B6.Cg-Rag1^tm1Mom Fcgrt^tm1Dcr Tg(CAG-FCGRT)276Dcr/DcrJ

Stock number: 016919
Product name: Rag1-/- mFcRn-/- hFcRn Tg 276
Research areas: Cancer Research, Hematological Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Research Tools, Virology Research

Description

Rag1 Fcgrt FCGRT knock-out/transgenic mice are immunodeficient and therefore applicable for xenograft studies. This humanized model may be useful in evaluating the pharmacokinetics, the pharmacodynamics and/or efficacy testing of human Fc-based molecules (e.g. human IgG, Fc-fusion proteins) or for analyzing the immunogenicity of antibodies.

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Detailed description

Rag1 Fcgrt FCGRT mice harbor knockout alleles of the Fcgrt (formerly FcRn) and Rag1 genes and express a human FCGRT (FcRn α-chain) transgene under the CAG promoter. These mice have a normal level of serum albumin, but are deficient in mature B- and T-cells. In this model, longer half-lives are observed with mice homozygous for the human FCGRT transgene when compared to hemizygous mice, indicating that higher copy number correlates with higher expression of FcRn and provides greater protection of IgG from clearance. This model is useful for pharmacokinetic and pharmacodynamic studies of human IgG. It has been shown to be useful for screening of hIgGs in evaluations of serum half-life. Being immunodeficient, they are suitable for efficacy testing requiring xenografts. Zalevsky et. al. 2010 have shown good correlation between this mouse model and studies performed with Cynomolgus monkeys.

Development

These Rag1-/- mFcRn-/- hFcRn Tg 276 mice were produced by crossing STOCK No. 004919 mice with STOCK No. 002216.

FcRn α-chain knockout mice expressing a human FcRn transgene (line 276) are also called FcRn-/- hFcRn (276) Tg mice, cDNA transgenic line 276, mFcRn-/- hFcRn (276) Tg [carrying one allele of the transgene] (STOCK No. 004919). The FcRn-/- hFcRn (276) Tg mice were generated in the laboratory of Derry Roopenian (The Jackson Laboratory) by crossing Fcgrt^tm1Dcr targeted mutant mice (backcrossed five generations to C57BL/6J) with Tg(CAG-FCGRT)276Dcr transgenic mice (coisogenic on a C57BL/6J genetic background).

To generate the FcRn α-chain knockout mice (Fcgrt^tm1Dcr; see also Stock No. 003982), a targeting vector was designed to replace 1588 nucleotide fragments (encoding promoter sequence 5' of the transcriptional start site, exon1, intron 2, and most of exon2) with a PGK-Neo^r cassette. The vector was electroporated into 129/SvJ-derived ESV/J-1182 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric animals were crossed to C57BL/6J mice. These FcRn α-chain mutant mice were backcrossed to C57BL/6J for five generations prior to breeding with hFcRn line 276 transgenic mice.

To generate the hFcRn line 276 transgenic mice, a transgene was designed with the 0.34 kb human cytomegalovirus immediate early promoter enhancer, 1.4 kb chicken beta-actin promoter and intron 1, a cDNA sequence encoding the human FcRn α-chain, 0.73 kb rabbit beta-globin intron, and 0.35 kb SV40 polyA sequence. The donating investigator reports that this transgene was injected into C57BL/6J embryos. The resulting transgenic offspring were bred to C57BL/6J mice to establish founder line 276. These hFcRn line 276 transgenic mice were maintained on a C57BL/6J genetic background prior to breeding with mice carrying the Fcgrt^tm1Dcr allele.

Allele

Symbol: Tg(CAG-FCGRT)276Dcr
Name: transgene insertion 276, Derry C Roopenian
MGI accession ID: MGI:4441040
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: hFcRn (276) Tg; Tg276
Marker symbol: Tg(CAG-FCGRT)276Dcr
Marker name: transgene insertion 276, Derry C Roopenian
Chromosome: 1
Strain of origin: C57BL/6J
Expressed genes: FCGRT,Fc fragment of IgG receptor and transporter,human
Molecular note: To generate the hFcRn line 276 transgenic mice, a transgene was designed with the 0.34 kb human cytomegalovirus immediate early promoter enhancer, 1.4 kb chicken beta-actin promoter and intron 1, a cDNA sequence encoding the human FcRn alpha-chain, 0.73 kb rabbit beta-globin intron, and 0.35 kb SV40 polyA sequence. Line 276 was established. Transgene insertion occurred on Chr 1, causing a 1 bp duplication.

Allele

Symbol: Rag1^tm1Mom
Name: targeted mutation 1, Peter Mombaerts
MGI accession ID: MGI:1857241
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: Rag-; RAG1^null; RAG-1-; Rag-1KO; Rag^1tm1Mom; Rag1^-
Marker symbol: Rag1
Marker name: recombination activating gene 1
Chromosome: 2
Strain of origin: 129S7/SvEvBrd-Hprt⁺
Site of expression: expression is seen in bone marrow derived cell lines.
Molecular note: A 1356 bp genomic fragment of the Rag1 gene, encoding the nuclear localization signal and the zinc-finger motif, was replaced by a neomycin cassette. A mutant transcript expressed from this allele was detected by Northern blot in bone marrow derived cell lines from homozygous mice.

Allele

Symbol: Fcgrt^tm1Dcr
Name: targeted mutation 1, Derry C Roopenian
MGI accession ID: MGI:3511510
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: FcRn^-
Marker symbol: Fcgrt
Marker name: Fc receptor, IgG, alpha chain transporter
Chromosome: 7
Strain of origin: 129X1/SvJ
Molecular note: Sequence from exon 1 and part of exon2 was replaced with a PGK-neo cassette. Quantitative PCR of liver cDNA indicated the absence of mRNA. Western blot analysis of neonatal intestinal extracts failed to reveal protein product.