title: Prevention of nonimmunologic loss of transplanted islets in monkeys.
abstract: The nonimmunologic loss of islets in the pre-, peri-, and early post-islet transplant periods is profound. To determine the potential role that transplantation of only a marginal mass of functioning beta cells may play in triggering late nonimmunologic graft loss, we studied the effect of treatment with alpha-1-antitrypsin (AAT) in the autologous cynomolgus islet transplant model. A marginal mass of autologous islets, that is islets prepared from 70% to 80% of the pancreas, was transplanted at 1600-4100 IEQ/kg into subtotal pancreatectomized, streptozotocin-treated and insulin-deficient diabetic hosts. In this marginal mass islet transplant model, islet function is insidiously lost over time and diabetes recurs in all untreated monkeys by 180 days posttransplantation. Short-term treatment with AAT, an acute phase reactant, in the peri-transplant period serves to terminate inflammation through effects upon expression of TGFβ, NFκB and AKT and favorably altering expression of cell death and survival pathways, as detected by a system biology approach and histology. These effects enabled functional expansion of the islet mass in transplanted hosts such that graft function improves rather than deteriorating over time.
authors.affiliation: Departments of Medicine and Surgery, The Transplant Institute, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA.
authors.forename: M
authors.initials: M
authors.lastname: Koulmanda
authors.forename: R S
authors.initials: RS
authors.lastname: Sampathkumar
authors.forename: M
authors.initials: M
authors.lastname: Bhasin
authors.forename: A
authors.initials: A
authors.lastname: Qipo
authors.forename: Z
authors.initials: Z
authors.lastname: Fan
authors.forename: G
authors.initials: G
authors.lastname: Singh
authors.forename: B
authors.initials: B
authors.lastname: Movahedi
authors.forename: M
authors.initials: M
authors.lastname: Duggan
authors.forename: V
authors.initials: V
authors.lastname: Chipashvili
authors.forename: T B
authors.initials: TB
authors.lastname: Strom
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000628:therapy*; D006084:Graft Rejection / Q000517:prevention & control*; D000882:Haplorhini; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology*; D016381:Islets of Langerhans Transplantation; D014182:Transplantation, Autologous; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007328:Insulin; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin
keywords: Alpha-1-antitrypsin (AAT); inflammation bioinformatics; islet transplantation; monkey