Prevention of type 1 diabetes by gene therapy
Chaorui Tian, Jessamyn Bagley, Nathalie Cretin, Nilufer Seth, Kai W. Wucherpfennig, John Iacomini
Chaorui Tian, Jessamyn Bagley, Nathalie Cretin, Nilufer Seth, Kai W. Wucherpfennig, John Iacomini
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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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Subcellular localization of retrovirally encoded I-Aβ chains. (A) Retrov...
Subcellular localization of retrovirally encoded I-Aβ chains. (A) Retrovirally encoded I-Aβ chains are expressed on the surface of MHC class II_positive cells. PBMCs were harvested from NOD mice reconstituted with either MMP-GFP_transduced (top panels) or MMP-IAβ-d-GFP_transduced bone marrow (bottom panels), fixed, and stained with antibodies specific for GFP (left panels, green) and I-Ad (middle panels, red). The anti_I-Ad antibody used cross-reacts with I-Ag7. Right panels: Overlay images showing colocalization of retrovirally encoded I-Ad_GFP fusion proteins with endogenous I-Ag7 on the surface in yellow. (B) Retrovirally encoded I-Aβ chains are expressed in the cytoplasm of surface-MHC class II negative cells. PBMCs from NOD mice reconstituted with MMP-IAβ-d-GFP_transduced bone marrow were fixed and stained with antibodies specific for GFP (left panel, green) and anti-CD3 (middle panel, red). An overlay of the 2 images is shown in the right panel, demonstrating that I-Aβd_GFP does not colocalize with CD3 on the cell surface of MHC class II_negative cells. Shown are representative results of 3 independent experiments.