Functional Human Humoral Immunity in Humanized Mice: A Spatiotemporal Framework

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.