Systemic Transforming Growth factor-beta1 Gene Therapy Induces Foxp3+ Regulatory Cells, Restores Self-Tolerance, and Facilitates Regeneration of Beta Cell Function in Overtly Diabetic Nonobese Diabetic Mice

Transplantation. 2005 May 15;79(9):1091-6. doi: 10.1097/01.tp.0000161223.54452.a2.

Abstract

Background: Type 1 diabetes results from auto-aggressive T-cell-mediated destruction of beta cells of the pancreas. Recent data suggest that restoration of self-tolerance may facilitate islet-cell regeneration/recovery. In view of the immunoregulatory activity of transforming growth factor (TGF)-beta1, we investigated whether systemic TGF-beta1 gene therapy blocks islet destructive autoimmunity and facilitates regeneration of beta-cell function in overtly diabetic nonobese diabetic (NOD) mice.

Methods: We used site-directed mutagenesis to create cysteine to serine mutation at sites 224 and 226 and constructed a replication deficient adenovirus (Ad) vector encoding active form of human TGF-beta1 (Ad-hTGF-beta1). Overtly diabetic NOD mice received intravenous injection of Ad-hTGF-beta1. Seven to 14 days after the injection, the mice received transplants with 500 syngeneic islets under the kidney capsule. Islet-graft survival and regeneration of endogenous beta-cell function were examined.

Results: Syngeneic islet grafts failed by day 17 in all untreated mice, whereas Ad-hTGF-beta1 therapy prolonged survival of islet grafts. Islet grafts from treated mice showed well-preserved islets with a peri-islet infiltrate primarily of CD4+ T cells and expression of CD25 and Foxp3. Systemic TGF-beta1 gene therapy was associated with islet regeneration in the native pancreas. Native pancreas of treated mice revealed islets staining strongly for insulin. Similar to what was found in the syngeneic islet graft, there were well-demarcated peri-islet infiltrates that were positive for CD4, TGF-beta1, and Foxp3.

Conclusions: Our data demonstrate that systemic TGF-beta1 gene therapy blocks islet destructive autoimmunity, facilitates islet regeneration, and cures diabetes in diabetic NOD mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics*
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology*
  • Disease Models, Animal
  • Extracellular Matrix Proteins / genetics*
  • Extracellular Matrix Proteins / immunology
  • Forkhead Transcription Factors
  • Genetic Therapy
  • Graft Survival / immunology*
  • Humans
  • Islets of Langerhans / physiopathology*
  • Islets of Langerhans Transplantation / immunology*
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Nephrectomy
  • Regeneration
  • Transforming Growth Factor beta / genetics*
  • Transforming Growth Factor beta / immunology

Substances

  • DNA-Binding Proteins
  • Extracellular Matrix Proteins
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Transforming Growth Factor beta
  • betaIG-H3 protein