Induction of chimerism permits low-dose islet grafts in the liver or pancreas to reverse refractory autoimmune diabetes.
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.


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 beta-cell proliferation, beta-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 beta-cell replication rate, better beta-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.
Departments of Diabetes Research and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, California, USA.
Chunyan
C
Zhang
Miao
M
Wang
Jeremy J
JJ
Racine
Hongjun
H
Liu
Chia-Lei
CL
Lin
Indu
I
Nair
Joyce
J
Lau
Yu-An
YA
Cao
Ivan
I
Todorov
Mark
M
Atkinson
Defu
D
Zeng
D000681:Amylases / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000276:immunology; D002455:Cell Division; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery*; D005260:Female; D005786:Gene Expression Regulation; D006085:Graft Survival; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000637:transplantation; D016381:Islets of Langerhans Transplantation / Q000379:methods / Q000502:physiology*; D008099:Liver / Q000601:surgery; D008156:Luciferases / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009928:Organ Specificity; D010179:Pancreas / Q000601:surgery; D018183:Transplantation Chimera
D001786:Blood Glucose; D007166:Immunosuppressive Agents; D008156:Luciferases; D000681:Amylases