title: Accumulation of intrahepatic islet amyloid in a nonhuman primate transplant model.
abstract: Islet amyloid is hypothesized to play a role in nonimmunologic transplanted islet graft loss. We performed a quantitative histologic analysis of liver biopsies from intrahepatic islet grafts transplanted in streptozotocin-induced diabetic cynomolgus macaques. Seven animals treated with antithymocyte globulin (ATG) and rapamycin or ATG and rituximab experienced islet graft rejection with lymphocytic infiltrates present on islet graft biopsies. Except for one case involving the oldest and largest donor where amyloid was present on initial biopsy 1 month after transplant, none of the six other cases with rejection contained amyloid, including one case biopsied serially to 25 months. In contrast, four out of six animals treated with ATG and rituximab and rapamycin had no evidence of rejection at the time of biopsy (two animals that discontinued rapamycin had mild periislet lymphocytes), and all four cases followed more than 4 months demonstrated amyloid deposition at subsequent time points. Amyloid severity increased with time after transplant (r = 0.68; P < 0.05) and with decreasing islet β-cell area (r = -0.68; P < 0.05). In two islet recipients with no evidence of rejection and still normoglycemic and insulin independent at the first detection of amyloid, β-cell secretory capacity declined over time coincident with increasing amyloid severity and decreasing β-cell area, with both animals eventually becoming hyperglycemic and insulin dependent. Transplanted islet amyloid also developed in autologous islets placed sc. These results indicate that in cynomolgus macaques, transplanted islets may accumulate amyloid over time associated with subsequent decline in β-cell mass and function and support the development of intrahepatic islet amyloid as a potential mechanism for nonimmunologic islet graft loss.
authors.affiliation: Division of Transplantation, Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104-5160, USA.
authors.forename: Chengyang
authors.initials: C
authors.lastname: Liu
authors.forename: Brigitte
authors.initials: B
authors.lastname: Koeberlein
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldman
authors.forename: Rebecca
authors.initials: R
authors.lastname: Mueller
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Wang
authors.forename: Yanjing
authors.initials: Y
authors.lastname: Li
authors.forename: Kristin
authors.initials: K
authors.lastname: Lane
authors.forename: Clifford C
authors.initials: CC
authors.lastname: Hoyt
authors.forename: John E
authors.initials: JE
authors.lastname: Tomaszewski
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rickels
mesh_terms: D000818:Animals; D001706:Biopsy; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000601:surgery*; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000209:etiology / Q000378:metabolism; D058228:Islet Amyloid Polypeptide / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008252:Macaca fascicularis / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D013311:Streptozocin / Q000009:adverse effects; D013997:Time Factors
chemical_list: D058228:Islet Amyloid Polypeptide; D013311:Streptozocin