique, 5 place d'Arsonval, 69003 Lyon, France. - Faculté de médecine Lyon-Est, Université Claude Bernard Lyon I, 8 avenue Rockfeller, 69373 Lyon, France
| | - Alice Koenig
- CIRI, Inserm U1111, Université Claude Bernard Lyon I, CNRS UMR5308, École normale supérieure de Lyon, Univ. Lyon, 21 avenue Tony-Garnier, 69007 Lyon, France. - Hospices civils de Lyon, Hôpital Edouard Herriot, Service de transplantation, néphrologie et immunologie clinique, 5 place d'Arsonval, 69003 Lyon, France. - Faculté de médecine Lyon-Est, Université Claude Bernard Lyon I, 8 avenue Rockfeller, 69373 Lyon, France
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Pontrelli P, Rascio F, Castellano G, Grandaliano G, Gesualdo L, Stallone G. The Role of Natural Killer Cells in the Immune Response in Kidney Transplantation. Front Immunol 2020; 11:1454. [PMID: 32793200 PMCID: PMC7390843 DOI: 10.3389/fimmu.2020.01454] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 06/04/2020] [Indexed: 12/13/2022] Open
Abstract
Natural killer cells (NK) represent a population of lymphocytes involved in innate immune response. In addition to their role in anti-viral and anti-tumor defense, they also regulate several aspects of the allo-immune response in kidney transplant recipients. Growing evidence suggests a key role of NK cells in the pathogenesis of immune-mediated graft damage in kidney transplantation. Specific NK cell subsets are associated with operational tolerance in kidney transplant patients. On the other side, allo-reactive NK cells are associated with chronic antibody-mediated rejection and graft loss. Moreover, NK cells can prime the adaptive immune system and promote the migration of other immune cells, such as dendritic cells, into the graft leading to an increased allo-immune response and, eventually, to chronic graft rejection. Finally, activated NK cells can infiltrate the transplanted kidney and cause a direct graft damage. Interestingly, immunosuppression can influence NK cell numbers and function, thus causing an increased risk of post-transplant neoplasia or infection. In this review, we will describe how these cells can influence the innate and the adaptive immune response in kidney transplantation and how immunosuppression can modulate NK behavior.
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Affiliation(s)
- Paola Pontrelli
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Federica Rascio
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Giuseppe Grandaliano
- Nephrology Unit, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy.,Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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Kummer L, Zaradzki M, Vijayan V, Arif R, Weigand MA, Immenschuh S, Wagner AH, Larmann J. Vascular Signaling in Allogenic Solid Organ Transplantation - The Role of Endothelial Cells. Front Physiol 2020; 11:443. [PMID: 32457653 PMCID: PMC7227440 DOI: 10.3389/fphys.2020.00443] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 04/09/2020] [Indexed: 12/12/2022] Open
Abstract
Graft rejection remains the major obstacle after vascularized solid organ transplantation. Endothelial cells, which form the interface between the transplanted graft and the host’s immunity, are the first target for host immune cells. During acute cellular rejection endothelial cells are directly attacked by HLA I and II-recognizing NK cells, macrophages, and T cells, and activation of the complement system leads to endothelial cell lysis. The established forms of immunosuppressive therapy provide effective treatment options, but the treatment of chronic rejection of solid organs remains challenging. Chronic rejection is mainly based on production of donor-specific antibodies that induce endothelial cell activation—a condition which phenotypically resembles chronic inflammation. Activated endothelial cells produce chemokines, and expression of adhesion molecules increases. Due to this pro-inflammatory microenvironment, leukocytes are recruited and transmigrate from the bloodstream across the endothelial monolayer into the vessel wall. This mononuclear infiltrate is a hallmark of transplant vasculopathy. Furthermore, expression profiles of different cytokines serve as clinical markers for the patient’s outcome. Besides their effects on immune cells, activated endothelial cells support the migration and proliferation of vascular smooth muscle cells. In turn, muscle cell recruitment leads to neointima formation followed by reduction in organ perfusion and eventually results in tissue injury. Activation of endothelial cells involves antibody ligation to the surface of endothelial cells. Subsequently, intracellular signaling pathways are initiated. These signaling cascades may serve as targets to prevent or treat adverse effects in antibody-activated endothelial cells. Preventive or therapeutic strategies for chronic rejection can be investigated in sophisticated mouse models of transplant vasculopathy, mimicking interactions between immune cells and endothelium.
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Affiliation(s)
- Laura Kummer
- Department of Anesthesiology, University Hospital Heidelberg, Heidelberg, Germany
| | - Marcin Zaradzki
- Institute of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Vijith Vijayan
- Institute for Transfusion Medicine, Hannover Medical School, Hanover, Germany
| | - Rawa Arif
- Institute of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Markus A Weigand
- Department of Anesthesiology, University Hospital Heidelberg, Heidelberg, Germany
| | - Stephan Immenschuh
- Institute for Transfusion Medicine, Hannover Medical School, Hanover, Germany
| | - Andreas H Wagner
- Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany
| | - Jan Larmann
- Department of Anesthesiology, University Hospital Heidelberg, Heidelberg, Germany
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Loupy A, Coutance G, Bonnet G, Van Keer J, Raynaud M, Aubert O, Bories MC, Racapé M, Yoo D, Duong Van Huyen JP, Bruneval P, Taupin JL, Lefaucheur C, Varnous S, Leprince P, Guillemain R, Empana JP, Levine R, Naesens M, Patel JK, Jouven X, Kobashigawa J. Identification and Characterization of Trajectories of Cardiac Allograft Vasculopathy After Heart Transplantation: A Population-Based Study. Circulation 2020; 141:1954-1967. [PMID: 32363949 DOI: 10.1161/circulationaha.119.044924] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Cardiac allograft vasculopathy (CAV) is a major contributor of heart transplant recipient mortality. Little is known about the prototypes of CAV trajectories at the population level. We aimed to identify the different evolutionary profiles of CAV and to determine the respective contribution of immune and nonimmune factors in CAV development. METHODS Heart transplant recipients were from 4 academic centers (Pitié-Salpêtrière and Georges Pompidou Hospital, Paris, Katholieke Universiteit Leuven, and Cedars-Sinai, Los Angeles; 2004-2016). Patients underwent prospective, protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical, histological, and immunologic parameters. The main outcome was a prediction for CAV trajectory. We identified CAV trajectories by using unsupervised latent class mixed models. We then identified the independent predictive variables of the CAV trajectories and their association with mortality. RESULTS A total of 1301 patients were included (815 and 486 in the European and US cohorts, respectively). The median follow-up after transplantation was 6.6 (interquartile range, 4-9.1) years with 4710 coronary angiographies analyzed. We identified 4 distinct profiles of CAV trajectories over 10 years. The 4 trajectories were characterized by (1) patients without CAV at 1 year and nonprogression over time (56.3%), (2) patients without CAV at 1 year and late-onset slow CAV progression (7.6%), (3) patients with mild CAV at 1 year and mild progression over time (23.1%), and (4) patients with mild CAV at 1 year and accelerated progression (13.0%). This model showed good discrimination (0.92). Among candidate predictors assessed, 6 early independent predictors of these trajectories were identified: donor age (P<0.001), donor male sex (P<0.001), donor tobacco consumption (P=0.001), recipient dyslipidemia (P=0.009), class II anti-human leukocyte antigen donor-specific antibodies (P=0.004), and acute cellular rejection ≥2R (P=0.028). The 4 CAV trajectories manifested consistently in the US independent cohort with similar discrimination (0.97) and in different clinical scenarios, and showed gradients for overall-cause mortality (P<0.001). CONCLUSIONS In a large multicenter and highly phenotyped prospective cohort of heart transplant recipients, we identified 4 CAV trajectories and their respective independent predictive variables. Our results provide the basis for a trajectory-based assessment of patients undergoing heart transplantation for early risk stratification, patient monitoring, and clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04117152.
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Affiliation(s)
- Alexandre Loupy
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.).,Kidney Transplant Department (A.L., O.A.), Necker Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Guillaume Coutance
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.).,Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié-Salpêtrière Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Sorbonne University Medical School, France (G.C., S.V., P.L.)
| | - Guillaume Bonnet
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.).,Cardiology and Heart Transplant Department (G.B., M.-C.B., R.G., J.-P.E., X.J.), Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Jan Van Keer
- Departments of Cardiology (J.V.K.), University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium
| | - Marc Raynaud
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.)
| | - Olivier Aubert
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.).,Kidney Transplant Department (A.L., O.A.), Necker Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Marie-Cécile Bories
- Cardiology and Heart Transplant Department (G.B., M.-C.B., R.G., J.-P.E., X.J.), Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Maud Racapé
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.)
| | - Daniel Yoo
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.)
| | | | - Patrick Bruneval
- Pathology Department (P.B.), Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Jean-Luc Taupin
- Laboratory of Immunology and Histocompatibility, AP-HP, Saint Louis Hospital, Paris, France (J.-L.T.)
| | - Carmen Lefaucheur
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.)
| | - Shaida Varnous
- Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié-Salpêtrière Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Sorbonne University Medical School, France (G.C., S.V., P.L.).,INSERM, UMRS 1166-ICAN, Institute of Cardiometabolism and Nutrition, Paris, France (S.V., P.L.)
| | - Pascal Leprince
- Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié-Salpêtrière Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Sorbonne University Medical School, France (G.C., S.V., P.L.).,INSERM, UMRS 1166-ICAN, Institute of Cardiometabolism and Nutrition, Paris, France (S.V., P.L.)
| | - Romain Guillemain
- Cardiology and Heart Transplant Department (G.B., M.-C.B., R.G., J.-P.E., X.J.), Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Jean-Philippe Empana
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.).,Cardiology and Heart Transplant Department (G.B., M.-C.B., R.G., J.-P.E., X.J.), Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Ryan Levine
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (R.L., J.K.P., J.K.)
| | - Maarten Naesens
- Microbiology, Immunology, and Transplantation and of Nephrology(M.N.), University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium.,Renal Transplantation (M.N.), University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium
| | - Jigneh K Patel
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (R.L., J.K.P., J.K.)
| | - Xavier Jouven
- Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.).,Cardiology and Heart Transplant Department (G.B., M.-C.B., R.G., J.-P.E., X.J.), Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France
| | - Jon Kobashigawa
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (R.L., J.K.P., J.K.)
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Gill RG, Lin CM. Linking innate immunity and chronic antibody-mediated allograft rejection. Curr Opin Organ Transplant 2020; 24:694-698. [PMID: 31599762 DOI: 10.1097/mot.0000000000000708] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW To summarize recent findings linking donor-specific antibodies with innate immunity resulting in chronic allograft rejection. RECENT FINDINGS Studies in recent years highlight the significance of donor-specific antibodies (DSA) in both acute and chronic allograft rejection. Since chronic rejection is the leading cause of graft failure, this review centers on the contribution of three areas of innate immunity of particular recent focus: complement, NK cells, and macrophages. Recent advances indicate the diverse roles that complement components play both in directly initiating allograft injury and indirectly by contributing to enhanced alloreactivity. NK cells also have emerged as an additional innate response that directly links DSA with chronic graft injury. Finally, recent studies identify alternatively activated macrophages as an additional arm of innate immunity contributing to chronic allograft rejection. SUMMARY Chronic allograft rejection involves a significant contribution of DSA and differing pathways of the innate immune system. However, key issues remain unresolved. First, it is not always clear which of these varied sources of innate immunity contributing to chronic rejection may be antibody dependent. Moreover, it is not yet clear if these innate pathways represent independent routes that contribute to chronic rejection or rather act in concert to mediate allograft injury.
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Affiliation(s)
- Ronald G Gill
- Department of Surgery, Division of Transplant, University of Colorado Aurora, Denver, Colorado
| | - Christine M Lin
- Department of Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, University of Florida, Gainesville, Florida, USA
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The clinical impact of donor-specific antibodies on antibody-mediated rejection and long-term prognosis after heart transplantation. Curr Opin Organ Transplant 2020; 24:245-251. [PMID: 31090631 DOI: 10.1097/mot.0000000000000636] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE OF REVIEW Outcomes after cardiac transplantation have improved over past decades, but long-term graft survival remains limited in part because of uncertainty regarding clinical implications of donor-specific antibodies (DSAs). The purpose of this review is to consolidate recent advances in knowledge on the topic of DSA and their potential to impact long-term prognosis after heart transplantation. RECENT FINDINGS The presence of persistent DSA increases the risk of poor outcome after heart transplantation, including development of antibody-mediated rejection (AMR), graft failure, cardiac allograft vasculopathy, and mortality. Importantly, different DSA vary in clinical significance. DSA capable of activating the complement cascade portend a higher risk of developing AMR. human leukocyte antigen class I and class II antigens are expressed differently within the heart, and so, clinical manifestations of class I and class II DSA vary accordingly. Further, compared with class I, class II DSA carry an increased risk of graft loss and mortality. When comparing preexisting DSA with formation of de-novo DSA, de-novo DSA are associated with worse outcome. SUMMARY DSAs are generally associated worse long-term prognosis after heart transplantation but vary in their clinical significance. Recognition of specific risk profiles is essential for guiding posttransplant antibody management.
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Research Highlights. Transplantation 2020. [DOI: 10.1097/tp.0000000000003096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Abstract
The kidney harbours different types of endothelia, each with specific structural and functional characteristics. The glomerular endothelium, which is highly fenestrated and covered by a rich glycocalyx, participates in the sieving properties of the glomerular filtration barrier and in the maintenance of podocyte structure. The microvascular endothelium in peritubular capillaries, which is also fenestrated, transports reabsorbed components and participates in epithelial cell function. The endothelium of large and small vessels supports the renal vasculature. These renal endothelia are protected by regulators of thrombosis, inflammation and complement, but endothelial injury (for example, induced by toxins, antibodies, immune cells or inflammatory cytokines) or defects in factors that provide endothelial protection (for example, regulators of complement or angiogenesis) can lead to acute or chronic renal injury. Moreover, renal endothelial cells can transition towards a mesenchymal phenotype, favouring renal fibrosis and the development of chronic kidney disease. Thus, the renal endothelium is both a target and a driver of kidney and systemic cardiovascular complications. Emerging therapeutic strategies that target the renal endothelium may lead to improved outcomes for both rare and common renal diseases.
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Koenig A, Chen CC, Marçais A, Barba T, Mathias V, Sicard A, Rabeyrin M, Racapé M, Duong-Van-Huyen JP, Bruneval P, Loupy A, Dussurgey S, Ducreux S, Meas-Yedid V, Olivo-Marin JC, Paidassi H, Guillemain R, Taupin JL, Callemeyn J, Morelon E, Nicoletti A, Charreau B, Dubois V, Naesens M, Walzer T, Defrance T, Thaunat O. Missing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants. Nat Commun 2019; 10:5350. [PMID: 31767837 PMCID: PMC6877588 DOI: 10.1038/s41467-019-13113-5] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 10/14/2019] [Indexed: 12/15/2022] Open
Abstract
Current doctrine is that microvascular inflammation (MVI) triggered by a transplant -recipient antibody response against alloantigens (antibody-mediated rejection) is the main cause of graft failure. Here, we show that histological lesions are not mediated by antibodies in approximately half the participants in a cohort of 129 renal recipients with MVI on graft biopsy. Genetic analysis of these patients shows a higher prevalence of mismatches between donor HLA I and recipient inhibitory killer cell immunoglobulin-like receptors (KIRs). Human in vitro models and transplantation of β2-microglobulin-deficient hearts into wild-type mice demonstrates that the inability of graft endothelial cells to provide HLA I-mediated inhibitory signals to recipient circulating NK cells triggers their activation, which in turn promotes endothelial damage. Missing self-induced NK cell activation is mTORC1-dependent and the mTOR inhibitor rapamycin can prevent the development of this type of chronic vascular rejection. ‘Missing self’ is a mode of natural killer (NK) cell activation aimed to detect the lack of HLA-I molecules on infected or neoplastic cells. Here, the authors show that mismatch between donor HLA-I and cognate receptors on recipient NK cells mediates microvascular inflammation-associated graft rejection, a pathology that is preventable by mTOR inhibition.
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Affiliation(s)
- Alice Koenig
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, 21, avenue Tony Garnier, 69007, Lyon, France.,Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology, 5, place d'Arsonval, 69003, Lyon, France.,Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), 8, avenue Rockfeller, 69373, Lyon, France
| | - Chien-Chia Chen
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, 21, avenue Tony Garnier, 69007, Lyon, France
| | - Antoine Marçais
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, 21, avenue Tony Garnier, 69007, Lyon, France
| | - Thomas Barba
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, 21, avenue Tony Garnier, 69007, Lyon, France.,Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology, 5, place d'Arsonval, 69003, Lyon, France.,Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), 8, avenue Rockfeller, 69373, Lyon, France
| | - Virginie Mathias
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, 21, avenue Tony Garnier, 69007, Lyon, France.,French National Blood Service (EFS), HLA Laboratory, 111, rue Elisée-Reclus, 69153, Décines-Charpieu, France
| | - Antoine Sicard
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, 21, avenue Tony Garnier, 69007, Lyon, France.,Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology, 5, place d'Arsonval, 69003, Lyon, France.,Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), 8, avenue Rockfeller, 69373, Lyon, France
| | - Maud Rabeyrin
- Hospices Civils de Lyon, Department of Pathology, 59, boulevard Pinel, 69500, Bron, France
| | - Maud Racapé
- Paris Translational Research Centre for Organ Transplantation, Paris Descartes University, 12, rue de l'Ecole de Médecine, 75006, Paris, France
| | - Jean-Paul Duong-Van-Huyen
- Paris Translational Research Centre for Organ Transplantation, Paris Descartes University, 12, rue de l'Ecole de Médecine, 75006, Paris, France
| | - Patrick Bruneval
- Paris Translational Research Centre for Organ Transplantation, Paris Descartes University, 12, rue de l'Ecole de Médecine, 75006, Paris, France
| | - Alexandre Loupy
- Paris Translational Research Centre for Organ Transplantation, Paris Descartes University, 12, rue de l'Ecole de Médecine, 75006, Paris, France
| | - Sébastien Dussurgey
- SFR Biosciences (UMS3444/CNRS, US8/Inserm, ENS de Lyon, UCBL), 50, avenue Tony-Garnier, 69007, Lyon, France
| | - Stéphanie Ducreux
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, 21, avenue Tony Garnier, 69007, Lyon, France.,French National Blood Service (EFS), HLA Laboratory, 111, rue Elisée-Reclus, 69153, Décines-Charpieu, France
| | - Vannary Meas-Yedid
- Unité d'Analyse d'Images Biologiques, Pasteur Institut, 25-28, rue du Docteur-Roux, 75015, Paris, France
| | | | - Héléna Paidassi
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, 21, avenue Tony Garnier, 69007, Lyon, France
| | - Romain Guillemain
- Assistance Publique - Hôpitaux de Paris, Georges Pompidou Hospital, Cardiology and Heart Transplant Department, 20, rue Leblanc, 75015, Paris, France
| | - Jean-Luc Taupin
- Assistance Publique - Hôpitaux de Paris, Immunology and HLA Laboratory, Saint-Louis Hospital, 1, avenue Claude-Vellefaux, 75010, Paris, France.,French National Institute of Health and Medical Research (Inserm) Unit 1160, 1, avenue Claude-Vellefaux, 75010, Paris, France.,Paris Diderot University, 5, rue Thomas-Mann, 75013, Paris, France
| | - Jasper Callemeyn
- Department of Microbiology and Immunology, KU Leuven, University of Leuven, Herestraat 49, Box 7003, 3000, Leuven, Belgium.,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium
| | - Emmanuel Morelon
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, 21, avenue Tony Garnier, 69007, Lyon, France.,Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology, 5, place d'Arsonval, 69003, Lyon, France.,Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), 8, avenue Rockfeller, 69373, Lyon, France
| | - Antonino Nicoletti
- Paris Diderot University, 5, rue Thomas-Mann, 75013, Paris, France.,French National Institute of Health and Medical Research (Inserm) Unit 1148, Laboratory of Vascular Translational Science, 46, rue Henri-Huchard, 75018, Paris, France
| | - Béatrice Charreau
- French National Institute of Health and Medical Research (Inserm) UMR1064, 30, boulevard Jean-Monnet, 44093, Nantes Cedex 01, France
| | - Valérie Dubois
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, 21, avenue Tony Garnier, 69007, Lyon, France.,French National Blood Service (EFS), HLA Laboratory, 111, rue Elisée-Reclus, 69153, Décines-Charpieu, France
| | - Maarten Naesens
- Department of Microbiology and Immunology, KU Leuven, University of Leuven, Herestraat 49, Box 7003, 3000, Leuven, Belgium.,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium
| | - Thierry Walzer
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, 21, avenue Tony Garnier, 69007, Lyon, France
| | - Thierry Defrance
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, 21, avenue Tony Garnier, 69007, Lyon, France
| | - Olivier Thaunat
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, 21, avenue Tony Garnier, 69007, Lyon, France. .,Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology, 5, place d'Arsonval, 69003, Lyon, France. .,Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), 8, avenue Rockfeller, 69373, Lyon, France.
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