The TLR9 agonist MGN1703 triggers a potent type I interferon response in the sigmoid colon

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  • A R Krarup
  • ,
  • M Abdel-Mohsen, The Wistar Institute, Philadelphia, Pennsylvania 19104-4268, USA
  • ,
  • M H Schleimann
  • ,
  • L Vibholm
  • P A Engen, Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
  • ,
  • A Dige
  • B Wittig, Foundation Institute Molecular Biology and Bioinformatics, Freie Universitaet, Berlin, Germany.
  • ,
  • M Schmidt
  • S J Green, Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois, USA.
  • ,
  • A Naqib, DNA Services Facility, Research Resources Center, University of Illinois at Chicago, Chicago, Illinois, USA.
  • ,
  • A Keshavarzian, Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
  • ,
  • X Deng
  • ,
  • R Olesen
  • A M Petersen, Department of Microbiology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
  • ,
  • T Benfield, c Department of Infectious Diseases , Hvidovre Hospital , Hvidovre , Denmark.
  • ,
  • L Østergaard
  • T A Rasmussen
  • J Agnholt
  • J R Nyengaard
  • A Landay, Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois, USA.
  • ,
  • O S Søgaard
  • S K Pillai, Multiple Sclerosis Center, University of California San Francisco, CA, USA.
  • ,
  • M Tolstrup
  • P W Denton

Toll-like receptor 9 (TLR9) agonists are being developed for treatment of colorectal and other cancers, yet the impact of these drugs on human intestines remains unknown. This, together with the fact that there are additional potential indications for TLR9 agonist therapy (e.g., autoimmune and infectious diseases), led us to investigate the impact of MGN1703 (Lefitolimod) on intestinal homeostasis and viral persistence in HIV-positive individuals. Colonic sigmoid biopsies were collected (baseline and week four) from 11 HIV+ individuals on suppressive antiretroviral therapy, who received MGN1703 (60 mg s.c.) twice weekly for 4 weeks in a single-arm, phase 1b/2a study. Within sigmoid mucosa, global transcriptomic analyses revealed 248 modulated genes (false discovery rate<0.05) including many type I interferon (IFN)-stimulated genes. MGN1703 increased the frequencies of cells exhibiting MX1 (P=0.001) and ISG15 (P=0.014) protein expression. No changes were observed in neutrophil infiltration (myeloperoxidase; P=0.97). No systematic effect on fecal microbiota structure was observed (analysis of similarity Global R=-0.105; P=0.929). TLR9 expression at baseline was inversely proportional to the change in integrated HIV DNA during MGN1703 treatment (P=0.020). In conclusion, MGN1703 induced a potent type I IFN response, without a concomitant general inflammatory response, in the intestines.Mucosal Immunology advance online publication, 02 August 2017; doi:10.1038/mi.2017.59.

OriginalsprogEngelsk
TidsskriftMucosal Immunology
Vol/bind11
Sider (fra-til)449–461
ISSN1933-0219
DOI
StatusUdgivet - 2018

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