title: Neu5Gc and α1-3 GAL Xenoantigen Knockout Does Not Affect Glycemia Homeostasis and Insulin Secretion in Pigs.
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) andN-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.
authors.affiliation: IECM, Immuno-endocrinology, EA4644 Oniris, University of Nantes, USC1383 INRA, Oniris, Nantes, France.|Société d'Accélération du Transfert de Technologies Ouest Valorisation, Rennes, France.|INSERM CRTI UMR 1064, University of Nantes, Nantes, France.|Institute of Transplantation, Urology and Nephrology (ITUN), Nantes University Hospital-CHU de Nantes, Nantes, France.
authors.forename: Apolline
authors.initials: A
authors.lastname: Salama
authors.affiliation: IECM, Immuno-endocrinology, EA4644 Oniris, University of Nantes, USC1383 INRA, Oniris, Nantes, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Mosser
authors.affiliation: IECM, Immuno-endocrinology, EA4644 Oniris, University of Nantes, USC1383 INRA, Oniris, Nantes, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Lévêque
authors.affiliation: Avantea Laboratory of Reproductive Technologies, Cremona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Perota
authors.affiliation: INSERM CRTI UMR 1064, University of Nantes, Nantes, France.|Institute of Transplantation, Urology and Nephrology (ITUN), Nantes University Hospital-CHU de Nantes, Nantes, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Judor
authors.affiliation: IECM, Immuno-endocrinology, EA4644 Oniris, University of Nantes, USC1383 INRA, Oniris, Nantes, France.
authors.forename: Corentin
authors.initials: C
authors.lastname: Danna
authors.affiliation: IECM, Immuno-endocrinology, EA4644 Oniris, University of Nantes, USC1383 INRA, Oniris, Nantes, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pogu
authors.affiliation: IECM, Immuno-endocrinology, EA4644 Oniris, University of Nantes, USC1383 INRA, Oniris, Nantes, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Mouré
authors.affiliation: IECM, Immuno-endocrinology, EA4644 Oniris, University of Nantes, USC1383 INRA, Oniris, Nantes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Jégou
authors.affiliation: Animal cancers as Models for Research in comparative Oncology (AMaROC), Oniris, Nantes, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gaide
authors.affiliation: Animal cancers as Models for Research in comparative Oncology (AMaROC), Oniris, Nantes, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Abadie
authors.affiliation: Department of Experimental Surgery, Center for Research and Preclinical Investigation, Oniris, Nantes, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Gauthier
authors.affiliation: Muséum National d'Histoire Naturelle, Paris, France.|CNRS UMR 7196, Paris, France.|INSERM U1154, Paris, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Concordet
authors.affiliation: INSERM CRTI UMR 1064, University of Nantes, Nantes, France.|Institute of Transplantation, Urology and Nephrology (ITUN), Nantes University Hospital-CHU de Nantes, Nantes, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Le Bas-Bernardet
authors.affiliation: INSERM CRTI UMR 1064, University of Nantes, Nantes, France.|Institute of Transplantation, Urology and Nephrology (ITUN), Nantes University Hospital-CHU de Nantes, Nantes, France.|Department of Pediatrics, Nantes University Hospital-CHU de Nantes, Nantes, France.
authors.forename: David
authors.initials: D
authors.lastname: Riochet
authors.affiliation: INSERM CRTI UMR 1064, University of Nantes, Nantes, France.|Institute of Transplantation, Urology and Nephrology (ITUN), Nantes University Hospital-CHU de Nantes, Nantes, France.
authors.forename: Ludmilla
authors.initials: L
authors.lastname: Le Berre
authors.affiliation: INSERM CRTI UMR 1064, University of Nantes, Nantes, France.|Institute of Transplantation, Urology and Nephrology (ITUN), Nantes University Hospital-CHU de Nantes, Nantes, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Hervouet
authors.affiliation: INSERM CRTI UMR 1064, University of Nantes, Nantes, France.|Institute of Transplantation, Urology and Nephrology (ITUN), Nantes University Hospital-CHU de Nantes, Nantes, France.
authors.forename: David
authors.initials: D
authors.lastname: Minault
authors.affiliation: INSERM UMRS 791, Laboratoire d'ingénierie Ostéo-Articulaire et Dentaire (LIOAD), Nantes, France; University of Nantes, UFR Odontologie, Nantes, France.|Nantes University Hospital-CHU de Nantes, PHU4 OTONN, Nantes, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Weiss
authors.affiliation: INSERM UMRS 791, Laboratoire d'ingénierie Ostéo-Articulaire et Dentaire (LIOAD), Nantes, France; University of Nantes, UFR Odontologie, Nantes, France.|Nantes University Hospital-CHU de Nantes, PHU4 OTONN, Nantes, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Guicheux
authors.affiliation: INSERM CRTI UMR 1064, University of Nantes, Nantes, France.|Institute of Transplantation, Urology and Nephrology (ITUN), Nantes University Hospital-CHU de Nantes, Nantes, France.|Centre d'investigation clinique (CIC) Biotherapy, Nantes University Hospital-CHU de Nantes, Nantes, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Brouard
authors.affiliation: IECM, Immuno-endocrinology, EA4644 Oniris, University of Nantes, USC1383 INRA, Oniris, Nantes, France.
authors.forename: Steffi
authors.initials: S
authors.lastname: Bosch
authors.affiliation: Avantea Laboratory of Reproductive Technologies, Cremona, Italy.
authors.forename: Irina
authors.initials: I
authors.lastname: Lagutina
authors.affiliation: Avantea Laboratory of Reproductive Technologies, Cremona, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Duchi
authors.affiliation: Avantea Laboratory of Reproductive Technologies, Cremona, Italy.|Avantea Foundation, Cremona, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lazzari
authors.affiliation: Transplantation Immunology Unit, Department of Transfusion Medicine, University of Padua-Ospedale Giustinianeo, Padua, Italy.|CORIT (Consortium for Research in Organ Transplantation), Padua, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Cozzi
authors.affiliation: INSERM CRTI UMR 1064, University of Nantes, Nantes, France.|Institute of Transplantation, Urology and Nephrology (ITUN), Nantes University Hospital-CHU de Nantes, Nantes, France.|Centre d'investigation clinique (CIC) Biotherapy, Nantes University Hospital-CHU de Nantes, Nantes, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Blancho
authors.affiliation: INSERM CRTI UMR 1064, University of Nantes, Nantes, France.|Institute of Transplantation, Urology and Nephrology (ITUN), Nantes University Hospital-CHU de Nantes, Nantes, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Conchon
authors.affiliation: Avantea Laboratory of Reproductive Technologies, Cremona, Italy jean-marie.bach@oniris-nantes.fr soulillou@yahoo.fr cesaregalli@avantea.it.|Avantea Foundation, Cremona, Italy.|Department of Veterinary Medical Sciences, University of Bologna, Ozzano Emilia, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Galli
authors.affiliation: University of Nantes, Nantes, France jean-marie.bach@oniris-nantes.fr soulillou@yahoo.fr cesaregalli@avantea.it.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soulillou
authors.affiliation: IECM, Immuno-endocrinology, EA4644 Oniris, University of Nantes, USC1383 INRA, Oniris, Nantes, France jean-marie.bach@oniris-nantes.fr soulillou@yahoo.fr cesaregalli@avantea.it.
authors.forename: Jean-Marie
authors.identifier: 0000-0002-5265-8854
authors.initials: JM
authors.lastname: Bach
mesh_terms: D000818:Animals; D015478:Antigens, Heterophile; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002096:C-Peptide / Q000187:drug effects / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery; D005690:Galactose / Q000235:genetics* / Q000276:immunology; D055786:Gene Knockout Techniques; D005934:Glucagon / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D008297:Male; D009438:Neuraminic Acids / Q000276:immunology / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology*; D013552:Swine; D013806:Theophylline / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: D015478:Antigens, Heterophile; D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D009438:Neuraminic Acids; D058915:Purinergic P1 Receptor Antagonists; C032592:N-glycolylneuraminic acid; D005934:Glucagon; D013806:Theophylline; D005947:Glucose; D005690:Galactose