Transfection of human pancreatic islets with an anti-apoptotic gene (bcl-2) protects β-cells from cytokine-induced destruction

Alex Rabinovitch, Wilma Suarez-Pinzon, Ken Strynadka, Qida Ju, Diane Edelstein, Michael Brownlee, Gregory S. Korbutt, Ray V. Rajotte

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177 Scopus citations

Abstract

Apoptosis has been identified as a mechanism of pancreatic islet β- cell death in autoimmune diabetes. Proinflammatory cytokines are candidate mediators of β-cell death in autoimmune diabetes, and these cytokines can induce β-cell death by apoptosis. In the present study, we examined whether transfection of human islet β-cells with an anti-apoptotic gene, bcl-2, can prevent cytokine-induced β-cell destruction. Human islet β-cells were transfected by a replication-defective herpes simplex virus (HSV) amplicon vector that expressed the bcl-2 gene (HSVbcl-2) and, as a control, the same HSV vector that expressed a β-galactosidase reporter gene (HSVlac). Two- color immunohistochemical staining revealed that 95 ± 3% of β-cells transfected with HSVbcl-2 expressed Bcl-2 protein compared with 14 ± 3% of β-cells transfected with HSVlac and 19 ± 4% of nontransfected β-cells. The bcl-2-transfected β-cells were fully protected from impaired insulin secretion and destruction resulting from incubation for 5 days with the cytokine combination of interleukin (IL)-1β, tumor necrosis factor (TNF)- α, and interferon (IFN)-γ. In addition, the bcl-2-transfected islet cells were significantly protected from cytokine-induced lipid peroxidation and DNA fragmentation. These results demonstrate that cytokine-induced β-cell dysfunction and death involve mechanisms subject to regulation by an anti- apoptotic protein, Bcl-2. Therefore, bcl-2 gene therapy has the potential to protect human β-cells in pancreatic islets, or islet grafts, from immune- mediated damage in type 1 diabetes.

Original languageEnglish (US)
Pages (from-to)1223-1229
Number of pages7
JournalDiabetes
Volume48
Issue number6
DOIs
StatePublished - Jun 1 2000

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Rabinovitch, A., Suarez-Pinzon, W., Strynadka, K., Ju, Q., Edelstein, D., Brownlee, M., Korbutt, G. S., & Rajotte, R. V. (2000). Transfection of human pancreatic islets with an anti-apoptotic gene (bcl-2) protects β-cells from cytokine-induced destruction. Diabetes, 48(6), 1223-1229. https://doi.org/10.2337/diabetes.48.6.1223