Ectopic PDX-1 expression in liver ameliorates type 1 diabetes.
Type 1 diabetes mellitus (T1DM) results from a specific autoimmune mediated destruction of the pancreatic beta-cells. PDX-1 induced developmentally redirected liver cells were suggested to restore the ablated pancreatic function in chemically induced diabetes. However, developmentally redirected liver cells, may have acquired along with the desired beta-cell characteristics and functions, also undesired sensitivity to autoimmune attack and therefore may be inefficient in ameliorating T1DM. This study analyzes whether subjects with beta-cell autoimmunity could benefit from Ad-CMV-PDX-1 gene therapy. Using the model of cyclophosphamide-accelerated diabetes in non-obese diabetic (CAD-NOD) mice, we report that recombinant adenovirus mediated PDX-1 gene therapy, ameliorates hyperglycemia in CAD-NOD mice. Our data demonstrate that 43% of the overtly diabetic CAD-NOD mice treated with Ad-CMV-PDX-1 became normoglycemic and maintained a stable body weight. Ectopic PDX-1 expression induced pancreatic gene expression and insulin production in the mice livers. The amelioration of hyperglycemia, in PDX-1 treated diabetic mice was associated with an immune modulation manifested by Th1 to Th2 shift in the autoimmune T-cell response to antigens associated with NOD diabetes. Thus, liver-to-pancreas transdifferentiation ameliorates T1DM in a process which is associated with a concomitant modulation of the autoimmune attack. Our findings suggest a beneficial therapeutic effect of the PDX-1 gene therapy for treating autoimmune type 1 diabetes mellitus (T1DM).
Shternhall-Ron
Keren
K
The Endocrine Institute, Sheba Medical Ctr., Tel-Hashomer 52621, Israel.
Quintana
Francisco J
FJ
Perl
Shira
S
Meivar-Levy
Irit
I
Barshack
Iris
I
Cohen
Irun R
IR
Ferber
Sarah
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015551:Autoimmunity; D002851:Chromatography, High Pressure Liquid; D003520:Cyclophosphamide / Q000276:immunology / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000096:biosynthesis / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D003520:Cyclophosphamide