Yusuke Ohno

Functional human humoral immunity remains one of the greatest challenges in humanized mouse research. Although numerous humanized mouse models have been developed, reproducing efficient antigen-specific antibody responses remains difficult. This review proposes a conceptual framework for evaluating humanized mouse models based on the reconstruction of functional humoral immune modules rather than the presence of individual immune cell populations. Functional humoral immunity depends on the coordinated reconstruction of functional modules established through productive cognate interactions between immune cells within spatially organized lymphoid microenvironments. Comparative analyses of representative humanized mouse models demonstrated that these functional modules were only partially reconstructed and differed substantially among currently available models. Moreover, the duration of the humoral immunity window, during which the functional modules required for humoral immunity remain sufficiently coordinated to support productive cognate interactions and effective antigen-specific antibody responses, is limited in current humanized mouse models. Therefore, we propose a spatiotemporal framework for the design, evaluation, and application of next-generation humanized mouse models.

Functional human humoral immunity remains one of the greatest challenges in humanized mouse research. Although numerous humanized mouse models have been developed, efficient antigen-specific antibody responses remain difficult to reproduce. This review proposes a conceptual framework for evaluating humanized mouse models based on the reconstruction of functional humoral immune modules rather than the presence of individual immune-cell populations. Functional humoral immunity depends on the coordinated reconstruction of functional modules established through productive cognate interactions among immune cells within spatially organized lymphoid microenvironments. Comparative analyses of representative humanized mouse models demonstrate that these functional modules are only partially reconstructed and differ substantially among currently available models. Moreover, the duration of the humoral immunity window—the period during which the functional modules required for humoral immunity remain sufficiently coordinated to support productive cognate interactions and effective antigen-specific antibody responses—is limited in current humanized mouse models. We therefore propose a spatiotemporal framework for the design, evaluation, and fit-for-purpose application of next-generation humanized mouse models.

Zhu N, et al. Clin Exp Vaccine Res. 2026 ;15:e22. https://doi.org/10.7774/cevr.2026.15.e22

Humanized mice are invaluable models for investigating human cell engraftment in vivo post-transplantation. Mice engrafted with human red blood cells (hRBCs) are useful for examining the physiological roles of hRBCs in vivo, including studies on blood disorders, immune responses, and transfusion-related research. These models hold promise for malaria infection studies and vaccine development. However, engrafted hRBCs in vivo in immunodeficient mice present challenges that must be addressed to establish effective in vivo models. In this study, we explored the rejection mechanisms of hRBCs in immunodeficient NOD/Shi-scid-IL2rγnull (NOG) mice and developed a novel model for long-term RBC engraftment. We observed rapid depletion of fluorescently labeled hRBCs in the liver, but not in other organs, of NOG mice, with Gr-1midCD68+ mouse macrophages playing a significant role in the elimination of hRBCs in the liver. To counteract this, we created thymidine kinase (TK) transgenic (Tg) mice under the human CD68 promoter (NOG-pCD68-TK Tg), which, upon administration of valganciclovir (VGCV), led to the successful depletion of macrophages. Consequently, hRBCs showed significantly prolonged engraftment in NOG-pCD68-TK Tg mice compared to non-Tg mice following macrophage depletion, maintaining engraftment for up to 14 d post-transplantation. This study elucidates the erythrophagocytosis mechanisms of hRBCs in mice and establishes NOG-pCD68-TK Tg mice as a valuable model for the long-term engraftment of hRBCs, potentially advancing in vivo hRBC research.

T cell stimulation by bacterial superantigens induces a cytokine storm. After T cell activation and inflammatory cytokine secretion, regulatory T cells (Treg) are produced to suppress the immune response. Coccomyxa sp.KJ (IPOD FERM BP‐22254), a green alga, is reported to regulate immune reactions. Therefore, we examined the effects of Coccomyxa sp.KJ extract (CE) on the superantigen‐induced immune response. When human peripheral blood mononuclear cells (PBMCs) were stimulated with toxic shock syndrome‐1 (TSST‐1) in the presence of CE, the number of activated T cells decreased moderately. Purified T cells stimulated in the presence of CE comprised more non‐proliferating cells than those stimulated in the absence of CE, whereas some T cells proliferated more quickly. The levels of activation markers on the stimulated T cells increased in the presence of CE. Most of the inflammatory cytokines did not change but IL‐1β, IL‐17, IL‐4, and IL‐13 secretion increased, whereas that of IL‐2, TNF‐α, and IL‐18 decreased. IL‐10 secretion was also decreased by CE treatment, suggesting that the immune response was not suppressed by Treg cells. CE enhanced the expression of stem cell‐like memory cell markers in T cells. These results suggest that CE can regulate the fate of T cells and can help to ameliorate superantigen‐induced T cell hyperactivation and immune suppression.