Overview

Also Known As:NOD.B.2m^null.HHD, NOD.beta2m-.HHD, NOD.Β2m^null.HHD, NOD.B2m^null, HHD

This strain is currently unavailable due to replenishing of cryopreserved stocks. Interested customers can register interest.

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

Donating Investigator

Dr. David Serreze, The Jackson Laboratory

Genetic overview

Genetic Background	Generation

B2m^tm1Unc

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	B2m	beta-2 microglobulin

Allele Type
Transgenic (Inserted expressed sequence, Humanized sequence)

Research Applications

Hematological Research
Internal/Organ Research
Immunology, Inflammation and Autoimmunity Research
Research Tools
Metabolism Research
Diabetes and Obesity Research

View All Research Applications

Details

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.

Expression Data

Expressed Gene	B2M, beta-2-microglobulin, human
Expressed Gene	HLA-A, major histocompatibility complex, class I, A, human
Site of Expression

Selected References

Serreze DV; Marron MP; Dilorenzo TP. 2007. 'Humanized' HLA transgenic NOD mice to identify pancreatic beta cell autoantigens of potential clinical relevance to type 1 diabetes. Ann N Y Acad Sci 1103:103-11PubMed: 17376821 MGI: J:123948
Takaki T; Marron MP; Mathews CE; Guttmann ST; Bottino R; Trucco M; DiLorenzo TP; Serreze DV. 2006. HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes. J Immunol 176(5):3257-65PubMed: 16493087 MGI: J:121685

View All References

Genetics

B2m^tm1Unc

Allele Symbol: B2m^tm1Unc

Allele Name	targeted mutation 1, University of North Carolina
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	b2m^null; beta2M-; beta2m⁰; beta2m^null; beta2m^o; beta2m^tm1Unc; beta2MKO; beta2-m-KO; I⁰; MHC-I^-
Gene Symbol and Name	B2m, beta-2 microglobulin
Gene Synonym(s)
Strain of Origin	129P2/OlaHsd
Chromosome	2
Molecular Note	Insertion of a neomycin-resistance gene into the second exon.
Mutations Made By	Dr. Oliver Smithies, University of North Carolina at Chapel Hill

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

Allele Symbol: Tg(HLA-A/H2-D/B2M)1Dvs

Allele Name	transgene insertion 1, David Serreze
Allele Type	Transgenic (Inserted expressed sequence, Humanized sequence)
Allele Synonym(s)	HDD; HHD
Gene Symbol and Name	Tg(HLA-A/H2-D/B2M)1Dvs, transgene insertion 1, David Serreze
Gene Synonym(s)
Promoter	HLA-A2.1, major histocompatibility complex, class I, subtype A2.1, human
Expressed Gene	B2M, beta-2-microglobulin, human
Expressed Gene	HLA-A, major histocompatibility complex, class I, A, human
Strain of Origin	NOD/ShiLtDvs
Chromosome	UN
General Note	The HDD construct was created and used to generate a differnet transgenic mouse line in J:41077.
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.
Mutations Made By	Dr. David Serreze, The Jackson Laboratory

Disease/Phenotype

Disease Terms

Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

type 1 diabetes mellitus

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: B2m^tm1Unc related

Hematological Research
- Anemia, Iron Deficiency and Transport Defects
  - hemochromatosis
Internal/Organ Research
- Liver Defects
  - hemochromatosis
Immunology, Inflammation and Autoimmunity Research
- Immunodeficiency
  - MHC class I deficiency
Research Tools
- Immunology, Inflammation and Autoimmunity Research
  - MHC class I deficiency
Metabolism Research
- Hemochromatosis
  - iron metabolism defects

Immunology, Inflammation and Autoimmunity Research
- Autoimmunity
  - Type 1 Diabetes
- HLA transgenics
Diabetes and Obesity Research
- Type 1 Diabetes (IDDM) Analysis Strains
  - NOD Transgenics
Research Tools
- Immunology, Inflammation and Autoimmunity Research
  - T cell deficiency

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: B2m^tm1Unc/B2m^tm1Unc Tg(HLA-A/H2-D/B2M)1Dvs/0
NOD.Cg-B2m Tg(HLA-A/H2-D/B2M)1Dvs

hematopoietic system phenotype

abnormal cytotoxic T cell physiology
- T cells from islets show HLA-A2-restricted cytotoxicity against human HLA-A2.1-positive human pancreatic islets, as well as mouse islets

abnormal CD8-positive, alpha-beta T cell physiology
- islet-infiltrating T cells show different patterns of recognition to various IGRP peptides; peptide 228-236 is immunodominant HLA-A2.1-binding epitope of IGRP in 12-13 week old nondiabetic female mice

decreased CD8-positive, alpha-beta T cell number
- CD8+ T cells develop, but at significantly reduced numbers (~10%) compared to NOD controls

immune system phenotype

abnormal cell-mediated immunity
- HLA-A2.1-restricted T cells from mice as young as 5 weeks of age respond to IGRP (islet-specific glucose-6-phophatase catalytic subunit-related protein) peptides

abnormal cytotoxic T cell physiology
- T cells from islets show HLA-A2-restricted cytotoxicity against human HLA-A2.1-positive human pancreatic islets, as well as mouse islets

abnormal CD8-positive, alpha-beta T cell physiology
- islet-infiltrating T cells show different patterns of recognition to various IGRP peptides; peptide 228-236 is immunodominant HLA-A2.1-binding epitope of IGRP in 12-13 week old nondiabetic female mice

decreased CD8-positive, alpha-beta T cell number
- CD8+ T cells develop, but at significantly reduced numbers (~10%) compared to NOD controls

increased susceptibility to autoimmune diabetes
- 55% of females develop type I diabetes by 30 weeks of age, with significantly accelerated onset compared with non transgenic littermates

References

Serreze DV; Marron MP; Dilorenzo TP. 2007. 'Humanized' HLA transgenic NOD mice to identify pancreatic beta cell autoantigens of potential clinical relevance to type 1 diabetes. Ann N Y Acad Sci 1103:103-11PubMed: 17376821 MGI: J:123948
Takaki T; Marron MP; Mathews CE; Guttmann ST; Bottino R; Trucco M; DiLorenzo TP; Serreze DV. 2006. HLA-A*0201-restricted T cells from humanized NOD mice recognize autoantigens of potential clinical relevance to type 1 diabetes. J Immunol 176(5):3257-65PubMed: 16493087 MGI: J:121685

Additional - B2m^tm1Unc related

Additional - Tg(HLA-A/H2-D/B2M)1Dvs related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- QPCR:Tg(HLA-A)-2
- Standard PCR:B2m
- Standard PCR:Tg(HLA-A/H2-D)
- Standard PCR:B2m
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, female mice heterozygous for the B2m^tm1Unc allele and homozygous for the transgene can be bred to males homozygous for the B2m^tm1Unc allele and transgene.
- Additional Breeding and Husbandry Support
Appearance
- albino, pink eyed
  
  Related Genotype: A/A Tyr^c/Tyr^c
Citation
When using the NOD.B2m^null, HHD mouse strain in a publication, please cite the originating article(s) and include JAX stock #006611 in your Materials and Methods section.

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This information helps us manage the colony build and better meet the broad needs of the research community.
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Terms Of Use

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Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:NOD.B.2mnull.HHD, NOD.beta2m-.HHD, NOD.Β2mnull.HHD, NOD.B2mnull, HHD

Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Expression Data

Selected References

B2mtm1Unc

Allele Symbol: B2mtm1Unc

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

Allele Symbol: Tg(HLA-A/H2-D/B2M)1Dvs

Disease Terms

Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: B2mtm1Unc related

Mammalian Phenotype Terms by Genotype

Genotype: B2mtm1Unc/B2mtm1Unc Tg(HLA-A/H2-D/B2M)1Dvs/0NOD.Cg-B2m Tg(HLA-A/H2-D/B2M)1Dvs

hematopoietic system phenotype

immune system phenotype

References

Additional - B2mtm1Unc related

Additional - Tg(HLA-A/H2-D/B2M)1Dvs related

Genotyping Protocols

Breeding Considerations

Appearance

Citation

Strain Interest Registration

Contact Information

Interest

Terms Of Use

Licensing Information

Also Known As:NOD.B.2m^null.HHD, NOD.beta2m-.HHD, NOD.Β2m^null.HHD, NOD.B2m^null, HHD

B2m^tm1Unc

Allele Symbol: B2m^tm1Unc

Genotype: B2m^tm1Unc related

Genotype: B2m^tm1Unc/B2m^tm1Unc Tg(HLA-A/H2-D/B2M)1Dvs/0
NOD.Cg-B2m Tg(HLA-A/H2-D/B2M)1Dvs

Additional - B2m^tm1Unc related