title: Dual islet transplantation modeling of the instant blood-mediated inflammatory reaction.
abstract: Islet xenotransplantation is a potential treatment for diabetes without the limitations of tissue availability. Although successful experimentally, early islet loss remains substantial and attributed to an instant blood-mediated inflammatory reaction (IBMIR). This syndrome of islet destruction has been incompletely defined and characterization in pig-to-primate models has been hampered by logistical and statistical limitations of large animal studies. To further investigate IBMIR, we developed a novel in vivo dual islet transplant model to precisely characterize IBMIR as proof-of-concept that this model can serve to properly control experiments comparing modified xenoislet preparations. WT and α1,3-galactosyltransferase knockout (GTKO) neonatal porcine islets were studied in nonimmunosuppressed rhesus macaques. Inert polyethylene microspheres served as a control for the effects of portal embolization. Digital analysis of immunohistochemistry targeting IBMIR mediators was performed at 1 and 24 h after intraportal islet infusion. Early findings observed in transplanted islets include complement and antibody deposition, and infiltration by neutrophils, macrophages and platelets. Insulin, complement, antibody, neutrophils, macrophages and platelets were similar between GTKO and WT islets, with increasing macrophage infiltration at 24 h in both phenotypes. This model provides an objective and internally controlled study of distinct islet preparations and documents the temporal histology of IBMIR.
authors.affiliation: Emory Transplant Center, Emory University School of Medicine, Atlanta, GA.
authors.forename: B M
authors.initials: BM
authors.lastname: Martin
authors.forename: K P
authors.initials: KP
authors.lastname: Samy
authors.forename: M C
authors.initials: MC
authors.lastname: Lowe
authors.forename: P W
authors.initials: PW
authors.lastname: Thompson
authors.forename: J
authors.initials: J
authors.lastname: Cano
authors.forename: A B
authors.initials: AB
authors.lastname: Farris
authors.forename: M
authors.initials: M
authors.lastname: Song
authors.forename: C R
authors.initials: CR
authors.lastname: Dove
authors.forename: F V
authors.initials: FV
authors.lastname: Leopardi
authors.forename: E A
authors.initials: EA
authors.lastname: Strobert
authors.forename: J B
authors.initials: JB
authors.lastname: Jenkins
authors.forename: B H
authors.initials: BH
authors.lastname: Collins
authors.forename: C P
authors.initials: CP
authors.lastname: Larsen
authors.forename: A D
authors.initials: AD
authors.lastname: Kirk
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001786:Blood Glucose / Q000737:chemistry; D001792:Blood Platelets / Q000276:immunology; D003167:Complement Activation; D004195:Disease Models, Animal; D005700:Galactosyltransferases / Q000235:genetics; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology*; D007515:Islets of Langerhans / Q000166:cytology*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008253:Macaca mulatta; D008264:Macrophages / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D010641:Phenotype; D013552:Swine; D013997:Time Factors; D014183:Transplantation, Heterologous
chemical_list: D001786:Blood Glucose; D005700:Galactosyltransferases; C530267:alpha-1,3-galactosyltransferase 1, porcine
keywords: animal models: nonhuman primate; animal models: porcine; basic (laboratory) research / science; islet transplantation; islets of Langerhans; xenotransplantation