Abstract
Humanized mouse models generated with human hematopoietic stem cells (HSCs) and reconstituting the human immune system (HIS-mice) are invigorating preclinical testing of vaccines and immunotherapies. We have recently shown that human engineered dendritic cells boosted bonafide human T and B cell maturation and antigen-specific responses in HIS-mice. Here, we evaluated a cell-free system based on in vivo co-delivery of lentiviral vectors (LVs) for expression of a human leukocyte antigen (HLA-DRA*01/ HLA-DRB1*0401 functional complex, “DR4”), and a LV vaccine expressing human cytokines (GM-CSF and IFN-α) and a human cytomegalovirus gB antigen (HCMV-gB). Humanized NOD/Rag1null/IL2Rγnull (NRG) mice injected by i.v. with LV-DR4/fLuc showed long-lasting (up to 20 weeks) vector distribution and expression in the spleen and liver. In vivo administration of the LV vaccine after LV-DR4/fLuc delivery boosted the cellularity of lymph nodes, promoted maturation of terminal effector CD4+ T cells, and promoted significantly higher development of IgG+ and IgA+ B cells. This modular lentigenic system opens several perspectives for basic human immunology research and preclinical utilization of LVs to deliver HLAs into HIS-mice.
Highlights
Human immune system (HIS)-mice are generated with human stem cell transplantation (HCT) applied to immunodeficient mouse strains
The LVG2α/gB was used as a vaccine (VAC) to induce immune responses against human cytomegalovirus gB antigen (HCMV-gB)
The lentiviral vectors (LVs)-DR4/fLuc vector alone (DR4)/fLuc vector was used for HLA-DR4 gene delivery and was designed to express the DR4 dimer on the cell surface and intracellular firefly luciferase for tracking the vector expression by bioluminescence imaging (BLI) analyses (Figure 1B)
Summary
Human immune system (HIS)-mice are generated with human stem cell transplantation (HCT) applied to immunodeficient mouse strains. This type of model is a practical option to investigate human immunobiology and test human-specific biomedicines without the ethical concerns of research performed on human subjects. From the inception of primordial HIS-models in the 800 s until today, considerable progress has been achieved. The development of advanced severely immunodeficient mouse strains containing multiple mutations or transgenesis allowed for high engraftment of human HSCs and enduring long-term human immune reconstitutions [1,2]. Ishikawa, and colleagues pioneered the transplantation of CD34+ hematopoietic stem cells (HSCs) into immunodeficient mouse strains lacking the common interleukin-2 receptor gamma chain (IL2Rγ).
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