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Transgenic Multiple Sclerosis model that co-expresses HLA-DR15 and a human TCR specific for HLA-DR15/MBP 85-99. The mice develop spontaneous disease, allowing the analysis of CNS pathology that is faithful to clinical Multiple Sclerosis.

Background:

The HLA gene family encodes a group of related proteins known as the human leukocyte antigen (HLA) complex. Products of the HLA complex act at the surface of antigen presenting cells, presenting peptidic antigen fragments to facilitate immune recognition of pathogens. HLA class II proteins are primarily expressed by antigen-presenting cells such as macrophages, B cells, and dendritic cells. These cells take up an antigen, process it and present the HLA/antigen complex on the cell surface where is can act to prime CD4 T-cells via interaction with T-cell receptors (TCRs).

In humans, the HLA complex consists of more than 200 genes located close together on chromosome 6. Genes in this complex are categorized into three basic groups: class I, class II, and class III. There are three cell-surface HLA class II heterodimers: DP, DQ, and DR. Each is a combination of two proteins, an α-chain and a β-chain encoded by separate genes (HLA-DPA1 and HLA-DPB1, HLA-DQA1 and HLA-DQB1, HLA-DRA, and HLA-DRB1). With the exception of the DR alpha chain, there are multiple genes and/or pseudogenes for each class II chain. The α-chain and a β-chain associate inside the cell, bind to a peptide, and travel to the cell surface for presentation of the peptide to T cells.

HLA class II molecules have been associated with susceptibility to several autoimmune or immune-mediated disorders, including multiple sclerosis. It has been speculated that this association stems from the ability of class II molecules to bind and present certain self-peptides. HLA-class II genes, particularly those of the HLA-DR15 haplotype (HLA-DQB1*0602- HLA-DQA1*0102; HLA-DRB1*1501; HLA-DRB5*0101) show the strongest association in multiple sclerosis. Candidate gene association studies for HLA association in MS tend to indicate DRB1*1501 as the primary risk factor for increased susceptibility.

Professor Danny Altmann has developed a transgenic mouse expressing human DR15 and a MBP (84-102)-specific T cell receptor (TCR). Mice develop spontaneous paralysis, varying with the microbial status of the animal facility, and considerably enhanced on a RAG-2 knockout background. These mice have been characterised in the publication: Ellmerich et al. 2005.

 

Internal case number: 2074

DR15 and a MBP (84-102)-specific T cell receptor (TCR) mouse

Transgenic multiple sclerosis model

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