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Front. Immunol. | doi: 10.3389/fimmu.2018.00894

Co-stimulation-impaired bone marrow-derived dendritic cells prevent DSS-induced colitis in mice

Carl Engman1, Yesica Garciafigueroa1,  Brett E. Phillips1,  Massimo Trucco1 and  Nick Giannoukakis1*
  • 1Institute of Cellular Therapeutics, Allegheny Health Network, United States

Dendritic cells (DC) are important in the onset and severity of inflammatory bowel disease (IBD). Tolerogenic DC induce T-cells to become therapeutic Foxp3+ regulatory T-cells (Tregs). We therefore asked if experimental IBD could be prevented by administration of bone marrow-derived DC generated under conventional GM-CSF/IL-4 conditions but in the presence of a mixture of antisense DNA oligonucleotides targeting the primary transcripts of CD40, CD80, and CD86. These cell products (which we call AS-ODN BM-DC) have demonstrated tolerogenic activity in preventing type 1 diabetes and preserving beta cell mass in new-onset type 1 diabetes in the NOD mouse strain, in earlier studies. In addition to measuring efficacy in prevention of experimental IBD, we also sought to identify possible mechanism(s) of action.

Weight, behaviour, stool frequency and character were observed daily for 7-10 days in experimentally-induced colitis in mice exposed to dextran sodium sulfate (DSS) following injection of the AS-ODN BM-DC. After euthanasia, the colons were processed for histology while spleen and mesenteric lymph nodes (MLN) were made into single cells to measure Foxp3+ Treg as well as IL-10+ regulatory B-cell (Breg) population frequency by flow cytometry.

AS-ODN BM-DC prevented DSS-induced colitis development. Recipients of these cells exhibited significant increases in Foxp3+ Treg as well as IL-10+ Breg in MLN and spleen. Histological examination of colon sections of colitis-free mice remained largely architecturally physiologic and mostly free of leukocyte infiltration when compared to DSS-treated animals.

Although DSS colitis is mainly an innate immunity-driven condition, our study adds to the growing body of evidence showing that Foxp3+ Treg and IL-10 Bregs can suppress a mainly innate-driven inflammation. The already-established safety of human DC generated from monocytic progenitors in the presence of the mixture of antisense DNA targeting the primary transcripts of CD40, CD80, and CD86 in humans offers the potential to adapt them for clinical IBD therapy.

Keywords: Dendritic Cells, immune hyporesponsiveness, Autoimmunity, Tolerogenic dendritic cells, Regulatory Sequences, Nucleic Acid, Bregs, Tregs, Colitis, Retinoic acid

Received: 27 Nov 2017; Accepted: 10 Apr 2018.

Edited by:

John Isaacs, Newcastle University, United Kingdom

Reviewed by:

Muriel Moser, Free University of Brussels, Belgium
Femke Broere, Utrecht University, Netherlands
Catharien Hilkens, Newcastle University, United Kingdom  

Copyright: © 2018 Engman, Garciafigueroa, Phillips, Trucco and Giannoukakis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Nick Giannoukakis, Allegheny Health Network, Institute of Cellular Therapeutics, 11th Floor South Tower, 320 East North Avenue, Pittsburgh, 15212, PA, United States, ngiann1@pitt.edu