Human immune responses and potential for vaccine assessment in humanized mice

Abstract

The new humanized mouse models with a transplanted human immune system have a capacity for de novo multilineage human hematopoiesis and generate T cells, B cells, macrophages, dendritic cells and NK cells. Of the two current leading humanized mouse models, the hu-HSC model is created by human hematopoietic stem cell (HSC) engraftment whereas the BLT mouse model is prepared by co-transplantation of human fetal liver, thymus and HSC. Humoral and cellular immune responses are seen in both models after immunization with antigens or infection with hematotropic pathogens such as EBV, HIV-1 and dengue viruses. While consistent antigen specific IgM production is seen, IgG responses were found to be generally feeble which is attributed to inefficient immunoglobulin class switching. BLT mice permit human HLA restricted T cell responses due to the autologous human thymus contributing to T cell maturation. Use of HLA Class I and II transgenic hu-HSC mice recently demonstrated that the HLA restriction deficiency could be overcome in this model. However, the overall vigor of the immune responses needs further improvement in both the models to approach that of the human. Towards this goal, supplementation with human cytokines and growth factors by transgenesis to improve human cell reconstitution and their homeostatic maintenance are beginning to yield improved mouse strains to create more robust human immune competent mice for immunoprophylaxis studies.

Figure 1

Hu-Mice Generation and Immune Responses A schematic describing the generation of the two current leading models of hu-Mice and immune responses. Hu-HSC mice are prepared by transplantation of human CD34+ HSC, whereas the BLT mice are generated by co-transplantation of human fetal liver, thymus and autologous HSC.