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TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes.
Schleimann, Mariane H; Kobberø, Maria-Louise; Vibholm, Line K; Kjær, Kathrine; Giron, Leila B; Busman-Sahay, Kathleen; Chan, Chi Ngai; Nekorchuk, Michael; Schmidt, Manuel; Wittig, Burghardt; Damsgaard, Tine E; Ahlburg, Peter; Hellfritzsch, Michel B; Zuwala, Kaja; Rothemejer, Frederik H; Olesen, Rikke; Schommers, Phillipp; Klein, Florian; Dweep, Harsh; Kossenkov, Andrew; Nyengaard, Jens R; Estes, Jacob D; Abdel-Mohsen, Mohamed; Østergaard, Lars; Tolstrup, Martin; Søgaard, Ole S; Denton, Paul W.
Afiliación
  • 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, Par
  • 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.
EBioMedicine ; 45: 328-340, 2019 Jul.
Article en En | MEDLINE | ID: mdl-31300344
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN / Infecciones por VIH / Diferenciación Celular / Receptor Toll-Like 9 Límite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: EBioMedicine Año: 2019 Tipo del documento: Article Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN / Infecciones por VIH / Diferenciación Celular / Receptor Toll-Like 9 Límite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: EBioMedicine Año: 2019 Tipo del documento: Article Pais de publicación: Países Bajos