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

Apolline Salama 1, 2, 3, 4 Mathilde Mosser 3 Xavier Lévêque 3 Andrea Perota 5 Jean-Paul Judor 2, 4 Corentin Danna 3 Sylvie Pogu 3 Anne Mouré 3 Dominique Jégou 3 Nicolas Gaide 6 Jérôme Abadie 6 Olivier Gauthier 7 Jean-Paul Concordet 8 Stéphanie Le Bas-Bernardet 2, 4 David Riochet 2, 9, 4 Ludmilla Le Berre 2, 4 Jérémy Hervouet 2, 4 David Minault 2, 4 Pierre Weiss 10, 9 Jérôme Guicheux 10, 9 Sophie Brouard 2, 4, 11 Steffi Bosch 3 Irina Lagutina 5 Roberto Duchi 5 Giovanna Lazzari 5, 12 Emanuele Cozzi 13, 14 Gilles Blancho 2, 4, 11 Sophie Conchon 2, 4 Cesare Galli 15, 5, 12, * Jean-Paul Soulillou 16, * Jean-Marie Bach 3, * 
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 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.
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Submitted on : Monday, July 17, 2017 - 12:14:05 PM
Last modification on : Tuesday, September 27, 2022 - 4:26:57 AM
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Apolline Salama, Mathilde Mosser, Xavier Lévêque, Andrea Perota, Jean-Paul Judor, et al.. Neu5Gc and α1-3 GAL Xenoantigen Knockout Does Not Affect Glycemia Homeostasis and Insulin Secretion in Pigs. Diabetes, American Diabetes Association, 2017, 66 (4), pp.987-993. ⟨10.2337/db16-1060⟩. ⟨inserm-01563129⟩



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