TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes.

Autor:	Schleimann MH; Department of Infectious Diseases, Aarhus University Hospital, Denmark; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, OR, USA. Electronic address: Marsch@rm.dk., Kobberø ML; Department of Clinical Medicine, Aarhus University, Denmark., Vibholm LK; Department of Infectious Diseases, Aarhus University Hospital, Denmark; Department of Clinical Medicine, Aarhus University, Denmark., Kjær K; Department of Infectious Diseases, Aarhus University Hospital, Denmark; Department of Clinical Medicine, Aarhus University, Denmark., Giron LB; Vaccine & Immunotherapy Center, The Wistar Institute, Philadelphia, PA, USA., Busman-Sahay K; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, OR, USA., Chan CN; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, OR, USA., Nekorchuk M; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, OR, USA., Schmidt M; Mologen AG, Berlin, Germany., Wittig B; Mologen AG, Berlin, Germany; MolBio2Math - Molecular Biology & Integral Biomathics, a non-profit Foundation Institute, Berlin, Germany., Damsgaard TE; Department of Clinical Medicine, Aarhus University, Denmark; Department of Plastic and Breast Surgery, Plastic Surgery Research Unit, Aarhus University Hospital, Denmark., Ahlburg P; Department of Anesthesiology, Aarhus University Hospital, Denmark., Hellfritzsch MB; Department of Clinical Medicine, Aarhus University, Denmark; Department of Radiology, Aarhus University Hospital, Denmark., Zuwala K; Department of Infectious Diseases, Aarhus University Hospital, Denmark; Department of Clinical Medicine, Aarhus University, Denmark., Rothemejer FH; Department of Clinical Medicine, Aarhus University, Denmark., Olesen R; Department of Clinical Medicine, Aarhus University, Denmark., Schommers P; Institute of Virology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany; Department of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research, Partner Site Bonn-Cologne, 50931 Cologne, Germany., Klein F; Institute of Virology, Faculty of Medicine and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany; German Center for Infection Research, Partner Site Bonn-Cologne, 50931 Cologne, Germany., Dweep H; Bioinformatics Facility, The Wistar Institute, Philadelphia, PA, USA., Kossenkov A; Bioinformatics Facility, The Wistar Institute, Philadelphia, PA, USA., Nyengaard JR; Department of Clinical Medicine, Aarhus University, Denmark; Core Centre for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus, Denmark., Estes JD; Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, OR, USA., Abdel-Mohsen M; Vaccine & Immunotherapy Center, The Wistar Institute, Philadelphia, PA, USA., Østergaard L; Department of Infectious Diseases, Aarhus University Hospital, Denmark; Department of Clinical Medicine, Aarhus University, Denmark., Tolstrup M; Department of Infectious Diseases, Aarhus University Hospital, Denmark; Department of Clinical Medicine, Aarhus University, Denmark., Søgaard OS; Department of Infectious Diseases, Aarhus University Hospital, Denmark; Department of Clinical Medicine, Aarhus University, Denmark., Denton PW; Department of Infectious Diseases, Aarhus University Hospital, Denmark; Department of Clinical Medicine, Aarhus University, Denmark. Electronic address: pdenton@unomaha.edu.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2019 Jul; Vol. 45, pp. 328-340. Date of Electronic Publication: 2019 Jul 09.
DOI:	10.1016/j.ebiom.2019.07.005
Abstrakt:	Background: TLR9 agonists are being developed as immunotherapy against malignancies and infections. TLR9 is primarily expressed in B cells and plasmacytoid dendritic cells (pDCs). TLR9 signalling may be critically important for B cell activity in lymph nodes but little is known about the in vivo impact of TLR9 agonism on human lymph node B cells. As a pre-defined sub-study within our clinical trial investigating TLR9 agonist MGN1703 (lefitolimod) treatment in the context of developing HIV cure strategies (NCT02443935), we assessed TLR9 agonist-mediated effects in lymph nodes. Methods: Participants received MGN1703 for 24 weeks concurrent with antiretroviral therapy. Seven participants completed the sub-study including lymph node resection at baseline and after 24 weeks of treatment. A variety of tissue-based immunologic and virologic parameters were assessed. Findings: MGN1703 dosing increased B cell differentiation; activated pDCs, NK cells, and T cells; and induced a robust interferon response in lymph nodes. Expression of Activation-Induced cytidine Deaminase, an essential regulator of B cell diversification and somatic hypermutation, was highly elevated. During MGN1703 treatment IgG production increased and antibody glycosylation patterns were changed. Interpretation: Our data present novel evidence that the TLR9 agonist MGN1703 modulates human lymph node B cells in vivo. These findings warrant further considerations in the development of TLR9 agonists as immunotherapy against cancers and infectious diseases. FUND: This work was supported by Aarhus University Research Foundation, the Danish Council for Independent Research and the NovoNordisk Foundation. Mologen AG provided study drug free of charge. (Copyright © 2019. Published by Elsevier B.V.)
Databáze:	MEDLINE
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