Theobald, Sebastian J., Kreer, Christoph, Khailaie, Sahamoddin, Bonifacius, Agnes ORCID: 0000-0002-0112-967X, Eiz-Vesper, Britta, Figueiredo, Constanca, Mach, Michael, Backovic, Marija ORCID: 0000-0001-8814-4428, Ballmaier, Matthias ORCID: 0000-0002-1352-5995, Koenig, Johannes, Olbrich, Henning, Schneider, Andreas, Volk, Valery, Danisch, Simon, Gieselmann, Lutz, Ercanoglu, Meryem Seda, Messerle, Martin, von Kaisenberg, Constantin, Witte, Torsten, Klawonn, Frank, Meyer-Hermann, Michael, Klein, Florian and Stripecke, Renata (2020). Repertoire characterization and validation of gB-specific human IgGs directly cloned from humanized mice vaccinated with dendritic cells and protected against HCMV. PLoS Pathog., 16 (7). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1553-7374

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Abstract

Human cytomegalovirus (HCMV) causes serious complications to immune compromised hosts. Dendritic cells (iDCgB) expressing granulocyte-macrophage colony-stimulating factor, interferon-alpha and HCMV-gB were developed to promotede novoantiviral adaptive responses. Mice reconstituted with a human immune system (HIS) were immunized with iDCgB and challenged with HCMV, resulting into 93% protection. Immunization stimulated the expansion of functional effector memory CD8(+)and CD4(+)T cells recognizing gB. Machine learning analyses confirmed bone marrow T/CD4(+), liver B/IgA(+)and spleen B/IgG(+)cells as predictive biomarkers of immunization (approximate to 87% accuracy). CD8(+)and CD4(+)T cell responses against gB were validated. Splenic gB-binding IgM(-)/IgG(+)B cells were sorted and analyzed at a single cell level. iDCgB immunizations elicited human-like IgG responses with a broad usage of various IgG heavy chain V gene segments harboring variable levels of somatic hypermutation. From this search, two gB-binding human monoclonal IgGs were generated that neutralized HCMV infectionin vitro. Passive immunization with these antibodies provided proof-of-concept evidence of protection against HCMV infection. This HIS/HCMVin vivomodel system supported the validation of novel active and passive immune therapies for future clinical translation. Author summary Human cytomegalovirus (HCMV) is a ubiquitous pathogen. As long as the immune system is functional, T and B cells can control HCMV. Yet, for patients who have debilitated immune functions, HCMV infections and reactivations cause major complications. Vaccines or antibodies to prevent or treat HCMV are not yet approved. Novel animal models for testing new immunization approaches are emerging and are important tools to identify biomedical products with a reasonable chance to work in patients. Here, we used a model based on mice transplanted with human immune cells and infected with a traceable HCMV. We tested a cell vaccine (iDCgB) carrying gB, a potent HCMV antigen. The model showed that iDCgB halted the HCMV infection in more than 90% of the mice. We found that antibodies were key players mediating protection. Using state-of-the-art methods, we were able to use the sequences of the human antibodies generated in the mice to construct and produce monoclonal antibodies in the laboratory. Proof-of-concept experiments indicated that administration of these monoclonal antibodies into mice protected them against HCMV infection. In summary, this humanized mouse model was useful to test a vaccine and to generate and test novel antibodies that can be further developed for human use.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Theobald, Sebastian J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreer, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khailaie, SahamoddinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bonifacius, AgnesUNSPECIFIEDorcid.org/0000-0002-0112-967XUNSPECIFIED
Eiz-Vesper, BrittaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Figueiredo, ConstancaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mach, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Backovic, MarijaUNSPECIFIEDorcid.org/0000-0001-8814-4428UNSPECIFIED
Ballmaier, MatthiasUNSPECIFIEDorcid.org/0000-0002-1352-5995UNSPECIFIED
Koenig, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olbrich, HenningUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Volk, ValeryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Danisch, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gieselmann, LutzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ercanoglu, Meryem SedaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Messerle, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Kaisenberg, ConstantinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witte, TorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klawonn, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meyer-Hermann, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stripecke, RenataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-327618
DOI: 10.1371/journal.ppat.1008560
Journal or Publication Title: PLoS Pathog.
Volume: 16
Number: 7
Date: 2020
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1553-7374
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MOUSE MODEL; T-CELLS; HUMAN CYTOMEGALOVIRUS; MONOCLONAL-ANTIBODIES; GLYCOPROTEIN B; SINGLE-CELL; PROPHYLAXIS; GENERATION; EXPRESSION; DISEASEMultiple languages
Microbiology; Parasitology; VirologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/32761

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