Prevention of type 1 diabetes by gene therapy
Chaorui Tian, … , Kai W. Wucherpfennig, John Iacomini
Chaorui Tian, … , Kai W. Wucherpfennig, John Iacomini
Published October 1, 2004
Citation Information: J Clin Invest. 2004;114(7):969-978. https://doi.org/10.1172/JCI22103.
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Article Metabolism

Prevention of type 1 diabetes by gene therapy

Abstract

The autoimmune disease type 1 diabetes in humans and NOD mice is determined by multiple genetic factors, among the strongest of which is the inheritance of diabetes-permissive MHC class II alleles associated with susceptibility to disease. Here we examined whether expression of MHC class II alleles associated with resistance to disease could be used to prevent the occurrence of diabetes. Expression of diabetes-resistant MHC class II I-Aβ chain molecules in NOD mice following retroviral transduction of autologous bone marrow hematopoietic stem cells prevented the development of autoreactive T cells by intrathymic deletion and protected the mice from the development of insulitis and diabetes. These data suggest that type 1 diabetes could be prevented in individuals expressing MHC alleles associated with susceptibility to disease by restoration of protective MHC class II expression through genetic engineering of hematopoietic stem cells.

Authors

Chaorui Tian, Jessamyn Bagley, Nathalie Cretin, Nilufer Seth, Kai W. Wucherpfennig, John Iacomini

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NOD mice reconstituted with either MMP-IAβ-d-GFP_ or MMP-IAβ-k-GFP_trans...
NOD mice reconstituted with either MMP-IAβ-d-GFP_ or MMP-IAβ-k-GFP_transduced bone marrow are protected from diabetes. (A) NOD mice were reconstituted with bone marrow retrovirally transduced with MMP-IAβ-d-GFP (open circles, n = 6), MMP-IAβ-k-GFP (×, n = 6), or control MMP-GFP (filled squares, n = 6). Shown are the percentages of normoglycemic mice at each time point after bone marrow transplantation. (B) NOD mice reconstituted with bone marrow retrovirally transduced with either MMP-IAβ-d-GFP or MMP-IAβ-k-GFP are protected from cyclophosphamide-induced diabetes. NOD mice were reconstituted with bone marrow transduced with MMP-IAβ-d-GFP (open circles, n = 12), MMP-IAβ-k-GFP (×, n = 12), or control MMP-GFP (filled squares, n = 14). Twenty-one weeks after bone marrow transplantation, mice were injected intraperitoneally with 200 mg/kg cyclophosphamide. Shown are the percentages of normoglycemic mice at each time point after bone marrow transplantation. Data in A and B are the combined results of 2 independent experiments. In all experiments, blood glucose levels were measured weekly.