Approaches to HIS mouse model optimization

Some HIS mouse models exhibit enhanced human myeloid cell development, with different genetic approaches having been used to express human cytokines in various combinations and at varying levels in these animals. However, these mice only partially mimic in vivo human immune responses in vivo and far more to achieve complete immunological humanization. For example, current myeloid-improved mouse models present with a reduced life span after humanization associated with profound anemia. Non-physiological high levels of persistent cytokine occur during the terminal stages of humanization, leading to the over-activation of human macrophages. Ideally, such cytokine expression should be optimized at a physiological level or minimized after the establishment of the human immune system. Human T cells in HIS mice do not undergo human HLA education, and lymph node development in these animals remains deficient. Moreover, there are no established HIS mouse models displaying germinal centers in secondary lymphoid tissues, thus limiting memory B cell development and constraining the sufficiency of antigen-specific antibody responses and cellular responses. The hu-PBL mice will develop graft versus host disease (GvHD) four weeks after human PBMC infusion. While B2M knockout NSG/NOG mice can delay the emergence of GvHD, they also express constitutively high levels of circulating human interferon-gamma in vivo. The deletion of B2M also leads to the disruption of the neonatal Fc receptor (FcRn), which results in reduced stability of circulating antibodies and impairs PK/PD studies of antibody-based immunotherapeutics. More comprehensive genetic modifications are thus vital to the future optimization of HIS mouse models, and some promising approaches to upgrading HIS mouse models are discussed in below.