Induction of Chimerism Permits Low-Dose Islet Grafts in the Liver or Pancreas to Reverse Refractory Autoimmune Diabetes

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. 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 beta-cell proliferation, beta-cell functional gene expression, and revascularization. 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 beta-cell replication rate, better beta-cell functional gene expression, and higher vascular density of graft islets in the pancreas. 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.