Immunohistochemistry demonstrated massive infiltration of human T cells in the regressing tumor. Expression of cytotoxic molecules like Perforin or Granzyme B was detected in the infiltrating human T cells, suggesting that they were activated by Nivolumab3).DiscussionOur studies have demonstrated that mouse innate-immune cells recognize human cells as foreign substances through glycoproteins and such interactions influence the survival of human cells and even their functions. Indeed, identification of mouse clec(X) suggests that some glycans on human RBCs are recognized by the lectin domain of clec(x) in mouse macrophages. Further exploration of the molecular mechanisms involved in the engulfment of human RBCs by splenic macrophages in C3/clec(x) DKO mice is critical for establishing humanized mice harboring human RBCs. Such mice are now considered essential for research of malaria, development of Referencesnovel drug delivery systems using RBCs, or artificial RBCs induced in vitro. The therapeutic effects of anti-PD-1 antibody in huNOG-FcγR KO mice were surprising, since there have been no reliable humanized mouse models for evaluation of immune checkpoint inhibitors. This mouse strain seems to recapitulate clinical situations of checkpoint inhibitors better than NOG mice and will be useful for development of novel anti-cancer drugs. Regarding the higher engraftment level of human cells in NOG-FcγR KO mice than in NOG mice, our speculation is that the deficiency of FcRγ disturbed signal transmission from various receptors including CLRs, resulting in the compromised recognition of human cells by mouse innate immune cells. We are currently investigating whether any mouse CLRs receptors using FcRγ as a subunit can bind human cells. Elucidation of the mechanisms is important for developing next generation immune-deficient mice.Figure 2. Rejection of human lung adenocarcinoma cell line by Nivolmab in humanized NOG-FcR KO mice1) Yamaguchi, T. et al. Generation of Novel Human Red Blood Cell-Bearing Humanized Mouse Models Based on C3-Deficient NOG Mice. Front Immunol 12, 671648, doi:10.3389/fimmu.2021.671648 (2021).2) Katano, I., Ito, R., Kawai, K. & Takahashi, T. Improved Detection of in vivo Human NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity Using a Novel NOG-FcgammaR-Deficient Human IL-15 Transgenic Mouse. Front Immunol 11, 532684, doi:10.3389/fimmu.2020.532684 (2020).3) Katano, I. et al. Development of a novel humanized mouse model for improved evaluation of in vivo anti-cancer effects of anti-PD-1 antibody. Sci Rep 11, 21087, doi:10.1038/s41598-021-00641-8 (2021).121
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