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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2018.03104

BET Bromodomain Inhibitors Which Permit Treg Function Enable a Combinatorial Strategy to Suppress GVHD in Pre-clinical Allogeneic HSCT

 SABRINA N. COPSEL1, 2*, Casey O. Lightbourn1,  Henry Barreras1, Ines Lohse2, 3,  Dietlinde Wolf2,  Cameron S. Bader1, John Manov1,  Brandon J. Kale1, Devangi Shah1, Shaun P. Brothers2, 3,  Victor L. Perez4, Krishna V. Komanduri1, 2, 5, Claes Wahlestedt2, 3 and  Robert B. Levy1, 2, 4, 5, 6*
  • 1Department of Microbiology and Immunology, Leonard M. Miller School of Medicine, University of Miami, United States
  • 2Sylvester Comprehensive Cancer Center, United States
  • 3Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, United States
  • 4Bascom Palmer Eye Institute, University of Miami Health System, United States
  • 5Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, United States
  • 6Leonard M. Miller School of Medicine, United States

A recent approach for limiting production of pro-inflammatory cytokines has been to target bromodomain and extra-terminal (BET) proteins. These epigenetic readers of histone acetylation regulate transcription of genes involved in inflammation, cardiovascular disease, and cancer. Development of BET inhibitors (BETi) has generated enormous interest for their therapeutic potential. Because inflammatory signals and donor T cells promote graft-versus-host disease (GVHD), regulating both pathways could be effective to abrogate this disorder. The objective of the present study was to identify a BETi which did not interfere in vivo with CD4+FoxP3+ regulatory T cell (Treg) expansion and function to utilize together with Tregs following allogeneic hematopoietic stem cell transplantation (aHSCT) to ameliorate GVHD. We have reported that Tregs can be markedly expanded and selectively activated with increased functional capacity by targeting TNFRSF25 and CD25 with TL1A-Ig and low dose IL-2, respectively. Here, mice were treated over 7 days (TL1A-Ig+IL-2) together with BETi. We found that the BETi EP11313 did not decrease frequency/numbers or phenotype of expanded Tregs as well as effector molecules such as IL-10 and TGF-β. However, BETi JQ1 interfered with Treg expansion and altered subset distribution and phenotype. Notably, in Treg expanded mice, EP11313 diminished tnfa and ifng but not il-2 RNA levels. Remarkably, Treg pSTAT5 expression was not affected by EP11313 supporting the notion that Treg IL-2 signaling remained intact. MHC-mismatched aHSCT (B6BALB/c) was performed using in vivo expanded donor Tregs with or without EP11313 short-term treatment in the recipient. Early post-transplant, improvement in the splenic and LN CD4/CD8 ratio along with fewer effector cells and high Treg levels in aHSCT recipients treated with expanded Tregs+EP11313 was detected. Interestingly, this group exhibited a significant diminution of GVHD clinical score with less skin and ocular involvement. Finally, using low numbers of highly purified expanded Tregs, improved clinical GVHD scores were observed in EP11313 treated recipients. In total, we conclude that use of this novel combinatorial strategy can suppress pre-clinical GVHD and posit, in vivo EP11313 treatment might be useful combined with Treg expansion therapy for treatment of diseases involving inflammatory responses.

Keywords: Tregs ( Regulatory T cells), Bromodomain inhibitor, GvHD, TNFRSF25, CD25, Epigenetic regulation

Received: 28 Sep 2018; Accepted: 17 Dec 2018.

Edited by:

Xue-Zhong Yu, Medical University of South Carolina, United States

Reviewed by:

Dennis O. Adeegbe, Moffitt Cancer Center, United States
Jessica Voss, Feinberg School of Medicine, Northwestern University, United States  

Copyright: © 2018 COPSEL, Lightbourn, Barreras, Lohse, Wolf, Bader, Manov, Kale, Shah, Brothers, Perez, Komanduri, Wahlestedt and Levy. 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(s) 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. SABRINA N. COPSEL, Department of Microbiology and Immunology, Leonard M. Miller School of Medicine, University of Miami, Miami, United States,
Prof. Robert B. Levy, Leonard M. Miller School of Medicine, Miami, United States,