In Vivo Lentiviral Gene Delivery of HLA-DR and Vaccination of Humanized Mice for Improving the Human T and B Cell Immune Reconstitution
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
Affiliations
Suresh Kumar
Laboratory of Regenerative Immune Therapies Applied, REBIRTH-Research Center for Translational Regenerative Medicine, D-30625 Hannover, Germany
Johannes Koenig
Laboratory of Regenerative Immune Therapies Applied, REBIRTH-Research Center for Translational Regenerative Medicine, D-30625 Hannover, Germany
Andreas Schneider
Laboratory of Regenerative Immune Therapies Applied, REBIRTH-Research Center for Translational Regenerative Medicine, D-30625 Hannover, Germany
Fredrik Wermeling
Division of Rheumatology, Department of Medicine Solna, Center for Molecular Medicine, Karolinska University Hospital and Karolinska Institute, 17177 Solna, Sweden
Sanjaykumar Boddul
Division of Rheumatology, Department of Medicine Solna, Center for Molecular Medicine, Karolinska University Hospital and Karolinska Institute, 17177 Solna, Sweden
Sebastian J. Theobald
Department of Internal Medicine I, Faculty of Medicine and University Hospital of Cologne, University of Cologne, D-50924 Cologne, Germany
Miriam Vollmer
Laboratory of Regenerative Immune Therapies Applied, REBIRTH-Research Center for Translational Regenerative Medicine, D-30625 Hannover, Germany
Doreen Kloos
Institute of Experimental Hematology, Hannover Medical School, D-30625 Hannover, Germany
Nico Lachmann
Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, D-30625 Hannover, Germany
Frank Klawonn
Biostatistics Group, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany
Stefan Lienenklaus
Institute for Laboratory Animal Science, Hannover Medical School, D-30625 Hannover, Germany
Steven R. Talbot
Institute for Laboratory Animal Science, Hannover Medical School, D-30625 Hannover, Germany
André Bleich
Institute for Laboratory Animal Science, Hannover Medical School, D-30625 Hannover, Germany
Nadine Wenzel
Institute for Transfusion Medicine and Transplant Engineering, Hannover Medical School, D-30625 Hannover, Germany
Constantin von Kaisenberg
Department of Obstetrics, Gynecology and Reproductive Medicine, Hannover Medical School, D-30625 Hannover, Germany
James Keck
The Jackson Laboratory, Sacramento, CA 95838, USA
Renata Stripecke
Laboratory of Regenerative Immune Therapies Applied, REBIRTH-Research Center for Translational Regenerative Medicine, D-30625 Hannover, Germany
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.
