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

Zhang C, Wang M, Racine JJ, Liu H, Lin CL, Nair I, Lau J, Cao YA, Todorov I, Atkinson M, Zeng D - Diabetes (2010)

Bottom Line: Islet grafts were evaluated for beta-cell proliferation, beta-cell functional gene expression, and revascularization.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.In addition, this process renders the pancreas a more superior site than the liver for donor islets in autoimmune mice.

View Article: PubMed Central - PubMed

Affiliation: Departments of Diabetes Research and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, California, USA.

ABSTRACT

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 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.

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Related in: MedlinePlus

Transplantation of a large number of donor islets was needed to reverse diabetes in immunosuppressant-treated late-stage diabetic NOD mice. Late-stage diabetic NOD mice were transplanted with 1,000 or 600 islets from FVB/N mice into the liver (A) or the pancreas (B) after the mice were given immunosuppressant therapy. The recipients were monitored twice weekly for blood glucose for 30 days after transplantation. For recipients with 600 donor islets in the liver or 1,000 donor islets in the pancreas, exogenous insulin was used to ensure the survival of the recipients after transplantation. If a recipient's blood glucose was >500 mg/dl, the mouse was injected with insulin (1 unit daily) for the subsequent 5 days, and injections were stopped 2 days before blood glucose measuring. There were 6 recipients in each group.
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Figure 1: Transplantation of a large number of donor islets was needed to reverse diabetes in immunosuppressant-treated late-stage diabetic NOD mice. Late-stage diabetic NOD mice were transplanted with 1,000 or 600 islets from FVB/N mice into the liver (A) or the pancreas (B) after the mice were given immunosuppressant therapy. The recipients were monitored twice weekly for blood glucose for 30 days after transplantation. For recipients with 600 donor islets in the liver or 1,000 donor islets in the pancreas, exogenous insulin was used to ensure the survival of the recipients after transplantation. If a recipient's blood glucose was >500 mg/dl, the mouse was injected with insulin (1 unit daily) for the subsequent 5 days, and injections were stopped 2 days before blood glucose measuring. There were 6 recipients in each group.

Mentions: It was reported that islet grafts functioned better in the pancreas than in the liver in nonautoimmune recipients (15,16). However, it is not yet clear whether the pancreas of the autoimmune recipients can be used as a site of donor islets. Under immunosuppressant therapy, 600 or 1,000 donor islets were required to reverse diabetes in diabetic NOD mice (39,40). Therefore, we transplanted 600 or 1,000 donor islets into the liver or pancreas of the late-stage diabetic NOD mice, while immunosuppressant therapy of Edmonton protocol was used to prevent graft rejection. Harvesting 1,000 islets required ∼5 donors because the average yield in our studies was 209 ± 8 per donor (mean ± SE, N = 20), which was similar to a previous report (41). We observed that although 1,000 donor islets implanted in the liver were able to reverse diabetes in all (6 of 6) of the recipients, the same amount of donor islets implanted in the pancreas did not reverse diabetes (0 of 6) (P < 0.001, Fig. 1A and B). Lowering the donor islet dose to 600 in the liver also resulted in an inability to stably reverse diabetes (Fig. 1A). These results indicate that under this form of immunosuppressant therapy, the pancreas of the autoimmune NOD mice is not a suitable site for donor islets.


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

Zhang C, Wang M, Racine JJ, Liu H, Lin CL, Nair I, Lau J, Cao YA, Todorov I, Atkinson M, Zeng D - Diabetes (2010)

Transplantation of a large number of donor islets was needed to reverse diabetes in immunosuppressant-treated late-stage diabetic NOD mice. Late-stage diabetic NOD mice were transplanted with 1,000 or 600 islets from FVB/N mice into the liver (A) or the pancreas (B) after the mice were given immunosuppressant therapy. The recipients were monitored twice weekly for blood glucose for 30 days after transplantation. For recipients with 600 donor islets in the liver or 1,000 donor islets in the pancreas, exogenous insulin was used to ensure the survival of the recipients after transplantation. If a recipient's blood glucose was >500 mg/dl, the mouse was injected with insulin (1 unit daily) for the subsequent 5 days, and injections were stopped 2 days before blood glucose measuring. There were 6 recipients in each group.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927945&req=5

Figure 1: Transplantation of a large number of donor islets was needed to reverse diabetes in immunosuppressant-treated late-stage diabetic NOD mice. Late-stage diabetic NOD mice were transplanted with 1,000 or 600 islets from FVB/N mice into the liver (A) or the pancreas (B) after the mice were given immunosuppressant therapy. The recipients were monitored twice weekly for blood glucose for 30 days after transplantation. For recipients with 600 donor islets in the liver or 1,000 donor islets in the pancreas, exogenous insulin was used to ensure the survival of the recipients after transplantation. If a recipient's blood glucose was >500 mg/dl, the mouse was injected with insulin (1 unit daily) for the subsequent 5 days, and injections were stopped 2 days before blood glucose measuring. There were 6 recipients in each group.
Mentions: It was reported that islet grafts functioned better in the pancreas than in the liver in nonautoimmune recipients (15,16). However, it is not yet clear whether the pancreas of the autoimmune recipients can be used as a site of donor islets. Under immunosuppressant therapy, 600 or 1,000 donor islets were required to reverse diabetes in diabetic NOD mice (39,40). Therefore, we transplanted 600 or 1,000 donor islets into the liver or pancreas of the late-stage diabetic NOD mice, while immunosuppressant therapy of Edmonton protocol was used to prevent graft rejection. Harvesting 1,000 islets required ∼5 donors because the average yield in our studies was 209 ± 8 per donor (mean ± SE, N = 20), which was similar to a previous report (41). We observed that although 1,000 donor islets implanted in the liver were able to reverse diabetes in all (6 of 6) of the recipients, the same amount of donor islets implanted in the pancreas did not reverse diabetes (0 of 6) (P < 0.001, Fig. 1A and B). Lowering the donor islet dose to 600 in the liver also resulted in an inability to stably reverse diabetes (Fig. 1A). These results indicate that under this form of immunosuppressant therapy, the pancreas of the autoimmune NOD mice is not a suitable site for donor islets.

Bottom Line: Islet grafts were evaluated for beta-cell proliferation, beta-cell functional gene expression, and revascularization.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.In addition, this process renders the pancreas a more superior site than the liver for donor islets in autoimmune mice.

View Article: PubMed Central - PubMed

Affiliation: Departments of Diabetes Research and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, California, USA.

ABSTRACT

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 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.

Show MeSH
Related in: MedlinePlus