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
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|
|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)||ALPS5; CD; CD152; CD152 antigen; CELIAC3; CTLA-4; Cd152; Cd152; Ctla-4; Ctla-4; GRD4; GSE; IDDM12; Ly-56; cytotoxic T lymphocyte-associated protein 4; sCTLA4|
|Strain of Origin||(129X1/SvJ x 129S1/Sv)F1-Kitl<+>|
|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.
|Heterozygous or Wild-type for Ctla4<tm1All>|
We will fulfill your order by providing at least two carriers for each strain ordered. The total number, sex, and genotypes provided will vary, although typically 8 or more animals are provided. Please check genotypes which will be recovered. While the genotypes of all animals produced will be communicated to you prior to scheduling shipment, the genotypes of animals provided may not reflect the mating scheme and genotypes described in the strain description. Animals are typically ready to ship in 11-14 weeks. If a second recovery is required to produce the minimum number of animals, then delivery time would increase to approximately 25 weeks. If we fail to produce animals of the correct genotype, you will not be charged. We cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.
Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation.
|Frozen Mouse Embryo||$2,595.00 per straw or vial|
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