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Repertoire characterization and validation of gB-specific human IgGs directly cloned from humanized mice vaccinated with dendritic cells and protected against HCMV.
Theobald, Sebastian J Kreer, Christoph Khailaie, Sahamoddin Bonifacius, Agnes Eiz-Vesper, Britta Figueiredo, Constanca Mach, Michael Backovic, Marija Ballmaier, Matthias Koenig, Johannes
Theobald, Sebastian J
Kreer, Christoph
Khailaie, Sahamoddin
Bonifacius, Agnes
Eiz-Vesper, Britta
Figueiredo, Constanca
Mach, Michael
Backovic, Marija
Ballmaier, Matthias
Koenig, Johannes
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2020-07-15
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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 promote de novo antiviral 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 (≈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 infection in vitro. Passive immunization with these antibodies provided proof-of-concept evidence of protection against HCMV infection. This HIS/HCMV in vivo model system supported the validation of novel active and passive immune therapies for future clinical translation.
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PLoS Pathog. 2020 Jul 15;16(7):e1008560. doi: 10.1371/journal.ppat.1008560.
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Article
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en
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1553-7374
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Attribution-NonCommercial-ShareAlike 4.0 International