NOD/ShiLtDvs-Tg(HLA-A/H2-D/B2M)1Dvs/J

Stock number: 006604
Product name: NOD.HHD
Research areas: Diabetes and Obesity Research, Immunology, Inflammation and Autoimmunity Research

Description

These transgenic mice express a chimeric transgene containing  the alpha1 and alpha2 binding domains of the human histocompatibility complex (MHC) class I HLA-A2.1 allele covalently linked to the human B2m and the alpha3, cytoplasmic and transmembrane domains of the murine H2-D^b on the Type 1 diabetes-susceptible NOD/ShiLtDvs background.

Detailed description

This transgenic NOD mouse model, commonly referred to as NOD.HHD, develops significantly accelerated diabetes onset compared to NOD/ShiLtDvs (NOD) inbred mice. This model provides humanized T cells that will be a useful tool to identify MHC class I epitopes recognized by CD8⁺ T cells in type 1 diabetes patients and for testing new therapies focusing on restoring immune tolerance.

When transgenic mice are bred to NOD-B2m-deficient mice (e.g. Stock No. 002309), which completely lack CD8⁺ T cells, CD8⁺ T cells are restored in the double mutant mice, but at significantly lower levels than in NOD inbred mice. FACS analysis indicates that the transgenic NOD-B2m-deficient mice express only the HLA-A2.1/H2-D^b chimeric class I molecule. In contrast to NOD.B2m^tm1Unc females, which are diabetes free, 55% of the transgenic NOD B2m-deficient females develop diabetes by 30 weeks of age. Insulitis scores determined by histological examination are similar between the NOD double mutant mice and NOD/ShiLtDvs inbred mice, and cultured pancreatic islets from transgenic NOD B2m-deficient mice and from NOD inbred mice produce comparable numbers of CD8⁺ T cells. Further, the T cells isolated from the transgenic NOD B2m-deficient-derived islet cultures are HLA-A2.1 specific, and are able to recognize islet-specific antigens, such as the Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP).

NOD transgenic mice carrying the Prkdc^scid (Stock No. 006605) do not become diabetic.

Development

This transgene encodes a human B2-microglubulin (B2M) covalently linked to the MHC class 1, alpha1 and alpha2 binding domains of the human HLA-A2.1 gene and the alpha3, cytoplasmic and transmembrane domains of the murine H2-D^b. The transgene was injected into NOD/ShiLtDvs embryos. In 2007, the T1DR received this stock at N1F15. The T1DR mated to NOD/ShiLtJ once prior to sibling mating.

Allele

Symbol: Tg(HLA-A/H2-D/B2M)1Dvs
Name: transgene insertion 1, David Serreze
MGI accession ID: MGI:3711057
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: HDD; HHD
Marker symbol: Tg(HLA-A/H2-D/B2M)1Dvs
Marker name: transgene insertion 1, David Serreze
Marker synonyms: HDD; HHD
Chromosome: UN
Strain of origin: NOD/ShiLtDvs
Expressed genes: B2M,beta-2-microglobulin,human; HLA-A,major histocompatibility complex, class I, A,human
Molecular note: This transgene encodes a human B2-microglubulin (B2M) covalently linked to the MHC class 1, alpha1 and alpha2 binding domains of the human HLA-A2.1 gene, and the alpha3, cytoplasmic and transmembrane domains of the murine H2-D^b. The construct was injected into fertilized NOD/ShiLtDvs oocytes. The construct was originally described in J:41077 and used to create a different transgenic line.
General note: The HDD construct was created and used to generate a differnet transgenic mouse line in J:41077.