Search

Your search keyword '"Bach, Jean-Marie"' showing total 10 results
Start Over Author "Bach, Jean-Marie" Topic neuraminic acids
10 results on '"Bach, Jean-Marie"'

2. The Possible Role of Anti-Neu5Gc as an Obstacle in Xenotransplantation.

Author

Tector AJ, Mosser M, Tector M, and Bach JM

Subjects
Animals, Disease Models, Animal, Gene Knockout Techniques, Humans, Swine, Antibodies, Heterophile metabolism, Graft Rejection immunology, Heterografts immunology, Islets of Langerhans immunology, Islets of Langerhans Transplantation, Neuraminic Acids immunology, Transplantation, Heterologous
Abstract

Seventy to ninety percentage of preformed xenoreactive antibodies in human serum bind to the galactose-α(1,3)-galactose Gal epitope, and the creation of Gal knockout (KO) pigs has eliminated hyperacute rejection as a barrier to xenotransplantation. Now other glycan antigens are barriers to move ahead with xenotransplantation, and the N-glycolyl neuraminic acid, Neu5Gc (or Hanganutziu-Deicher antigen), is also a major pig xenoantigen. Humans have anti-Neu5Gc antibodies. Several data indicate a strong immunogenicity of Neu5Gc in humans that may contribute to an important part in antibody-dependent injury to pig xenografts. Pig islets express Neu5Gc, which reacted with diet-derived human antibodies and mice deleted for Neu5Gc reject pancreatic islets from wild-type counterpart. However, Neu5Gc positive heart were not rejected in Neu5Gc KO mice indicating that the role of Neu5Gc-specific antibodies has to be nuanced and depend of the graft situation parameters (organ/tissue, recipient, implication of other glycan antigens). Recently generated Gal/Neu5Gc KO pigs eliminate the expression of Gal and Neu5Gc, and improve the crossmatch of humans with the pig. This review summarizes the current and recent experimental and (pre)clinical data on the Neu5Gc immunogenicity and emphasize of the potential impact of anti-Neu5Gc antibodies in limiting xenotransplantation in humans., (Copyright © 2020 Tector, Mosser, Tector and Bach.)

Published
2020
Full Text
View/download PDF

3. Generation of cattle knockout for galactose-α1,3-galactose and N-glycolylneuraminic acid antigens.

Author

Perota A, Lagutina I, Duchi R, Zanfrini E, Lazzari G, Judor JP, Conchon S, Bach JM, Bottio T, Gerosa G, Costa C, Galiñanes M, Roussel JC, Padler-Karavani V, Cozzi E, Soulillou JP, and Galli C

Subjects
Animals, Antigens, Heterophile immunology, Bioprosthesis, Cattle, Cytidine Monophosphate immunology, Cytidine Monophosphate metabolism, Female, Fibroblasts immunology, Food Hypersensitivity immunology, Galactose immunology, Galactosyltransferases deficiency, Heart Valve Prosthesis, Humans, Male, Mixed Function Oxygenases deficiency, Neuraminic Acids immunology, Transplantation, Heterologous, Animals, Genetically Modified, Antigens, Heterophile metabolism, Cytidine Monophosphate analogs & derivatives, Galactose metabolism, Galactosyltransferases genetics, Gene Knockout Techniques, Mixed Function Oxygenases genetics, Neuraminic Acids metabolism
Abstract

Two well-characterized carbohydrate epitopes are absent in humans but present in other mammals. These are galactose-α1,3-galactose (αGal) and N-glycolylneuraminic acid (Neu5Gc) which are introduced by the activities of two enzymes including α(1,3) galactosyltransferase (encoded by the GGTA1 gene) and CMP-Neu5Gc hydroxylase (encoded by the CMAH gene) that are inactive in humans but present in cattle. Hence, bovine-derived products are antigenic in humans who receive bioprosthetic heart valves (BHVs) or those that suffer from red meat syndrome. Using programmable nucleases, we disrupted (knockout, KO) GGTA1 and CMAH genes encoding for the enzymes that catalyse the synthesis of αGal and Neu5Gc, respectively, in both male and female bovine fibroblasts. The KO in clonally selected fibroblasts was detected by polymerase chain reaction (PCR) and confirmed by Sanger sequencing. Selected fibroblasts colonies were used for somatic cell nuclear transfer (SCNT) to produce cloned embryos that were implanted in surrogate recipient heifers. Fifty-three embryos were implanted in 33 recipients heifers; 3 pregnancies were carried to term and delivered 3 live calves. Primary cell cultures were established from the 3 calves and following molecular analyses confirmed the genetic deletions. FACS analysis showed the double-KO phenotype for both antigens confirming the mutated genotypes. Availability of such cattle double-KO model lacking both αGal and Neu5Gc offers a unique opportunity to study the functionality of BHV manufactured with tissues of potentially lower immunogenicity, as well as a possible new clinical approaches to help patients with red meat allergy syndrome due to the presence of these xenoantigens in the diet., (© 2019 The Authors. Xenotransplantation Published by John Wiley & Sons Ltd.)

Published
2019
Full Text
View/download PDF

4. Quantitative and qualitative changes in anti-Neu5Gc antibody response following rabbit anti-thymocyte IgG induction in kidney allograft recipients.

Author

Rousse J, Salama A, Leviatan Ben-Arye S, Hruba P, Slatinska J, Evanno G, Duvaux O, Blanchard D, Yu H, Chen X, Bach JM, Padler-Karavani V, Viklicky O, and Soulillou JP

Subjects
Adult, Aged, Antibodies metabolism, Case-Control Studies, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Prospective Studies, Thymocytes immunology, Transplantation Immunology physiology, Transplantation, Homologous, Antibodies immunology, Immunity, Cellular physiology, Immunoglobulin G pharmacology, Immunologic Factors pharmacology, Kidney Transplantation methods, Neuraminic Acids immunology
Abstract

Antibodies of non-human mammals are glycosylated with carbohydrate antigens, such as galactose-α-1-3-galactose (α-Gal) and N-glycolylneuraminic acid (Neu5Gc). These non-human carbohydrate antigens are highly immunogenic in humans due to loss-of-function mutations of the key genes involved in their synthesis. Such immunogenic carbohydrates are expressed on therapeutic polyclonal rabbit anti-human T-cell IgGs (anti-thymocyte globulin; ATG), the most popular induction treatment in allograft recipients. To decipher the quantitative and qualitative response against these antigens in immunosuppressed patients, particularly against Neu5Gc, which may induce endothelial inflammation in both the graft and the host. We report a prospective study of the antibody response against α-Gal and Neu5Gc-containing glycans following rabbit ATG induction compared to controls. We show a drop in the overall levels of anti-Neu5Gc antibodies at 6 and 12 months post-graft compared to the pre-existing levels due to the major early immunosuppression. However, in contrast, in a cross-sectional study there was a highly significant increase in anti-Neu5Gc IgGs levels at 6 months post-graft in the ATG-treated compared to non-treated patients(P = 0.007), with a clear hierarchy favouring anti-Neu5Gc over anti-Gal response. A sialoglycan microarray analysis revealed that the increased anti-Neu5Gc IgG response was still highly diverse against multiple different Neu5Gc-containing glycans. Furthermore, some of the ATG-treated patients developed a shift in their anti-Neu5Gc IgG repertoire compared with the baseline, recognizing different patterns of Neu5Gc-glycans. In contrast to Gal, Neu5Gc epitopes remain antigenic in severely immunosuppressed patients, who also develop an anti-Neu5Gc repertoire shift. The clinical implications of these observations are discussed., (© 2019 Stichting European Society for Clinical Investigation Journal Foundation.)

Published
2019
Full Text
View/download PDF

5. Neu5Gc and α1-3 GAL Xenoantigen Knockout Does Not Affect Glycemia Homeostasis and Insulin Secretion in Pigs.

Author

Salama A, Mosser M, Lévêque X, Perota A, Judor JP, Danna C, Pogu S, Mouré A, Jégou D, Gaide N, Abadie J, Gauthier O, Concordet JP, Le Bas-Bernardet S, Riochet D, Le Berre L, Hervouet J, Minault D, Weiss P, Guicheux J, Brouard S, Bosch S, Lagutina I, Duchi R, Lazzari G, Cozzi E, Blancho G, Conchon S, Galli C, Soulillou JP, and Bach JM

Subjects
Animals, Antigens, Heterophile, Blood Glucose drug effects, Blood Glucose metabolism, C-Peptide drug effects, C-Peptide metabolism, Diabetes Mellitus, Type 1 surgery, Galactose immunology, Gene Knockout Techniques, Glucagon drug effects, Glucagon metabolism, Homeostasis, Insulin Secretion, Islets of Langerhans metabolism, Islets of Langerhans pathology, Islets of Langerhans Transplantation, Male, Neuraminic Acids immunology, Pancreas metabolism, Swine, Transplantation, Heterologous, Galactose genetics, Glucose pharmacology, Insulin metabolism, Islets of Langerhans drug effects, Neuraminic Acids metabolism, Purinergic P1 Receptor Antagonists pharmacology, Theophylline pharmacology
Abstract

Xenocell therapy from neonate or adult pig pancreatic islets is one of the most promising alternatives to allograft in type 1 diabetes for addressing organ shortage. In humans, however, natural and elicited antibodies specific for pig xenoantigens, α-(1,3)-galactose (GAL) and N -glycolylneuraminic acid (Neu5Gc), are likely to significantly contribute to xenoislet rejection. We obtained double-knockout (DKO) pigs lacking GAL and Neu5Gc. Because Neu5Gc -/- mice exhibit glycemic dysregulations and pancreatic β-cell dysfunctions, we evaluated islet function and glucose metabolism regulation in DKO pigs. Isolation of islets from neonate piglets yielded identical islet equivalent quantities to quantities obtained from control wild-type pigs. In contrast to wild-type islets, DKO islets did not induce anti-Neu5Gc antibody when grafted in cytidine monophosphate- N -acetylneuraminic acid hydroxylase KO mice and exhibited in vitro normal insulin secretion stimulated by glucose and theophylline. Adult DKO pancreata showed no histological abnormalities, and immunostaining of insulin and glucagon was similar to that from wild-type pancreata. Blood glucose, insulin, C-peptide, the insulin-to-glucagon ratio, and HOMA-insulin resistance in fasted adult DKO pigs and blood glucose and C-peptide changes after intravenous glucose or insulin administration were similar to wild-type pigs. This first evaluation of glucose homeostasis in DKO pigs for two major xenoantigens paves the way to their use in (pre)clinical studies., (© 2017 by the American Diabetes Association.)

Published
2017
Full Text
View/download PDF

6. Anti-EBOV GP IgGs Lacking α1-3-Galactose and Neu5Gc Prolong Survival and Decrease Blood Viral Load in EBOV-Infected Guinea Pigs.

Author

Reynard O, Jacquot F, Evanno G, Mai HL, Salama A, Martinet B, Duvaux O, Bach JM, Conchon S, Judor JP, Perota A, Lagutina I, Duchi R, Lazzari G, Le Berre L, Perreault H, Lheriteau E, Raoul H, Volchkov V, Galli C, and Soulillou JP

Subjects
Animals, Antibodies, Anti-Idiotypic immunology, Ebola Vaccines immunology, Ebolavirus immunology, Guinea Pigs, Hemorrhagic Fever, Ebola blood, Hemorrhagic Fever, Ebola immunology, Male, Swine, Vaccination, Viral Load, Antibodies, Viral blood, Ebola Vaccines therapeutic use, Galactose deficiency, Hemorrhagic Fever, Ebola prevention & control, Immunoglobulin G immunology, Neuraminic Acids metabolism, Viral Envelope Proteins immunology
Abstract

Polyclonal xenogenic IgGs, although having been used in the prevention and cure of severe infectious diseases, are highly immunogenic, which may restrict their usage in new applications such as Ebola hemorrhagic fever. IgG glycans display powerful xenogeneic antigens in humans, for example α1-3 Galactose and the glycolyl form of neuraminic acid Neu5Gc, and IgGs deprived of these key sugar epitopes may represent an advantage for passive immunotherapy. In this paper, we explored whether low immunogenicity IgGs had a protective effect on a guinea pig model of Ebola virus (EBOV) infection. For this purpose, a double knock-out pig lacking α1-3 Galactose and Neu5Gc was immunized against virus-like particles displaying surface EBOV glycoprotein GP. Following purification from serum, hyper-immune polyclonal IgGs were obtained, exhibiting an anti-EBOV GP titer of 1:100,000 and a virus neutralizing titer of 1:100. Guinea pigs were injected intramuscularly with purified IgGs on day 0 and day 3 post-EBOV infection. Compared to control animals treated with IgGs from non-immunized double KO pigs, the anti-EBOV IgGs-treated animals exhibited a significantly prolonged survival and a decreased virus load in blood on day 3. The data obtained indicated that IgGs lacking α1-3 Galactose and Neu5Gc, two highly immunogenic epitopes in humans, have a protective effect upon EBOV infection.

Published
2016
Full Text
View/download PDF

7. Can We Extrapolate From a Cmah -/- Ldlr -/- Mouse Model a Susceptibility for Atherosclerosis in Humans?

Author

Soulillou, Jean-Paul, Cozzi, Emanuele, Galli, Cesare, Bach, Jean-Marie, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), 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), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), University Hospital of Padua, Avantea Laboratory of Reproductive Technologies [Cremona, Italy], Immuno-Endocrinologie Cellulaire et Moléculaire (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes, Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Le Bihan, Sylvie, Azienda Ospedale Università di Padova = Hospital-University of Padua (AOUP), and Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
[SDV] Life Sciences [q-bio], [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV]Life Sciences [q-bio], Models, Animal, Animals, Humans, Neuraminic Acids, Letters, Atherosclerosis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, ComputingMilieux_MISCELLANEOUS, Mixed Function Oxygenases
Abstract

International audience

Published
2020

8. Generation of cattle knockout for galactose‐α1,3‐galactose and N‐glycolylneuraminic acid antigens

Author

Perota, Andrea, Lagutina, Irina, Duchi, Roberto, Zanfrini, Elisa, Lazzari, Giovanna, Judor, Jean Paul, Conchon, Sophie, Bach, Jean Marie, Bottio, Tomaso, Gerosa, Gino, Costa Farré, Cristina, Galiñanes, Manuel, Roussel, Jean Christian, Padler-Karavani, Vered, Cozzi, Emanuele, Soulillou, Jean Paul, Galli, Cesare, Universitat Autònoma de Barcelona, Avantea Laboratory of Reproductive Technologies [Cremona, Italy], Fondazione Avantea [Cremona, Italy], Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Immunoregulation And Immunointervention in Transplantation and Autoimmunity (Team 4 - U1064 Inserm - CRTI), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), 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)-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), Immuno-Endocrinologie Cellulaire et Moléculaire [Nantes] (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Department of Cardiac, Thoracic and Vascular Sciences and Public Health [Padova, Italy] (Cardiac Surgery Unit), Padova University School of Medicine [Padova, Italy] -Consorzio per la Ricerca Sanitaria - CORIS [Padova, Italy], Infectious Diseases and Transplantation Division [Barcelona, Spain], L’Hospitalet de Llobregat [Barcelona, Spain]-Bellvitge Biomedical Research Institute IDIBELL [Barcelona, Spain], Department of Cardiac Surgery & Reparative Therapy of the Heart [Barcelona, Spain], Vall d’Hebron Institute of Research [Barcelona, Spain]-Hospital Universitari Vall d'Hebron [Barcelona, Spain], Département de chirurgie thoracique et cardiovasculaire [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Cell Research and Immunology, Tel Aviv University [Tel Aviv], Transplantation Immunology Unit [Padua, Italy] (Department of Transfusion Medicine), University of Padua–Ospedale Giustinianeo [Padua, Italy], Le Bihan, Sylvie, Defining the role of xeno-directed and autoimmune events in patients receiving animal-derived bioprosthetic heart valves - TRANSLINK - - EC:FP7:HEALTH2013-09-01 - 2017-08-31 - 603049 - VALID, Immuno-Endocrinologie Cellulaire et Moléculaire (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Università degli Studi di Padova = University of Padua (Unipd)-Consorzio per la Ricerca Sanitaria - CORIS [Padova, Italy], Vall d'Hebron University Hospital [Barcelona]-Vall d’Hebron Research Institute (VHIR), Tel Aviv University (TAU), Università degli Studi di Padova = University of Padua (Unipd), and European Project: 603049,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,TRANSLINK(2013)

Subjects
Male, 0301 basic medicine, knockout, Neu5Gc, 030230 surgery, Epitope, Mixed Function Oxygenases, law.invention, Animals, Genetically Modified, Gene Knockout Techniques, chemistry.chemical_compound, 0302 clinical medicine, Carn de boví, N-Glycolylneuraminic acid, law, xenotransplantation, Polymerase chain reaction, 2. Zero hunger, Sanger sequencing, Heart valves, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Immunogenicity, Galactosyltransferases, Vàlvules cardíaques, Heart Valve Prosthesis, symbols, bioprosthetic Heart Valve (BHV), Somatic cell nuclear transfer, Xenotransplantation, Female, Original Article, Beef, cattle, CMAH, GGTA1, αGal, Food Hypersensitivity, Knockout, Transplantation, Heterologous, Immunology, Biology, 03 medical and health sciences, symbols.namesake, Antigens, Heterophile, Cytidine Monophosphate, Animals, Humans, Gene, Bioprosthesis, Galactosyltransferase, Transplantation, Galactose, Original Articles, Fibroblasts, Bioprosthetic Heart Valve (BHV), Molecular biology, 030104 developmental biology, chemistry, Cattle, Neuraminic Acids, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Two well-characterized carbohydrate epitopes are absent in humans but present in other mammals. These are galactose-α1,3-galactose (αGal) and N-glycolylneuraminic acid (Neu5Gc) which are introduced by the activities of two enzymes including α(1,3) galactosyltransferase (encoded by the GGTA1 gene) and CMP-Neu5Gc hydroxylase (encoded by the CMAH gene) that are inactive in humans but present in cattle. Hence, bovine-derived products are antigenic in humans who receive bioprosthetic heart valves (BHVs) or those that suffer from red meat syndrome. Using programmable nucleases, we disrupted (knockout, KO) GGTA1 and CMAH genes encoding for the enzymes that catalyse the synthesis of αGal and Neu5Gc, respectively, in both male and female bovine fibroblasts. The KO in clonally selected fibroblasts was detected by polymerase chain reaction (PCR) and confirmed by Sanger sequencing. Selected fibroblasts colonies were used for somatic cell nuclear transfer (SCNT) to produce cloned embryos that were implanted in surrogate recipient heifers. Fifty-three embryos were implanted in 33 recipients heifers; 3 pregnancies were carried to term and delivered 3 live calves. Primary cell cultures were established from the 3 calves and following molecular analyses confirmed the genetic deletions. FACS analysis showed the double-KO phenotype for both antigens confirming the mutated genotypes. Availability of such cattle double-KO model lacking both αGal and Neu5Gc offers a unique opportunity to study the functionality of BHV manufactured with tissues of potentially lower immunogenicity, as well as a possible new clinical approaches to help patients with red meat allergy syndrome due to the presence of these xenoantigens in the diet.

Published
2019

9. Neu5Gc and α1-3 GAL Xenoantigen Knockout Does Not Affect Glycemia Homeostasis and Insulin Secretion in Pigs

Author

Andrea Perota, Pierre Weiss, Nicolas Gaide, Steffi Bosch, Anne Moure, Jean-Paul Concordet, Emanuele Cozzi, Mathilde Mosser, Cesare Galli, Jérôme Guicheux, Jeremy Hervouet, David Minault, Jean-Marie Bach, Jean-Paul Soulillou, Jérôme Abadie, Sylvie Pogu, Apolline Salama, Xavier Lévêque, Olivier Gauthier, Dominique Jégou, Roberto Duchi, Gilles Blancho, Jean-Paul Judor, Sophie Brouard, Stéphanie Le Bas-Bernardet, Giovanna Lazzari, Ludmilla Le Berre, Sophie Conchon, David Riochet, Corentin Danna, Irina Lagutina, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), 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), Immuno-Endocrinologie Cellulaire et Moléculaire [Nantes] (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Société d'Accélération du Transfert de Technologies (SATT OUEST VALORISATION), Avantea Laboratory of Reproductive Technologies, Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Animaux Modèles pour la Recherche en Oncologie [Nantes] (AMaROC), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Muséum national d'Histoire naturelle (MNHN), Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'ingénierie osteo-articulaire et dentaire (LIOAD), Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), PHU 4 OTONN, Centre hospitalier universitaire de Nantes (CHU Nantes), CIC - Nantes, Avantea Foundation, Transplantation Immunology Unit, Universita degli Studi di Padova, Consortium for Research in Organ Transplantation (CORIT), University of Bologna, Université de Nantes (UN), Avantea Laboratory of Reproductive Technologies [Cremona, Italy], Département de Chirurgie Expérimentale [Nantes] (Oniris - Centre de recherche et d'investigation préclinique), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre de recherche et d'investigation préclinique [Nantes], Museum National d'Histoire Naturelle de Paris, Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de pédiatrie [CHU Nantes], Université de Nantes - UFR Odontologie, Ostéo-articulaire - Tête et cou - Odontologie - Neurochirurgie - Neurotraumatologie [CHU Nantes] (Pôle hospitalo-universitaire PHU4 - OTONN), CIC biothérapies CBT 0503 [Nantes], Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Avantea Foundation [Cremona, Italy], Transplantation Immunology Unit [Padua, Italy] (Department of Transfusion Medicine), University of Padua–Ospedale Giustinianeo [Padua, Italy], Consortium for Research in Organ Transplantation [Padua, Italy] (CORIT), Department of Veterinary Medical Sciences [Ozzano dell'Emilia, Italy], Pays de la Loire Region (France) (Xenothera academic program and to A.S.), the Société d’Accélération du Transfert de Technologies Ouest Valorisation (to A.S.)., ANR: ANR-10IBHU-005, ANR: ANR-II-INSB-0014, European Project: LSHB-CT-2006-037377, European Project: 603049, European Project: ECTIS, Université de Nantes (UN)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Recherche Agronomique (INRA), Animaux modèles pour la recherche en oncologie comparée (AMaROC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Muséum national d'Histoire naturelle (MNHN), Institut de Transplantation Urologie Néphrologie, AMaROC - Oniris Nantes, Centre d'Investigation Clinique (CIC) Biotherapy, This work was supported by Pays de la Loire Region (France) (Xenothera academic program and to A.S.), the Société d’Accélération du Transfert de Technologies Ouest Valorisation (to A.S.), the European Center for Transplantation and Immunotherapy Sciences (ECTIS IHU, Nantes, France), the National Research Agency 'Investment Into The Future' programs (ANR-10-IBHU-005, to X.L., and ANR-II-INSB-0014), the European Commission’s Xenome Sixth Framework Programme (LSHB-CT-2006-037377), and the European Seventh Framework Programme 'Translink' research program (grant agreement 603049 and to L.L.B.)., ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), ANR-11-INBS-0014,TEFOR,Transgenèse pour les Etudes Fonctionnelles sur les Organismes modèles(2011), Immuno-Endocrinologie Cellulaire et Moléculaire (IECM), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Padova = University of Padua (Unipd), Consorzio per la Ricerca sul Trapianto d'Organ = Consortium for Research in Organ Transplantation (CORIT), University of Bologna/Università di Bologna, European Project: 603049,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,TRANSLINK(2013), Mosser, Mathilde, Lévêque, Xavier, Perota, Andrea, Galli, Cesare, Soulillou, Jean-Paul, Bach, Jean-Marie, Jehan, Frederic, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, Infrastructures - Transgenèse pour les Etudes Fonctionnelles sur les Organismes modèles - - TEFOR2011 - ANR-11-INBS-0014 - INBS - VALID, and Defining the role of xeno-directed and autoimmune events in patients receiving animal-derived bioprosthetic heart valves - TRANSLINK - - EC:FP7:HEALTH2013-09-01 - 2017-08-31 - 603049 - VALID

Subjects
Blood Glucose, Male, 0301 basic medicine, Swine, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Islets of Langerhans Transplantation, 030230 surgery, Gene Knockout Techniques, 0302 clinical medicine, Insulin Secretion, Homeostasis, Insulin, Glucose homeostasis, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Heterologous, geography.geographical_feature_category, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, C-Peptide, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Islet, 3. Good health, Heterophile, medicine.anatomical_structure, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Type 1, medicine.medical_specialty, endocrine system, Transplantation, Heterologous, Animals, Antigens, Heterophile, Diabetes Mellitus, Type 1, Galactose, Glucagon, Glucose, Islets of Langerhans, Neuraminic Acids, Pancreas, Purinergic P1 Receptor Antagonists, Theophylline, Carbohydrate metabolism, Biology, 03 medical and health sciences, Internal medicine, Diabetes mellitus, Diabetes Mellitus, Internal Medicine, medicine, Antigens, Transplantation, Type 1 diabetes, geography, Pancreatic islets, medicine.disease, 030104 developmental biology, Endocrinology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Xenocell therapy from neonate or adult pig pancreatic islets is one of the most promising alternatives to allograft in type 1 diabetes for addressing organ shortage. In humans, however, natural and elicited anti-bodies specific for pig xenoantigens, α-(1,3)-galactose (GAL) and N-glycolylneuraminic acid (Neu5Gc), are likely to significantly contribute to xenoislet rejection. We obtained double-knockout (DKO) pigs lacking GAL and Neu5Gc. Because Neu5Gc 2/2 mice exhibit glycemic dys-regulations and pancreatic b-cell dysfunctions, we evaluated islet function and glucose metabolism regulation in DKO pigs. Isolation of islets from neonate piglets yielded identical islet equivalent quantities to quantities obtained from control wild-type pigs. In contrast to wild-type islets, DKO islets did not induce anti-Neu5Gc antibody when grafted in cytidine monophosphate-N-acetylneuraminic acid hydroxylase KO mice and exhibited in vitro normal insulin secretion stimulated by glucose and theophylline. Adult DKO pancreata showed no histological abnormalities , and immunostaining of insulin and glucagon was similar to that from wild-type pancreata. Blood glucose, insulin, C-peptide, the insulin-to-glucagon ratio, and HOMA-insulin resistance in fasted adult DKO pigs and blood glucose and C-peptide changes after intravenous glucose or insulin administration were similar to wild-type pigs. This first evaluation of glucose homeostasis in DKO pigs for two major xenoantigens paves the way to their use in (pre)clinical studies.

Published
2017

10. Anti-EBOV GP IgGs Lacking α1-3-Galactose and Neu5Gc Prolong Survival and Decrease Blood Viral Load in EBOV-Infected Guinea Pigs

Author

Odile Duvaux, Andrea Perota, Hélène Perreault, Elsa Lheriteau, Bernard Martinet, Irina Lagutina, Gwénaëlle Evanno, Ludmilla Le Berre, Hervé Raoul, Olivier Reynard, Cesare Galli, Giovanna Lazzari, Apolline Salama, Frédéric Jacquot, Roberto Duchi, Sophie Conchon, Jean-Paul Judor, Viktor E. Volchkov, Jean-Marie Bach, Jean-Paul Soulillou, Hoa Le Mai, Bases moléculaires de la pathogénicité virale – Molecular Basis of Viral Pathogenicity (BMPV), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire P4 - Jean Mérieux, Centre Européen de Virologie/Immunologie-Institut National de la Santé et de la Recherche Médicale (INSERM), Xenothera [Nantes, France], Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), 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), Immuno-Endocrinologie Cellulaire et Moléculaire (IECM), Ecole Nationale Vétérinaire de Nantes-Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Avantea Laboratory of Reproductive Technologies [Cremona, Italy], University of Manitoba [Winnipeg], Anti-EBOV GP IgGs Lacking alpha 1-3-Galactose and Neu5Gc Prolong Survival and Decrease Blood Viral Load in EBOV-Infected Guinea Pigs, Reynard, Olivier, Jacquot, Frédéric, Evanno, Gwénaëlle, Mai, Hoa Le, Salama, Apolline, Martinet, Bernard, Duvaux, Odile, Bach, Jean-Marie, Conchon, Sophie, Judor, Jean-Paul, Perota, Andrea, Lagutina, Irina, Duchi, Roberto, Lazzari, Giovanna, Le Berre, Ludmilla, Perreault, Hélène, Lheriteau, Elsa, Raoul, Hervé, Volchkov, Viktor, Galli, Cesare, Soulillou, Jean-Paul, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Davoine, Laure-Hélène, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bases moléculaires de la pathogénicité virale – Molecular Basis of Viral Pathogenicity, Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Ecole Nationale Vétérinaire de Nantes, University of Manitoba, and University of Bologna

Subjects
0301 basic medicine, Male, Physiology, Swine, lcsh:Medicine, medicine.disease_cause, Antibodies, Viral, Biochemistry, Epitope, Immunoglobulin G, 0302 clinical medicine, Viral Envelope Proteins, Pig Models, Intraperitoneal Injections, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immune Physiology, Medicine and Health Sciences, 030212 general & internal medicine, Viral, Enzyme-Linked Immunoassays, lcsh:Science, Routes of Administration, Mammals, Multidisciplinary, Immune System Proteins, Immunogenicity, Vaccination, Agriculture, Animal Models, Hematology, Viral Load, Ebolavirus, 3. Good health, Antibodies, Anti-Idiotypic, Body Fluids, Titer, Blood, Anti-Idiotypic, Vertebrates, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Ebola, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, Anatomy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Viral load, Research Article, EBOV, Livestock, Immunology, Guinea Pigs, α1-3-Galactose, Biology, rabbit antithymocyte globulin, hemorrhagic-fever, virus-infection, nonhuman-primates, sialic-acid, molecular characterization, monoclonal-antibody, immunoglobulin-g, disease, immunotherapy, Research and Analysis Methods, Rodents, Virus, Antibodies, 03 medical and health sciences, Model Organisms, medicine, Animals, Antigens, Ebola Vaccines, Immunoassays, Pharmacology, Ebola virus, lcsh:R, Organisms, Biology and Life Sciences, Proteins, Galactose, Anti-EBOV, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Hemorrhagic Fever, Ebola, Guinea pig, Virology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 030104 developmental biology, Amniotes, biology.protein, Immunologic Techniques, Hemorrhagic Fever, lcsh:Q, Neuraminic Acids
Abstract

International audience; Polyclonal xenogenic IgGs, although having been used in the prevention and cure of severe infectious diseases, are highly immunogenic, which may restrict their usage in new applications such as Ebola hemorrhagic fever. IgG glycans display powerful xenogeneic antigens in humans, for example α1-3 Galactose and the glycolyl form of neuraminic acid Neu5Gc, and IgGs deprived of these key sugar epitopes may represent an advantage for passive immunotherapy. In this paper, we explored whether low immunogenicity IgGs had a protective effect on a guinea pig model of Ebola virus (EBOV) infection. For this purpose, a double knock-out pig lacking α1-3 Galactose and Neu5Gc was immunized against virus-like particles displaying surface EBOV glycoprotein GP. Following purification from serum, hyper-immune polyclonal IgGs were obtained, exhibiting an anti-EBOV GP titer of 1:100,000 and a virus neutralizing titer of 1:100. Guinea pigs were injected intramuscularly with purified IgGs on day 0 and day 3 post-EBOV infection. Compared to control animals treated with IgGs from non-immunized double KO pigs, the anti-EBOV IgGs-treated animals exhibited a significantly prolonged survival and a decreased virus load in blood on day 3. The data obtained indicated that IgGs lacking α1-3 Galactose and Neu5Gc, two highly immunogenic epitopes in humans, have a protective effect upon EBOV infection.

Published
2016

Catalog

Books, media, physical & digital resources
See catalog results