BRGS A2DR2

The BRGS A2DR2 strain is a highly immunodeficient inbred model with two knockout mutations in the Il2rg (interleukin-2 receptor subunit gamma) and Rag2 (recombination activating gene 2) genes and carrying a NOD background gene.

The Rag2^tm1 mutation is a knockout of one of the two genes controlling the expression of recombinase activity for VDJ genes, crucial for the formation of B and T cell receptors. This absence hinders the development of these cells, resulting in a total lack of T and B lymphocytes.

The Il2rg^tm1 mutation is a knockout of the gene encoding the gamma c chain, shared by several interleukins (IL-2, IL-4, IL-7, IL-9, and IL-15). This gene is essential for the differentiation and proper functioning of many immune system cells, including natural killer (NK) cells.

The combination of these two mutations, Rag2^tm1 and Il2rg^tm1, induces severe immunodeficiency, characterized by the absence of T, B, and NK cells. The BRGS A2DR2 strain also carries the NOD variant of the polymorphic Sirpa gene. This expression of the SIRPA protein on murine bone marrow macrophages allows cross-recognition with CD47 ligands on human cells, reducing phagocytosis of transplanted human cells.

Finally, this strain expresses two human transgenes: HLA-A*02 and HLA-DR2. The presence of these two transgenes allows for a more rapid emergence of T cells in the hosts’ circulation, indicating a potentially more efficient development of human T cells in the mouse thymus following the engraftment of human

CD34+ stem cells. The acceleration of CD4+ and CD8+ T cell development in BRGS A2DR2-HIS mice leads to a more balanced composition of B and T cell compartments in peripheral lymphoid organs. The presence of human HLA transgenes enhances both B- and T-cell functions, resulting in elevated levels of class-switched Ig, increased percentages of polyfunctional T cells, and clear indications of antigen-specific T-cell responses post-immunization.

JANVIER LABS has licensed the BRGS A2DR2 strain from the Institut Pasteur. The use of this strain is restricted to private sector users. The animals are bred to maintain both the genetic background and the mutations of interest in their homozygous forms. The BRGS A2DR2 strain is bred in inbred mode and the phenotype is controlled in accordance with the JANVIER LABS GENETIC POLICY®.

In summary, this strain combines a severe immunodeficiency resulting in the total absence of murine T, B, and NK cells, and the expression of class I and II HLA that enhance the differentiation, maturation, and specificity of human T cells after transplantation. It serves an ideal model for the development of T-cell focused therapies, particularly those based on the development of an HLA and epitope specific response such as vaccines.

Main application and research fields