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The role of islet amyloid and CHOP in islet graft dysfunction and failure

University of British Columbia

Islet transplantation has great promise as a treatment for patients with insulin-dependent diabetes but its long-term success is limited by progressive graft dysfunction. Many measures of cell dysfunction in transplantation are similar to those observed in the type 2 diabetic cell. We focused upon two particular genes underlying pathology of the latter, namely islet amyloid polypeptide (IAPP) and C/EBP homologous protein (CHOP). We hypothesized that CHOP and islet amyloid composed of IAPP played distinct roles in progressive dysfunction and loss of the transplanted cell. Human islets and murine islets expressing the IAPP transgene developed islet amyloid following transplantation. Amyloid deposition correlated with loss of glycemic control and was exacerbated by transplantation of a marginal islet mass. Further, pre-existing amyloid in human islets prior to transplantation correlated with graft dysfunction at one year following islet transplantation into human allograft recipients. We tested several strategies to protect against islet amyloid toxicity in a pre-clinical model of human islet culture. Human IAPP deposition and toxicity was abrogated by siRNA against IAPP and by peptide inhibitors of IAPP aggregation. As an alternate strategy, transplantation of porcine islets expressing minimally amyloidogenic forms of IAPP yields excellent long-term outcomes. Islet amyloid deposition and toxicity is particularly rapid in the transplanted islet. This phenomenon may relate to factors in the transplant environment. We demonstrated that heparin, used in clinical islet transplantation, potentiates amyloid deposition in human islets. In addition, it exacerbates IAPP toxicity to cultured cells and accelerates graft failure in marginal mass human islet grafts. CHOP is activated by prolonged endoplasmic reticulum or oxidative stress. We demonstrated that CHOP immunostaining is increased in marginal mass islet grafts. Transplantation of islets in which CHOP has been deleted or silenced by RNA significantly improves glycemic normalization in marginal mass grafts and reduces apoptosis. These data suggest that CHOP plays a detrimental role in islet graft dysfunction. These studies demonstrate a role for two independent non-immune factors in mediating islet graft dysfunction and for which therapeutic modulation may improve cell function and survival in both islet transplantation and type 2 diabetes.

Text

2012-02-29

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/36528

Pathology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/