NCG-MHC-dKO mice - an excellent model for PBMC reconstitution and pharmacodynamic evaluation in the absence of GvHD

Abstract Human immune cell reconstitution (Peripheral Blood Mononuclear Cells; PBMC or CD34 +hematopoietic stem cell; HSC) is commonly performed in immunodeficient mouse strains, such as NCG, NSG, NOG. utilizing PBMCs a much more rapid model, allowing for T-cell within 2 weeks. Due to the occurrence of xenogeneic graft-versus-host disease (xGvHD) around 4 weeks post-engrafment, application PBMC-reconstituted NCG mice relatively limited. xGvHD mainly induced by T cells derived from donor engraftment recognizing murine host MHC class I and II foreign attacking organs. Deleting β2m (NCG-β2m-KO) could reduce xGvHD; however, not only subunit but also FcRn subunit, which deletion shortens half-life IgG, making it unsuitable IgG antibody agent evaluation. In addition, alone results an imbalanced CD4/CD8 ratio. To solve these problems, we developed NCG-MHC-dKO model knocking out H2K1, H2D1, H2Ab1genes. Compared with existing NCG-B2m-KO significantly prolonged survival, reduced occurrence, did affect ratio when reconstituted PBMC. Furthermore, treatment anti-PD-L1 antibodies inhibited MDA-MB-231 tumor growth mice, similar mice. Based on our preliminary data, promising evaluating therapy agents, assessing treatment-related cytokine release syndrome, long-term toxicities therapies.