• Human PBMC-engrafted humanized mice are attractive models for in vivo analysis of human immune responses. We previously reported the successful engraftment of human PBMCs in B-NDG mice. However, due to the severe xenograft versus host disease (xeno-GvHD) in these mice, the experimental window is limited. The pathogenesis of GvHD is directly related to human T cell implantation, and the mismatch between human and mouse MHCs is the main cause of GvHD after human PBMCs engraftment. It has been shown that knocking out MHC I and/or II molecules in mice can reduce GvHD and extend the experimental window after engraftment of human PBMCs.
• MHC class I molecules are composed of two subunits, α and β chains, and the α chain in NOD background strain of mice is encoded by H2-K1, H2-D1 gene. Knocking out H2-K1 and H2-D1 gene in mice makes it unable to form a complete MHC Class I molecule. MHC class II molecules are also composed of two subunits, α and β chains, and the β chain is encoded by H2-Ab1 gene. Knocking out H2-Ab1 gene in mice makes it unable to form a complete MHC Class II molecule. These incomplete MHC Class I and MHC Class II molecules will not be able to effectively express on the cell surface and perform antigen-presenting functions, thereby potentially reducing the occurrence of GvHD.
• Application: This model can be used to study the mechanism of xeno-GvHD in vivo, the pathogenesis of immune-related diseases such as tumor, autoimmune and metabolic diseases, and to evaluate the efficacy of novel drugs .

Gene targeting strategy for B-NDG MHC I/II DKO mice ad. The exons 2-8 of mouse H2-K1 and H2-D1 gene, the exons 2-4 of mouse H2-Ab1 gene were knocked out in B-NDG MHC I/II DKO mice ad. So the transcription and translation of mouse H2-K1, H2-D1, H2-Ab1 genes will be disrupted.

The elimination of human IgG1 antibody in the plasma of B-NDG MHC I/II DKO mice ad was significantly slower than that in B-NDG mice. BALB/c mice (n=5), B-NDG mice (n=4) B-NDG MHC I/II DKO mice ad (n=4) were treated with anti-human CTLA4 antibody (hCTLA4-Ab1). Blood samples were collected at different time point for the PK assay. Results showed that B-NDG MHC I/II DKO mice ad can significantly extend the half-life of antibody drugs in mice.