NOD.Cg-B2m^tm1Unc Tg(HLA-A/H2-D/B2M)1Dvs/DvsJ

Stock number: 006611
Product name: NOD.B2m^null, HHD
Strain synonyms: NOD.B.2m^null.HHD, NOD.beta2m-.HHD, NOD.Β2m^null.HHD
Research areas: Diabetes and Obesity Research, Hematological Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Metabolism Research, Research Tools

Description

These double mutant mice uniquely express human HLA-A2.1.

Detailed description

NOD mice carrying only the HLA-A/H2-D/B2M transgene, commonly referred to as NOD.HHD, (Stock No. 006604) develop significantly accelerated diabetes onset compared to NOD/ShiLtDvs (NOD) inbred mice. This mutant stock is also homozygous for the B2m^tm1Unc mutation which normally prevents the development of of CD8⁺ T cells. The presence of the transgene in the B2m-deficient background, however, restores CD8⁺ T cells, but at a significantly lower level than in NOD inbred mice. Due to the covalently linked nature of the B2M component encoded into the transgene, the transgenic construct is unable to rescue murine MHC class 1 molecules in the NOD.B2m deficient (Stock No. 002309) mice. Thus, these double mutant mice only express human HLA-A2.1. Fifty-five percent of these NOD transgenic B2m-deficient mice develop diabetes by 30 weeks of age, while non-transgenic NOD.B2m^tm1Unc do not develop diabetes. Insulitis scores assessed via histological examination of pancreata are similar between NOD/ShiLtDvs and NOD transgenic B2m-deficient mice. Although CD8⁺ T cell numbers in NOD transgenic B2m-deficient are lower than in NOD inbred mice, comparable numbers of CD8⁺ T cells can be cultured from pancreatic islets from both strains. The infiltrating T cells cultured from the double mutant islets are HLA-A2.1-specific, and are able to recognize islet specific antigens, such as IGRP.

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

This model provides humanized T cells that will be useful tools to identify MHC class I epitopes recognized by CD8⁺ T cells in type 1 diabetes patients and for testing new therapies focused on restoring immune tolerance.

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-Db. The transgene was injected into NOD/ShiLtDvs embryos. In 2007, the T1DR received this Stock No. 006604 - NOD/ShiLtDvs-Tg(HLA-A/H2-D/B2M)1Dvs/J at generation N1F15. Stock No. 006604 was crossed to Stock No. 002309 - NOD.129P2(B6)-B2m^tm1Unc/J. The resulting offspring were sibling mated to provide double mutant HLA transgenic, B2m deficient mice.

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
Marker symbol: Tg(HLA-A/H2-D/B2M)1Dvs
Marker name: transgene insertion 1, David Serreze
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.

Allele

Symbol: B2m^tm1Unc
Name: targeted mutation 1, University of North Carolina
MGI accession ID: MGI:1857133
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: B2m
Marker name: beta-2 microglobulin
Chromosome: 2
Strain of origin: 129P2/OlaHsd
Molecular note: Insertion of a neomycin-resistance gene into the second exon.