Accumulation of Intrahepatic Islet Amyloid in a Nonhuman Primate Transplant Model

作者：Liu Chengyang; Koeberlein Brigitte; Feldman Michael D; Mueller Rebecca; Wang Zhonglin; Li Yanjing; Lane Kristin; Hoyt Clifford C; Tomaszewski John E; Naji Ali; Rickels Michael R^*

来源：Endocrinology, 2012, 153(4): 1673-1683.

DOI：10.1210/en.2011-1560

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 beta-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, beta-cell secretory capacity declined over time coincident with increasing amyloid severity and decreasing beta-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 beta-cell mass and function and support the development of intrahepatic islet amyloid as a potential mechanism for nonimmunologic islet graft loss. (Endocrinology 153: 1673-1683, 2012)

• 出版日期2012-4