title: Early islet damage after direct exposure of pig islets to blood: has humoral immunity been underestimated?
abstract: Currently, islet transplantation as a cell therapeutic option for type 1 diabetes occurs via islet injection into the portal vein. Direct contact between islets and blood is a pathophysiological "provocation" that results in the instant blood-mediated inflammatory reaction  (IBMIR) and is associated with early islet loss. However, the nature of the various insults on the islets in the blood stream remains mostly unknown. To gain insight into the mechanisms, we utilized a simplified in vitro model in which islets were exposed to blood in different clinically relevant  but increasingly challenging, autologous, allogeneic, and xenogeneic combinations. Irrespective of the blood type and species compatibility, islets triggered blood clotting. Islet damage was worse as islet, and blood compatibility diminished, with substantial islet injury after exposure of  porcine islets to human blood. Islet damage involved membrane leakage, antibody deposition, complement activation, positive staining for the membrane attack complex, and mitochondrial dysfunction. Islet damage occurred even after exposure to plasma only, and specific complement inactivation  and neutralization of IgM substantially prevented islet damage, indicating the importance of humoral immunity. Efficacious measures are needed to reduce this injury, especially in view of a potential clinical use of porcine islets to treat diabetes.
authors: Division of Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
authors: Dirk J
authors: DJ
authors: van der Windt
authors: Marco
authors: M
authors: Marigliano
authors: Jing
authors: J
authors: He
authors: Tatyana V
authors: TV
authors: Votyakova
authors: Gabriel J
authors: GJ
authors: Echeverri
authors: Burcin
authors: B
authors: Ekser
authors: David
authors: D
authors: Ayares
authors: Fadi G
authors: FG
authors: Lakkis
authors: David K C
authors: DK
authors: Cooper
authors: Massimo
authors: M
authors: Trucco
authors: Rita
authors: R
authors: Bottino
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000276:immunology; D002096:C-Peptide / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003167:Complement Activation / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D006801:Humans; D056724:Immunity, Humoral; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism; D013552:Swine
chemical_list: D002096:C-Peptide; D015938:Complement Membrane Attack Complex; D007074:Immunoglobulin G; D007075:Immunoglobulin M