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Neu5Gc and a1-3 GAL Xenoantigen Knockout Does Not Affect Glycemia Homeostasis and Insulin Secretion in Pigs

Apolline Salama 1, 2, 3, 4 Mathilde Mosser 2 Xavier Lévêque 2 Andrea Perota 5 Jean-Paul Judor 1, 4 Corentin Danna 2 Sylvie Pogu 2 Anne Mouré 2 Dominique Jégou 2 Nicolas Gaide 6 Jérôme Abadie 6 Olivier Gauthier 7 Jean-Paul Concordet 8 Stéphanie Le Bas-Bernardet 1, 4 David Riochet 1, 4, 9 Ludmilla Le Berre 1, 4 Jérémy Hervouet 1, 4 David Minault 1, 4 Pierre Weiss 10, 11, 12 Jérôme Guicheux 10, 11, 12 Sophie Brouard 1, 4, 13 Steffi Bosch 2 Irina Lagutina 5 Roberto Duchi 5 Giovanna Lazzari 5, 14 Emanuele Cozzi 15, 16 Gilles Blancho 1, 4, 13 Sophie Conchon 1, 4 Cesare Galli 5, 14, 17, * Jean-Paul Soulillou 18, * Jean-Marie Bach 2
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.
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Apolline Salama, Mathilde Mosser, Xavier Lévêque, Andrea Perota, Jean-Paul Judor, et al.. Neu5Gc and a1-3 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-02156128⟩

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