Induction of Chimerism Permits Low-Dose Islet Grafts in the Liver or Pancreas to Reverse Refractory Autoimmune Diabetes
- Chunyan Zhang1,
- Miao Wang1,
- Jeremy J. Racine1,2,
- Hongjun Liu1,
- Chia-Lei Lin1,
- Indu Nair1,
- Joyce Lau3,
- Yu-An Cao4,
- Ivan Todorov1,2,
- Mark Atkinson5 and
- Defu Zeng1,2
- 1Departments of Diabetes Research and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, California;
- 2Irell and Manella Graduate School of Biological Sciences of City of Hope, Duarte, California;
- 3Eugene and Ruth Roberts Summer Student Academy of City of Hope, Duarte, California;
- 4Stanford University School of Medicine, Stanford, California;
- 5University of Florida College of Medicine, Gainesville, Florida.
- Corresponding author: Defu Zeng, .
C.Z. and M.W. contributed equally to this study.
OBJECTIVE To test whether induction of chimerism lowers the amount of donor islets required for reversal of diabetes and renders the pancreas a suitable site for islet grafts in autoimmune diabetic mice.
RESEARCH DESIGN AND METHODS The required donor islet dose for reversal of diabetes in late-stage diabetic NOD mice after transplantation into the liver or pancreas was compared under immunosuppression or after induction of chimerism. Recipient mice were monitored for blood glucose levels and measured for insulin-secretion capacity. Islet grafts were evaluated for β-cell proliferation, β-cell functional gene expression, and revascularization.
RESULTS With immunosuppression, transplantation of 1,000, but not 600, donor islets was able to reverse diabetes when transplanted into the liver, but transplantation of 1,000 islets was not able to reverse diabetes when transplanted into the pancreas. In contrast, after induction of chimerism, transplantation of as few as 100 donor islets was able to reverse diabetes when transplanted into either the liver or pancreas. Interestingly, when lower doses (50 or 25) of islets were transplanted, donor islets in the pancreas were much more effective in reversal of diabetes than in the liver, which was associated with higher β-cell replication rate, better β-cell functional gene expression, and higher vascular density of graft islets in the pancreas.
CONCLUSIONS Induction of chimerism not only provides immune tolerance to donor islets, but also markedly reduces the required amount of donor islets for reversal of diabetes. In addition, this process renders the pancreas a more superior site than the liver for donor islets in autoimmune mice.
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- Received March 31, 2010.
- Accepted May 24, 2010.
- © 2010 by the American Diabetes Association.
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