Schleimann, Mariane H., Kobbero, Maria-Louise, Vibholm, Line K., Kjaer, Kathrine ORCID: 0000-0002-2367-2470, 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 ORCID: 0000-0002-5157-080X, Schommers, Phillipp, Klein, Florian, Dweep, Harsh, Kossenkov, Andrew, Nyengaard, Jens R., Estes, Jacob D., Abdel-Mohsen, Mohamed, Ostergaard, Lars ORCID: 0000-0002-7619-605X, Tolstrup, Martin ORCID: 0000-0001-7020-5173, Sogaard, Ole S. and Denton, Paul W. (2019). TLR9 agonist MGN1703 enhances B cell differentiation and function in lymph nodes. EBioMedicine, 45. S. 328 - 341. AMSTERDAM: ELSEVIER. ISSN 2352-3964

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Abstract

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 receivedMGN1703 for 24weeks concurrentwith antiretroviral therapy. Seven participants completed the sub-study including lymph node resection at baseline and after 24weeks 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 MGN 1703 modulates human lymph node B cells in vivo. These findingswarrant further considerations in the development of TLR9 agonists as immunotherapy against cancers and infectious diseases. (C) 2019 The Authors. Published by Elsevier B.V.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schleimann, Mariane H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kobbero, Maria-LouiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vibholm, Line K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kjaer, KathrineUNSPECIFIEDorcid.org/0000-0002-2367-2470UNSPECIFIED
Giron, Leila B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Busman-Sahay, KathleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chan, Chi NgaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nekorchuk, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, ManuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wittig, BurghardtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Damsgaard, Tine E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahlburg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hellfritzsch, Michel B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zuwala, KajaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rothemejer, Frederik H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olesen, RikkeUNSPECIFIEDorcid.org/0000-0002-5157-080XUNSPECIFIED
Schommers, PhillippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dweep, HarshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kossenkov, AndrewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nyengaard, Jens R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Estes, Jacob D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abdel-Mohsen, MohamedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ostergaard, LarsUNSPECIFIEDorcid.org/0000-0002-7619-605XUNSPECIFIED
Tolstrup, MartinUNSPECIFIEDorcid.org/0000-0001-7020-5173UNSPECIFIED
Sogaard, Ole S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Denton, Paul W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-136205
DOI: 10.1016/j.ebiom.2019.07.005
Journal or Publication Title: EBioMedicine
Volume: 45
Page Range: S. 328 - 341
Date: 2019
Publisher: ELSEVIER
Place of Publication: AMSTERDAM
ISSN: 2352-3964
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TOLL-LIKE RECEPTORS; IMMUNODEFICIENCY-VIRUS TYPE-1; FUSION INHIBITOR T-20; HIV-1 TRANSCRIPTION; DENDRITIC CELLS; PERSISTENCE; EXPRESSION; IMMUNITY; ANTIBODY; TISSUEMultiple languages
Medicine, General & Internal; Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/13620

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