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1. Pre-transplant CD45RC expression on blood T cells differentiates patients with cancer and rejection after kidney transplantation.

Author

Anne-Sophie Garnier, Martin Planchais, Jérémie Riou, Clément Jacquemin, Laurence Ordonez, Jean-Paul Saint-André, Anne Croue, Abdelhadi Saoudi, Yves Delneste, Anne Devys, Isabelle Boutin, Jean-François Subra, Agnès Duveau, and Jean-François Augusto

Subjects
Medicine, Science
Abstract

BackgroundBiological biomarkers to stratify cancer risk before kidney transplantation are lacking. Several data support that tumor development and growth is associated with a tolerant immune profile. T cells expressing low levels of CD45RC preferentially secrete regulatory cytokines and contain regulatory T cell subset. In contrast, T cells expressing high levels of CD45RC have been shown to secrete proinflammatory cytokines, to drive alloreactivity and to predict acute rejection (AR) in kidney transplant patients. In the present work, we evaluated whether pre-transplant CD45RClow T cell subset was predictive of post-transplant cancer occurrence.MethodsWe performed an observational cohort study of 89 consecutive first time kidney transplant patients whose CD45RC T cell expression was determined by flow cytometry before transplantation. Post-transplant events including cancer, AR, and death were assessed retrospectively.ResultsAfter a mean follow-up of 11.1±4.1 years, cancer occurred in 25 patients (28.1%) and was associated with a decreased pre-transplant proportion of CD4+CD45RChigh T cells, with a frequency below 51.9% conferring a 3.7-fold increased risk of post-transplant malignancy (HR 3.71 [1.24-11.1], p = 0.019). The sensibility, specificity, negative predictive and positive predictive values of CD4+CD45RChigh52.1% were 94.5, 68.0, 34.7 and 98.6% respectively. Frequency of CD4+CD45RChigh T cells was positively correlated with those of CD8+CD45RChigh (pConclusionHigh frequency of CD45RChigh T cells was associated with AR, while low frequency was associated with cancer. Thus, CD45RC expression on T cells appears as a double-edged sword biomarker of promising interest to assess both cancer and AR risk before kidney transplantation.

Published
2019
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2. Early post-transplant serum IgA level is associated with IgA nephropathy recurrence after kidney transplantation.

Author

Anne-Sophie Garnier, Agnès Duveau, Julien Demiselle, Anne Croué, Jean-François Subra, Johnny Sayegh, and Jean-François Augusto

Subjects
Medicine, Science
Abstract

IgA nephropathy (IgAN), the most frequent primary glomerulonephritis, affects young patients and is associated with a high risk of progression to end-stage renal disease. Consequently, patients with IgAN constitute an important proportion of candidates for kidney transplantation. Several studies showed a significant risk of IgAN recurrence on kidney graft, but the risks factors for recurrence remain to be accurately evaluated. Indeed, early identification of at risk patients may allow the optimization of treatment and the reduction of recurrence rate on the graft. In the present work, we studied the relationship between post-transplant serum IgA (sIgA) levels and the risk of IgAN recurrence after kidney transplantation. Recipients with IgAN had higher levels of sIgA as compared to patients with other nephropathies (p

Published
2018
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3. Detection of Anti-Pentraxin-3 Autoantibodies in ANCA-Associated Vasculitis.

Author

Amélie Simon, Jean-François Subra, Philippe Guilpain, Pascale Jeannin, Pascale Pignon, Simon Blanchard, Erwan Garo, Sébastien Jaillon, Alain Chevailler, Gilles Renier, Xavier Puéchal, Barbara Bottazzi, Alberto Mantovani, Yves Delneste, and Jean-François Augusto

Subjects
Medicine, Science
Abstract

Pentraxin 3 (PTX3), in common with myeloperoxidase and proteinase 3, is stored in human neutrophil granules and is expressed on apoptotic neutrophil surface. We therefore investigated the presence of anti-PTX3 autoantibodies (aAbs) in the sera of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients.Presence of anti-PTX3 autoantibodies was analysed by a specific enzyme-linked immunosorbent assay in sera from 150 patients with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA), and in sera of 227 healthy subjects (HS), 40 systemic sclerosis (SSc) patients, and 25 giant cell arteritis patients (GCA). Using indirect immunofluorescence on fixed human neutrophils, we also analyzed the staining pattern associated with the presence of anti-PTX3 aAbs.Anti-PTX3 aAbs were detected in 56 of 150 (37.3%) of the AAV patients (versus 12 of 227 (5.3%) of HS, p

Published
2016
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4. Low Serum Complement C3 Levels at Diagnosis of Renal ANCA-Associated Vasculitis Is Associated with Poor Prognosis.

Author

Jean-François Augusto, Virginie Langs, Julien Demiselle, Christian Lavigne, Benoit Brilland, Agnès Duveau, Caroline Poli, Alain Chevailler, Anne Croue, Frederic Tollis, Johnny Sayegh, and Jean-François Subra

Subjects
Medicine, Science
Abstract

Recent studies have demonstrated the key role of the complement alternative pathway (cAP) in the pathophysiology of experimental ANCA-associated vasculitis (AAV). However, in human AAV the role of cAP has not been extensively explored. In the present work, we analysed circulating serum C3 levels measured at AAV onset and their relation to outcomes.We conducted a retrospective observational cohort study including 45 consecutive patients with AAV diagnosed between 2000 and 2014 with serum C3 measurement at diagnosis, before immunosuppressive treatment initiation. Two groups were defined according to the median serum C3 level value: the low C3 group (C3

Published
2016
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5. A higher risk of acute rejection of human kidney allografts can be predicted from the level of CD45RC expressed by the recipients' CD8 T cells.

Author

Laurence Ordonez, Isabelle Bernard, Marianne Chabod, Jean-François Augusto, Valerie Lauwers-Cances, Christelle Cristini, Maria-Cristina Cuturi, Jean-François Subra, and Abdelhadi Saoudi

Subjects
Medicine, Science
Abstract

Although transplantation is the common treatment for end-stage renal failure, allograft rejection and marked morbidity from the use of immunosuppressive drugs remain important limitations. A major challenge in the field is to identify easy, reliable and noninvasive biomarkers allowing the prediction of deleterious alloreactive immune responses and the tailoring of immunosuppressive therapy in individuals according to the rejection risk. In this study, we first established that the expression of the RC isoform of the CD45 molecule (CD45RC) on CD4 and CD8 T cells from healthy individuals identifies functionally distinct alloreactive T cell subsets that behave differently in terms of proliferation and cytokine secretion. We then investigated whether the frequency of the recipients CD45RC T cell subsets before transplantation would predict acute graft rejection in a cohort of 89 patients who had undergone their first kidney transplantation. We showed that patients exhibiting more than 54.7% of CD8 CD45RC(high) T cells before transplantation had a 6 fold increased risk of acute kidney graft rejection. In contrast, the proportions of CD4 CD45RC T cells were not predictive. Thus, a higher risk of acute rejection of human kidney allografts can be predicted from the level of CD45RC expressed by the recipients' CD8 T cells.

Published
2013
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6. Pre-transplant CD45RC expression on blood T cells differentiates patients with cancer and rejection after kidney transplantation

Author

Isabelle Boutin, Jean-François Subra, Agnès Duveau, Jean-François Augusto, Anne Devys, C. Jacquemin, Jérémie Riou, Yves Delneste, Jean-Paul Saint-André, Abdelhadi Saoudi, Martin Planchais, Anne Croue, Anne-Sophie Garnier, Laurence Ordonez, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Néphrologie-Dialyse-Transplantation [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan (CPTP), Laboratoire d’anatomopathologie [CHU Angers], Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), LabEx IGO 'Immunotherapy, Graft, Oncology' [Nantes], Etablissement Français du Sang [Pays de la Loire] (EFS Pays de la Loire), EFS, Bernardo, Elizabeth, LUNAM Université [Nantes Angers Le Mans], PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), and Etablissement français du sang [Angers]

Subjects
Graft Rejection, Male, Oncology, MESH: Neoplasms / immunology, Epidemiology, 030230 surgery, acute rejection, DSA, 0302 clinical medicine, Animal Cells, Medicine, Cytotoxic T cell, MESH: Leukocyte Common Antigens / metabolism, AMR, Innate Immune System, MESH: Middle Aged, Cancer Risk Factors, Regulatory T cells, 3. Good health, [SDV] Life Sciences [q-bio], Cytokines, MESH: Neoplasms / complications, Cellular Types, medicine.medical_specialty, Regulatory T cell, Immune Cells, Science, T cell, Immunology, Cytotoxic T cells, Surgical and Invasive Medical Procedures, Urinary System Procedures, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Humans, T Helper Cells, Retrospective Studies, Pharmacology, MESH: Humans, Blood Cells, MESH: Cytokines / metabolism, Biology and Life Sciences, MESH: Adult, MESH: Retrospective Studies, Organ Transplantation, Molecular Development, medicine.disease, body regions, 030104 developmental biology, MESH: Graft Rejection / immunology, MESH: Female, Developmental Biology, AR, 0301 basic medicine, Physiology, T-Lymphocytes, [SDV]Life Sciences [q-bio], MESH: Kidney Transplantation, Cohort Studies, White Blood Cells, Immune Physiology, Neoplasms, Medicine and Health Sciences, Renal Transplantation, MESH: Cohort Studies, Kidney transplantation, Multidisciplinary, T Cells, Drugs, Cell Differentiation, Middle Aged, Immunosuppressives, medicine.anatomical_structure, antibody-mediated rejection, Female, Research Article, MESH: Cell Differentiation, Adult, MESH: T-Lymphocytes / immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Immune system, Internal medicine, MESH: T-Lymphocytes / cytology, Transplantation, business.industry, Donor specific anti-HLA, Cancer, Cell Biology, Kidney Transplantation, MESH: Male, Immune System, Medical Risk Factors, Leukocyte Common Antigens, business, CD8
Abstract

BackgroundBiological biomarkers to stratify cancer risk before kidney transplantation are lacking. Several data support that tumor development and growth is associated with a tolerant immune profile. T cells expressing low levels of CD45RC preferentially secrete regulatory cytokines and contain regulatory T cell subset. In contrast, T cells expressing high levels of CD45RC have been shown to secrete proinflammatory cytokines, to drive alloreactivity and to predict acute rejection (AR) in kidney transplant patients. In the present work, we evaluated whether pre-transplant CD45RClow T cell subset was predictive of post-transplant cancer occurrence.MethodsWe performed an observational cohort study of 89 consecutive first time kidney transplant patients whose CD45RC T cell expression was determined by flow cytometry before transplantation. Post-transplant events including cancer, AR, and death were assessed retrospectively.ResultsAfter a mean follow-up of 11.1±4.1 years, cancer occurred in 25 patients (28.1%) and was associated with a decreased pre-transplant proportion of CD4+CD45RChigh T cells, with a frequency below 51.9% conferring a 3.7-fold increased risk of post-transplant malignancy (HR 3.71 [1.24-11.1], p = 0.019). The sensibility, specificity, negative predictive and positive predictive values of CD4+CD45RChigh52.1% were 94.5, 68.0, 34.7 and 98.6% respectively. Frequency of CD4+CD45RChigh T cells was positively correlated with those of CD8+CD45RChigh (pConclusionHigh frequency of CD45RChigh T cells was associated with AR, while low frequency was associated with cancer. Thus, CD45RC expression on T cells appears as a double-edged sword biomarker of promising interest to assess both cancer and AR risk before kidney transplantation.

Published
2019

7. Detection of Anti-Pentraxin-3 Autoantibodies in ANCA-Associated Vasculitis

Author

Alberto Mantovani, Barbara Bottazzi, Jean Francois Subra, Philippe Guilpain, Pascale Pignon, Pascale Jeannin, Amelie Simon, Erwan Garo, Jean-François Augusto, Gilles Renier, Simon Blanchard, Yves Delneste, Xavier Puéchal, Sébastien Jaillon, Alain Chevailler, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Université d'Angers - Faculté de médecine (UA UFR Médecine), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université de Montpellier (UM), Laboratoire d'Immunologie et d'Allergologie, CHU d'Angers, PRES Université Nantes Angers Le Mans (UNAM), Département de Médecine Interne, Centre National de Référence Maladies Systémiques et Autoimmunes Rares, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), This work was supported by institutionalgrants from Institut National de la Santé et de laRecherche Médicale, France and the University ofAngers and by a grant from the Agence Nationale dela Recherche (project Pentraximmune). AmélieSimon and Sébastien Jaillon were supported bygrants from the Ministère de la Recherche et del’Enseignement supérieur (Bourse année-recherche)and the Conseil Général du Maine et Loire,respectively., and Bernardo, Elizabeth

Subjects
0301 basic medicine, Male, Pathology, Neutrophils, lcsh:Medicine, Apoptosis, Pathology and Laboratory Medicine, Biochemistry, White Blood Cells, 0302 clinical medicine, Proteinase 3, Animal Cells, Medicine and Health Sciences, Enzyme-Linked Immunoassays, lcsh:Science, skin and connective tissue diseases, Fluorescent Antibody Technique, Indirect, Staining, Multidisciplinary, biology, Cell Death, Middle Aged, Prognosis, 3. Good health, Serum Amyloid P-Component, C-Reactive Protein, Cell Processes, Myeloperoxidase, Female, Cellular Types, Microscopic polyangiitis, Granulomatosis with polyangiitis, Vasculitis, Research Article, Adult, medicine.medical_specialty, Immune Cells, Inflammatory Diseases, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Enzyme-Linked Immunosorbent Assay, Research and Analysis Methods, Autoimmune Diseases, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, Rheumatology, medicine, Humans, cardiovascular diseases, Wegener Granulomatosis, Immunoassays, Cytoplasmic Staining, Anti-neutrophil cytoplasmic antibody, Autoantibodies, 030203 arthritis & rheumatology, Blood Cells, business.industry, lcsh:R, Autoantibody, Biology and Life Sciences, Cell Biology, medicine.disease, 030104 developmental biology, Specimen Preparation and Treatment, Case-Control Studies, biology.protein, Immunologic Techniques, lcsh:Q, Clinical Immunology, Clinical Medicine, business, Biomarkers
Abstract

Objectives Pentraxin 3 (PTX3), in common with myeloperoxidase and proteinase 3, is stored in human neutrophil granules and is expressed on apoptotic neutrophil surface. We therefore investigated the presence of anti-PTX3 autoantibodies (aAbs) in the sera of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients. Methods Presence of anti-PTX3 autoantibodies was analysed by a specific enzyme-linked immunosorbent assay in sera from 150 patients with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA), and in sera of 227 healthy subjects (HS), 40 systemic sclerosis (SSc) patients, and 25 giant cell arteritis patients (GCA). Using indirect immunofluorescence on fixed human neutrophils, we also analyzed the staining pattern associated with the presence of anti-PTX3 aAbs. Results Anti-PTX3 aAbs were detected in 56 of 150 (37.3%) of the AAV patients (versus 12 of 227 (5.3%) of HS, p

Published
2016

8. Low Serum Complement C3 Levels at Diagnosis of Renal ANCA-Associated Vasculitis Is Associated with Poor Prognosis

Author

Johnny Sayegh, Frederic Tollis, Jean-François Augusto, Benoit Brilland, Virginie Langs, Caroline Poli, Alain Chevailler, Christian Lavigne, Jean-François Subra, Julien Demiselle, Anne Croue, Agnès Duveau, Augusto, jean-françois, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), LUNAM Université [Nantes Angers Le Mans], Département de Néphrologie-Dialyse-Transplantation [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de médecine interne et gérontologie clinique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), Laboratoire d'immunologie et allergologie [CHU Angers], Département de Pathologie Cellulaire et Tissulaire [CHU Angers] (Laboratoire d’Histopathologie-Cytopathologie), and Diaverum Dialysis Center [Angers] (2DC)

Subjects
Male, Physiology, Biopsy, viruses, Immunofluorescence, Complement System, 030232 urology & nephrology, lcsh:Medicine, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Biochemistry, 0302 clinical medicine, Immune Physiology, Medicine and Health Sciences, lcsh:Science, Aged, 80 and over, Immune System Proteins, Multidisciplinary, medicine.diagnostic_test, Complement C3, Middle Aged, Prognosis, Pathophysiology, Survival Rate, Bioassays and Physiological Analysis, Female, Kidney Diseases, Anatomy, Vasculitis, Research Article, Adult, Histology, Adolescent, Inflammatory Diseases, Immunology, Surgical and Invasive Medical Procedures, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Research and Analysis Methods, Disease-Free Survival, Autoimmune Diseases, 03 medical and health sciences, Rheumatology, Diagnostic Medicine, medicine, Humans, Immunoassays, Survival rate, Aged, Retrospective Studies, Renal Analysis, 030203 arthritis & rheumatology, business.industry, lcsh:R, Biology and Life Sciences, Proteins, Retrospective cohort study, Renal System, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Complement system, Immune System, Immunologic Techniques, Alternative complement pathway, lcsh:Q, Clinical Immunology, Clinical Medicine, business
Abstract

International audience; Background: Recent studies have demonstrated the key role of the complement alternative pathway (cAP) in the pathophysiology of experimental ANCA-associated vasculitis (AAV). However, in human AAV the role of cAP has not been extensively explored. In the present work, we analysed circulating serum C3 levels measured at AAV onset and their relation to outcomes.Methods: We conducted a retrospective observational cohort study including 45 consecutive patients with AAV diagnosed between 2000 and 2014 with serum C3 measurement at diagnosis, before immunosuppressive treatment initiation. Two groups were defined according to the median serum C3 level value: the low C3 group (C3

Published
2016

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