The HLA-DR4 allele is associated with the development of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.
In an attempt to provide a mouse model for these diseases, a hybrid MHC class II molecule between the peptide binding domains of human HLA-DRA and HLA-DRB*0401 and the membrane proximal domains of mouse I-E (H2-E) was engineered and co-injected into C57BL/6 fertilized eggs.
The transgenic offspring were bred to a mouse incapable of expressing other MHC class II molecules (Abb knockout on B6 background).
By preserving the alpha 2 and beta 2 domains of mouse MHC class II, interactions with CD4 co-receptors on T cells was preserved.
This mouse is healthy and breeds normally.
Immunization with a peptide from a proteolipid protein known to bind to HLA-DR4, provoked a strong T cell proliferative response, caused inflammatory lesions in CNS white matter, and symptoms of experimental allergic encephalomyelitis (EAE).
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Genetic Background: C57BL/6 Background
The antigen-binding domains of HLA-DRA and HLA-DRB1*0401 (representative of the DR4 supertype) were attached to the membrane-proximal domains of I-Ed alpha and I-Ed beta (H2-E), respectively, by replacing exon 2 of the mouse genes with exon 2 of the human genes. These constructs were then microinjected into C57BL/6 fertilized eggs. Transgenic founders were then crossed to MHC class II deficient mice: the GenPharm C2d line, now known as the Taconic Transgenic Model B6.129-H2-Ab1tm1Gru, which has the I-A beta gene inactivated by gene targeting in 129S2-derived ES cells and the unexpressed I-E alpha allele found in the C57BL/6 haplotype. Mice expressing HLA-DR and not endogenous I-E beta were selected to create the line (J18). The chimeric molecules were shown to have the same peptide binding specificity as HLA-DRB1*0401 molecules. The line was received at Taconic for the NIAID repository in 1998 and rederived via embryo transfer.
- Ito K, Bian HJ, Molina M, Han J, Magram J, Saar E, Belunis C, Bolin DR, Arceo R, Campbell R, Falcioni F, Vidovic D, Hammer J, Nagy ZA: HLA-DR4-IE chimeric class II transgenic, murine class II-deficient mice are susceptible to experimental allergic encephalomyelitis. J Exp Med 1996 Jun 1;183(6):2635-44.
- Grusby MJ, Johnson RS, Papaioannou VE, Glimcher LH. (1991) Depletion of CD4+ T-Cells in Major Histocompatibility Complex Class II - Deficient Mice. Science, 253(5026):1417-1420.