In Vivo Lentiviral Gene Delivery of HLA-DR and Vaccination of Humanized Mice for Improving the Human T and B Cell Immune Reconstitution

• Main Authors: Suresh Kumar, Johannes Koenig, Andreas Schneider, Fredrik Wermeling, Sanjaykumar Boddul, Sebastian J. Theobald, Miriam Vollmer, Doreen Kloos, Nico Lachmann, Frank Klawonn, Stefan Lienenklaus, Steven R. Talbot, André Bleich, Nadine Wenzel, Constantin von Kaisenberg, James Keck, Renata Stripecke
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: Biomedicines
• Subjects: humanized mice; stem cell transplantation; HLA match; lentiviral vector; vaccine; B cell maturation
• Online Access: https://www.mdpi.com/2227-9059/9/8/961
• ISSN: 2227-9059

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 <i>bonafide</i> 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/Rag1^null/IL2Rγ^null (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.