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

ORCID
0000-0002-1945-0621
Affiliation
Laboratory of Regenerative Immune Therapies Applied, REBIRTH-Research Center for Translational Regenerative Medicine, D-30625 Hannover, Germany; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, D-30625 Hannover, Germany
Kumar, Suresh;
ORCID
0000-0002-2018-9125
Affiliation
Laboratory of Regenerative Immune Therapies Applied, REBIRTH-Research Center for Translational Regenerative Medicine, D-30625 Hannover, Germany; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, D-30625 Hannover, Germany; German Centre for Infection Research (DZIF), DZIF Partner Site Hannover-Braunschweig, D-30625 Hannover, Germany
Koenig, Johannes;
Affiliation
Laboratory of Regenerative Immune Therapies Applied, REBIRTH-Research Center for Translational Regenerative Medicine, D-30625 Hannover, Germany; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, D-30625 Hannover, Germany
Schneider, Andreas;
ORCID
0000-0001-9633-677X
Affiliation
Division of Rheumatology, Department of Medicine Solna, Center for Molecular Medicine, Karolinska University Hospital and Karolinska Institute, 17177 Solna, Sweden
Wermeling, Fredrik;
ORCID
0000-0002-0711-1147
Affiliation
Division of Rheumatology, Department of Medicine Solna, Center for Molecular Medicine, Karolinska University Hospital and Karolinska Institute, 17177 Solna, Sweden
Boddul, Sanjaykumar;
ORCID
0000-0001-7042-8326
Affiliation
Department of Internal Medicine I, Faculty of Medicine and University Hospital of Cologne, University of Cologne, D-50924 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital of Cologne, University of Cologne, D-50924 Cologne, Germany
Theobald, Sebastian J;
GND
131515411
Affiliation
Laboratory of Regenerative Immune Therapies Applied, REBIRTH-Research Center for Translational Regenerative Medicine, D-30625 Hannover, Germany; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, D-30625 Hannover, Germany
Vollmer, Miriam;
Affiliation
Institute of Experimental Hematology, Hannover Medical School, D-30625 Hannover, Germany
Kloos, Doreen;
ORCID
0000-0002-4245-1497
Affiliation
Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, D-30625 Hannover, Germany
Lachmann, Nico;
GND
113214030
ORCID
0000-0001-9613-182X
Affiliation
Biostatistics Group, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany; Institute for Information Engineering, Ostfalia University, D-38302 Wolfenbuettel, Germany
Klawonn, Frank;
GND
123926513
ORCID
0000-0003-4790-3445
Affiliation
Institute for Laboratory Animal Science, Hannover Medical School, D-30625 Hannover, Germany
Lienenklaus, Stefan;
GND
139321209
ORCID
0000-0002-9062-4065
Affiliation
Institute for Laboratory Animal Science, Hannover Medical School, D-30625 Hannover, Germany
Talbot, Steven R;
GND
128772077
ORCID
0000-0002-3438-0254
Affiliation
Institute for Laboratory Animal Science, Hannover Medical School, D-30625 Hannover, Germany
Bleich, André;
GND
14008293X
ORCID
0000-0003-3607-9577
Affiliation
Institute for Transfusion Medicine and Transplant Engineering, Hannover Medical School, D-30625 Hannover, Germany
Wenzel, Nadine;
GND
1018996451
ORCID
0000-0001-5554-1937
Affiliation
Department of Obstetrics, Gynecology and Reproductive Medicine, Hannover Medical School, D-30625 Hannover, Germany
von Kaisenberg, Constantin;
Affiliation
The Jackson Laboratory, Sacramento, CA 95838, USA
Keck, James;
GND
1020246995
ORCID
0000-0001-7756-8460
Affiliation
Laboratory of Regenerative Immune Therapies Applied, REBIRTH-Research Center for Translational Regenerative Medicine, D-30625 Hannover, Germany; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, D-30625 Hannover, Germany; German Centre for Infection Research (DZIF), DZIF Partner Site Hannover-Braunschweig, D-30625 Hannover, Germany
Stripecke, Renata

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.

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Published in:
Biomedicines
Vol. 9, No. 8 (2021), p. 0961
Volume:
9
No.:
8
Date Issued:
2021
DOI:
10.3390/biomedicines9080961
Other identifier (pubmed):
34440166
Language:
English
Type of Resource:
Text
Keywords:
Vaccine; IgG; Cytomegalovirus; Stem cell transplantation; lentiviral vector; Humanized Mice; B Cell Maturation; Hla Match; Class-switch
DDC subject of DNB:
610 Medical sciences Medicine
URL:
https://europepmc.org/articles/PMC8393476
Hosting institution:
Central Facilities, REBIRTH
Hosting institution:
Hospitals and Institutes, Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation
Hosting institution:
Central Facilities, DZIF: Deutsche Zentrum für Infektionsforschung
Hosting institution:
Hospitals and Institutes, Institute of Experimental Hemalogy
Hosting institution:
Hospitals and Institutes, Klinik für Pädiatrische Pneumologie, Allergologie und Neonatologie
Hosting institution:
Central Facilities, Zentrales Tierlabor
Hosting institution:
Hospitals and Institutes, Institute of Transfusion Medicine and Transplant Engineering
Hosting institution:
Hospitals and Institutes, Department of Gynecology and Obstetrics
publications:
Erschienen in: Biomedicines 2021;9(8):961. https://doi.org/doi: 10.3390/biomedicines9080961
funding:
Veröffentlichung gefördert aus dem Publikationsfonds der MHH 2021

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