Articles

Mucosal Immunology advance online publication 2 August 2017; doi: 10.1038/mi.2017.59

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

A R Krarup1,17, M Abdel-Mohsen2,3,4,17, M H Schleimann1,17, L Vibholm1,5, P A Engen6, A Dige7, B Wittig8, M Schmidt9, S J Green10,11, A Naqib11, A Keshavarzian6, X Deng2, R Olesen1, A M Petersen12,13, T Benfield14, L Østergaard1,5, T A Rasmussen1, J Agnholt5,7, J R Nyengaard5,15, A Landay16, O S Søgaard1,5, S K Pillai2,3, M Tolstrup1,5 and P W Denton1,5

  1. 1Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
  2. 2Blood Systems Research Institute, San Francisco, California, USA
  3. 3University of California, San Francisco, California, USA
  4. 4The Wistar Institute, Philadelphia, Pennsylvania, USA
  5. 5Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
  6. 6Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
  7. 7Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
  8. 8Foundation Institute Molecular Biology and Bioinformatics, Freie Universitaet Berlin, Berlin, Germany
  9. 9Mologen AG, Berlin, Germany
  10. 10Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois, USA
  11. 11DNA Services Facility, Research Resources Center, University of Illinois at Chicago, Chicago, Illinois, USA
  12. 12Department of Microbiology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
  13. 13Department of Gastroenterology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
  14. 14Department of Infectious Diseases, Hvidovre Hospital, Hvidovre, Denmark
  15. 15Core Centre for Molecular Morphology, Section for Stereology and Electron Microscopy Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus, Denmark
  16. 16Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois, USA

Correspondence: PW Denton, pade@clin.au.dk

17These authors contributed equally to this work.

Received 27 March 2017; Accepted 25 May 2017
Advance online publication 2 August 2017

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Abstract

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 (60mg 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.

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