Journal Article

Repertoire characterization and validation of gB-specific human IgGs directly cloned from humanized mice vaccinated with dendritic cells and protected against HCMV

Mach, Michael, Eiz-Vesper, Britta, Bonifacius, Agnes, Backovic, Marija, Volk, Valery, Stripecke, Renata, Theobald, Sebastian J., Messerle, Martin, Witte, Torsten, Ballmaier, Matthias, Koenig, Johannes, Olbrich, Henning, Kaisenberg, Constantin von, Khailaie, Sahamoddin, Gieselmann, Lutz, Danisch, Simon, Figueiredo, Constanca, Schneider, Andreas, Meyer-Hermann, Michael, Kreer, Christoph, Ercanoglu, Meryem Seda, Klawonn, Frank, Klein, Florian

2020

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptive systems / Animals / Antibodies / Antibodies, Monoclonal / Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - pharmacology / Antibodies, Neutralizing / Antibodies, Neutralizing - immunology / Antibodies, Neutralizing - pharmacology / Antibodies, Viral / Antibodies, Viral - immunology / Antigens, Viral / Antigens, Viral - immunology / Antiviral drugs / Authorship / Binding / Biology and Life Sciences / Biomarkers / Bone marrow / Care and treatment / CD4 antigen / CD8 antigen / Clinical trials / Colony-stimulating factor / Complications / Cytomegalovirus / Cytomegalovirus - immunology / Cytomegalovirus Infections / Cytomegalovirus Infections - immunology / Cytomegalovirus Vaccines / Cytomegalovirus Vaccines - immunology / Dendritic Cells / Dendritic Cells - immunology / Development and progression / Disease Models, Animal / Engineering / Excellence / Funding / Granulocyte-macrophage colony stimulating factor / Health aspects / Hematology / Hospitals / Humans / Immune response / Immune system / Immunization / Immunization, Passive / Immunoglobulin A / Immunoglobulin G / Immunoglobulin G - immunology / Immunoglobulin G - pharmacology / Immunoglobulin M / Immunological memory / Immunology / Infections / Interferon / Laboratories / Learning algorithms / Life Sciences / Lymphocytes / Lymphocytes B / Lymphocytes T / Machine learning / Medical schools / Medicine / Medicine and Health Sciences / Memory cells / Mice / Observations / Obstetrics / Oncology / Research and Analysis Methods / Software / Somatic hypermutation / Spleen / Stem cells / Supervision / Transplants & implants / Vaccines / Viral infections / Virology / α-Interferon