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Diabetes. 2017 Apr;66(4):987-993. doi: 10.2337/db16-1060. Epub 2017 Jan 12.

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

Author information

1
IECM, Immuno-endocrinology, EA4644 Oniris, University of Nantes, USC1383 INRA, Oniris, Nantes, France.
2
Société d'Accélération du Transfert de Technologies Ouest Valorisation, Rennes, France.
3
INSERM CRTI UMR 1064, University of Nantes, Nantes, France.
4
Institute of Transplantation, Urology and Nephrology (ITUN), Nantes University Hospital-CHU de Nantes, Nantes, France.
5
Avantea Laboratory of Reproductive Technologies, Cremona, Italy.
6
Animal cancers as Models for Research in comparative Oncology (AMaROC), Oniris, Nantes, France.
7
Department of Experimental Surgery, Center for Research and Preclinical Investigation, Oniris, Nantes, France.
8
Muséum National d'Histoire Naturelle, Paris, France.
9
CNRS UMR 7196, Paris, France.
10
INSERM U1154, Paris, France.
11
Department of Pediatrics, Nantes University Hospital-CHU de Nantes, Nantes, France.
12
INSERM UMRS 791, Laboratoire d'ingénierie Ostéo-Articulaire et Dentaire (LIOAD), Nantes, France; University of Nantes, UFR Odontologie, Nantes, France.
13
Nantes University Hospital-CHU de Nantes, PHU4 OTONN, Nantes, France.
14
Centre d'investigation clinique (CIC) Biotherapy, Nantes University Hospital-CHU de Nantes, Nantes, France.
15
Avantea Foundation, Cremona, Italy.
16
Transplantation Immunology Unit, Department of Transfusion Medicine, University of Padua-Ospedale Giustinianeo, Padua, Italy.
17
CORIT (Consortium for Research in Organ Transplantation), Padua, Italy.
18
Avantea Laboratory of Reproductive Technologies, Cremona, Italy jean-marie.bach@oniris-nantes.fr soulillou@yahoo.fr cesaregalli@avantea.it.
19
Department of Veterinary Medical Sciences, University of Bologna, Ozzano Emilia, Italy.
20
University of Nantes, Nantes, France jean-marie.bach@oniris-nantes.fr soulillou@yahoo.fr cesaregalli@avantea.it.
21
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.

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.

PMID:
28082457
DOI:
10.2337/db16-1060
[Indexed for MEDLINE]
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