α1-Antitrypsin Gene Therapy Modulates Cellular Immunity and Efficiently Prevents Type 1 Diabetes in Nonobese Diabetic Mice
- 1 June 2006
- journal article
- research article
- Published by Mary Ann Liebert Inc in Human Gene Therapy
- Vol. 17 (6), 625-634
- https://doi.org/10.1089/hum.2006.17.625
Abstract
An imbalance of the immune-regulatory pathways plays an important role in the development of type 1 diabetes. Therefore, immunoregulatory and antiinflammatory strategies hold great potential for the prevention of this autoimmune disease. Studies have demonstrated that two serine proteinase inhibitors, α1-antitrypsin (AAT) and elafin, act as potent antiinflammatory agents. In the present study, we sought to develop an efficient gene therapy approach to prevent type 1 diabetes. Cohorts of 4-week-old female nonobese diabetic (NOD) mice were injected intramuscularly with rAAV1-CB-hAAT, rAAV1-CB-hElafin, or saline. AAV1 vector mediated sustained high levels of transgene expression, sufficient to overcome a humoral immune response against hAAT. AAT gene therapy, contrary to elafin and saline, was remarkably effective in preventing type 1 diabetes. T cell receptor spectratyping indicated that AAT gene therapy altered T cell repertoire diversity in splenocytes from NOD mice. Adoptive transfer experiments demonstrated that AAT gene therapy attenuated cellular immunity associated with beta cell destruction. This study demonstrates that AAT gene therapy attenuates cell-mediated autoimmunity, alters the T cell receptor repertoire, and efficiently prevents type 1 diabetes in the NOD mouse model. These results strongly suggest that rAAV1-mediated AAT gene therapy may be useful as a novel approach to prevent type 1 diabetes.Keywords
This publication has 42 references indexed in Scilit:
- Therapeutic level of functional human alpha 1 antitrypsin (hAAT) secreted from murine muscle transduced by adeno-associated virus (rAAV1) vectorThe Journal of Gene Medicine, 2006
- Inhibition of lipopolysaccharide-mediated human monocyte activation, in vitro, by α1-antitrypsinBiochemical and Biophysical Research Communications, 2004
- CD25+ CD4+ T Cells, Expanded with Dendritic Cells Presenting a Single Autoantigenic Peptide, Suppress Autoimmune DiabetesThe Journal of Experimental Medicine, 2004
- In Vitro–expanded Antigen-specific Regulatory T Cells Suppress Autoimmune DiabetesThe Journal of Experimental Medicine, 2004
- 1-Antitrypsin deficiency * 4: Molecular pathophysiologyThorax, 2004
- Immunity to adeno-associated virus serotype 2 delivered transgenes imparted by genetic predisposition to autoimmunityGene Therapy, 2004
- Recombinant adeno-associated virus-mediated alpha-1 antitrypsin gene therapy prevents type I diabetes in NOD miceGene Therapy, 2004
- Safety and efficacy of factor IX gene transfer to skeletal muscle in murine and canine hemophilia B models by adeno-associated viral vector serotype 1Blood, 2004
- A review and comparison of the murine α1-antitrypsin and α1-antichymotrypsin multigene clusters with the human clade A serpinsGenomics, 2003
- Stable therapeutic serum levels of human alpha-1 antitrypsin (AAT) after portal vein injection of recombinant adeno-associated virus (rAAV) vectorsGene Therapy, 2001