These Ctla4 knock-out mice develop develop a fatal lymphoproliferative disorder, and are suitable for use in applications related to the regulation of self tolerance and susceptibility to autoimmune diseases.
Christophe Benoist, Joslin Diabetes Center
Genetic Background | Generation |
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001976 NOD/ShiLtJ |
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Allele Type | Gene Symbol | Gene Name |
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Targeted (Null/Knockout) | Ctla4 | cytotoxic T-lymphocyte-associated protein 4 |
Heterozygous Ctla4tm1All mice are viable, fertile, and normal in size and exhibit diabetes incidence comparable to NOD.
Ctla4tm1All homozygous mice on various backgrounds, including C57BL/6, BALB/c, 129 and NOD, die at 3-4 weeks of age due to massive polyclonal expansion of T-cells and massive lymphocyte infiltration into non-lymphoid organs, such as heart, liver, lung and pancreas. Treatment with murine Ctla4Ig or depletion of CD4+ T-cells blocks this lymphoproliferative disease. Splenic and lymph node T-cells display an activated phenotype characterized as CD69+, CD25+, CD44hi, Mel14lo, CD45RBlo and Sca1hi and have down regulated the TCR. Lymph node and spleen cells cultured from Ctla4tm1All homozygous mice spontaneously proliferate while wild-type controls do not. Cells from whole lymph nodes or purified T-cells are unresponsive to anti CD28mAb stimulation, while rIl2 increases the proliferative response. Homozygous Ctla4tm1All NOD mice also transgenically expressing the BDC2.5 alpha and beta TCR chains do not exhibit the lymphoproliferative phenotype. Other TCR transgenes exert a similar effect on differing backgrounds. However, all of the mice develop aggressive autoimmunity and rapidly develop diabetes by7 weeks of age.In contrast, mice heterozygous for Ctla4tm1All and transgenically expressing the BDC2.5 TCR have late and relatively rare diabetes.
NOD.129(B6)-Ctla4tm1All/DoiJ may be useful for studying the role of Ctla4/Cd28:Cd80/Cd86 in the regulation of self tolerance and susceptibility to autoimmune diseases.
A construct containing a neomycin expression cassette inserted into exon 3 of Ctla4 (cloned from 129/Sv mouse) was transfected into R1 ((129X1/SvJ x 129S1/Sv)F1-Kitl +) embryonic stem cells (ES cells). These ES cells were injected into C57BL/6 blastocysts. To establish a colony and germ line transmission chimeric mice were backcrossed to C57BL/6 (Chambers et, al, 1997). Luhder et al. 2000, subsequently backcrossed this mutation to NOD/LtJ. In 2004, the Type 1 Diabetes Resource received NOD.129(B6)- Ctla4tm1All /DoiJ heterozygotes at generation N18.
Allele Name | targeted mutation 1, James P Allison |
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Allele Type | Targeted (Null/Knockout) |
Allele Synonym(s) | CTLA-4 KO; CTLA-4-; Ctla4o; Ctla4o |
Gene Symbol and Name | Ctla4, cytotoxic T-lymphocyte-associated protein 4 |
Gene Synonym(s) | |
Strain of Origin | (129X1/SvJ x 129S1/Sv)F1-Kitl+ |
Chromosome | 1 |
Molecular Note | The insertion of neomycin selection cassette under the control of a PGK promoter disrupted exon 3. |
Mutations Made By | James Allison, Mem. Sloan-Kettering Cancer Ctr., HHMI |
Homozygotes die at 3-4 weeks of age. Heterozygotes become diabetic similar to NOD/LtJ. A footpad injection of Complete Freund s Adjuvant (CFA) administered once at weaning will delay diabetes onset, thus extending the lifespan of breeders. Use of Complete Freund s Adjuvant in NOD mice can be found in Current Protocols in Immunology page 15.9.19, Reproduction.
When using the NOD.Ctla4null mouse strain in a publication, please cite the originating article(s) and include JAX stock #005144 in your Materials and Methods section.
Facility Barrier Level Descriptions
Service/Product | Description | Price |
---|---|---|
Heterozygous or Wild-type for Ctla4<tm1All> |
Frozen Mouse Embryo | NOD.129(B6)-Ctla4<tm1All>/DoiJ Frozen Embryos | $2595.00 |
Frozen Mouse Embryo | NOD.129(B6)-Ctla4<tm1All>/DoiJ Frozen Embryos | $2595.00 |
Frozen Mouse Embryo | NOD.129(B6)-Ctla4<tm1All>/DoiJ Frozen Embryos | $3373.50 |
Frozen Mouse Embryo | NOD.129(B6)-Ctla4<tm1All>/DoiJ Frozen Embryos | $3373.50 |
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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.
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