title: Human Recombinant Antithrombin (ATryn®) Administration Improves Survival and Prevents Intravascular Coagulation After Intraportal Islet Transplantation in a Piglet Model.
abstract: Human islet transplantation is a viable treatment option for type 1 diabetes mellitus (T1DM). However, pancreatic islet inflammation after transplantation induced by innate immune responses is likely to hinder graft function. This is mediated by incompatibility between islets and the blood interface, known as instant blood-mediated inflammatory reaction (IBMIR). Herein we hypothesized that portal venous administration of islet cells with human recombinant antithrombin (ATryn®), a serine protease inhibitor (serpin), which plays a central role in the physiological regulation of coagulation and exerts indirect anti-inflammatory activities, may offset coagulation abnormalities such as disseminated intravascular coagulation (DIC) and IBMIR. The current prospective, randomized experiment was conducted using an established preclinical pig model. Three groups were constituted for digested pancreatic tissue transplantation (0.15 ml/kg): control, NaCl 0.9% (n = 7); gold standard, heparin (25 UI/kg) (n = 7); and human recombinant ATryn® (500 UI/kg) (n = 7). Blood samples were collected over time (T0 to 24 h), and biochemical, coagulation, and inflammatory parameters were evaluated. In both the control and heparin groups, one animal died after a portal thrombosis, while no deaths occurred in the ATryn®-treated group. As expected, islet transplantation was associated with an increase in plasma IL-6 or TNF-α levels in all three groups. However, DIC was only observed in the control group, an effect that was suppressed after ATryn® administration. ATryn® administration increased antithrombin activity by 800%, which remained at 200% for the remaining period of the study, without any hemorrhagic complications. These studies suggest that coadministration of ATryn® and pancreatic islets via intraportal transplantation may be a valuable therapeutic approach for DIC without risk for islets and subjects.
authors.forename: Valery
authors.initials: V
authors.lastname: Gmyr
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonner
authors.forename: Ericka
authors.initials: E
authors.lastname: Moerman
authors.forename: Antoine
authors.initials: A
authors.lastname: Tournoys
authors.forename: Nathalie
authors.initials: N
authors.lastname: Delalleau
authors.forename: Audrey
authors.initials: A
authors.lastname: Quenon
authors.forename: Julien
authors.initials: J
authors.lastname: Thevenet
authors.forename: Mikael
authors.initials: M
authors.lastname: Chetboun
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr-Conte
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.forename: Thomas
authors.initials: T
authors.lastname: Hubert
authors.forename: Merce
authors.initials: M
authors.lastname: Jourdain
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D015850:Interleukin-6 / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000379:methods*; D053208:Kaplan-Meier Estimate; D011446:Prospective Studies; D011897:Random Allocation; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000990:Antithrombin III