Cytoprotection of pancreatic islets before and soon after transplantation by gene transfer of the anti-apoptotic Bcl-2 gene

被引:76
作者
Contreras, JL
Bilbao, G
Smyth, CA
Jiang, XL
Eckhoff, DE
Jenkins, SM
Thomas, FT
Curiel, DT
Thomas, JM
机构
[1] Univ Alabama Birmingham, Transplant Ctr, Transplant Immunobiol Div, Birmingham, AL 35294 USA
[2] Univ Alabama Birmingham, Dept Med, Div Human Gene Therapy, Birmingham, AL 35294 USA
[3] Univ Alabama Birmingham, Dept Surg, Birmingham, AL 35294 USA
[4] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA
关键词
D O I
10.1097/00007890-200104270-00001
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Isolated pancreatic islet transplantation is a promising alternative to conventional insulin-dependent diabetes treatment but is not yet a practical clinical therapy. In the first few days after pancreatic islet transplantation, substantial donor pancreatic islet dysfunction and apoptosis commonly occur. Islet apoptosis has been documented after extracellular matrix disruption and exposure to proinflammatory cytokines, and during hypoxia before islet revascularization and rejection. These studies show that targeting the apoptosis pathway by adenoviral-mediated gene transfer of the anti-apoptotic Bcl-2 gene exerts a major cytoprotective effect on isolated macaque pancreatic islets. Bcl-2 transfection ex vivo protects these islets from apoptosis induced by disruption of the islet extracellular matrix during pancreatic digestion. Additionally, overexpression of Bcl-2 confers long-term, stable protection and maintenance of functional islet mass after transplantation of macaque islets into diabetic severe combined immunodeficency mice. Notably, genetic modification of pancreatic islets also reduced the islet mass required to achieve stable euglycemia. Ex vivo gene transfer of anti-apoptotic genes has potential as a therapeutic approach to both minimize loss of functional islet mass after transplant and reduce the high donor islet requirement currently needed for successful stable reversal of insulin-dependent diabetes.
引用
收藏
页码:1015 / 1023
页数:9
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