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

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          Abstract

          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.

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          Most cited references30

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          A function for interleukin 2 in Foxp3-expressing regulatory T cells.

          Regulatory T cells (T(reg) cells) expressing the forkhead family transcription factor Foxp3 are critical mediators of dominant immune tolerance to self. Most T(reg) cells constitutively express the high-affinity interleukin 2 (IL-2) receptor alpha-chain (CD25); however, the precise function of IL-2 in T(reg) cell biology has remained controversial. To directly assess the effect of IL-2 signaling on T(reg) cell development and function, we analyzed mice containing the Foxp3(gfp) knock-in allele that were genetically deficient in either IL-2 (Il2(-/-)) or CD25 (Il2ra(-/-)). We found that IL-2 signaling was dispensable for the induction of Foxp3 expression in thymocytes from these mice, which indicated that IL-2 signaling does not have a nonredundant function in the development of T(reg) cells. Unexpectedly, Il2(-/-) and Il2ra(-/-) T(reg) cells were fully able to suppress T cell proliferation in vitro. In contrast, Foxp3 was not expressed in thymocytes or peripheral T cells from Il2rg(-/-) mice. Gene expression analysis showed that IL-2 signaling was required for maintenance of the expression of genes involved in the regulation of cell growth and metabolism. Thus, IL-2 signaling seems to be critically required for maintaining the homeostasis and competitive fitness of T(reg) cells in vivo.
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            Acute Graft-versus-Host Disease — Biologic Process, Prevention, and Therapy

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              Donor-type CD4+CD25+ Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation

              Acute graft-versus-host disease (aGVHD) is still a major obstacle in clinical allogeneic bone marrow (BM) transplantation. CD4+CD25+ regulatory T (Treg) cells have recently been shown to suppress proliferative responses of CD4+CD25− T cells to alloantigenic stimulation in vitro and are required for ex vivo tolerization of donor T cells, which results in their reduced potential to induce aGVHD. Here we show that CD4+CD25+ T cells isolated from the spleen or BM of donor C57BL/6 (H-2b) mice that have not been tolerized are still potent inhibitors of the alloresponse in vitro and of lethal aGVHD induced by C57BL/6 CD4+CD25− T cells in irradiated BALB/c (H-2d) hosts in vivo. The addition of the CD4+CD25+ Treg cells at a 1:1 ratio with responder/inducer CD4+CD25− T cells resulted in a >90% inhibition of the mixed leukocyte reaction and marked protection from lethal GVHD. This protective effect depended in part on the ability of the transferred CD4+CD25+ T cells to secrete interleukin 10 and occurred if the Treg cells were of donor, but not host, origin. Our results demonstrate that the balance of donor-type CD4+CD25+ Treg and conventional CD4+CD25− T cells can determine the outcome of aGVHD.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                24 January 2019
                2018
                : 9
                : 3104
                Affiliations
                [1] 1Department of Microbiology and Immunology, Miller School of Medicine, University of Miami , Miami, FL, United States
                [2] 2Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami , Miami, FL, United States
                [3] 3Center for Therapeutic Innovation and Department of Psychiatry and Behavior Sciences, Miller School of Medicine, University of Miami , Miami, FL, United States
                [4] 4Department of Ophthalmology, Miller School of Medicine, University of Miami , Miami, FL, United States
                [5] 5Department of Medicine, Miller School of Medicine, University of Miami , Miami, FL, United States
                Author notes

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

                Reviewed by: Dennis O. Adeegbe, Moffitt Cancer Center, United States; Jessica Voss, Northwestern University, United States

                *Correspondence: Sabrina N. Copsel snc49@ 123456med.miami.edu

                This article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2018.03104
                6353853
                30733722
                1756e8c2-3d1f-483d-af38-ba8e95ad0e94
                Copyright © 2019 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.

                History
                : 28 September 2018
                : 17 December 2018
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 44, Pages: 13, Words: 8804
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: RO1 EY024484-01
                Award ID: DA035592
                Award ID: DA035055
                Award ID: AA023781
                Award ID: R01NS092671
                Award ID: R01MH110441
                Funded by: Florida Department of Health 10.13039/100006827
                Award ID: 6AZ08
                Categories
                Immunology
                Original Research

                Immunology
                tregs,bromodomain inhibitors,epigenetic regulation,gvhd,tnfrsf25,cd25
                Immunology
                tregs, bromodomain inhibitors, epigenetic regulation, gvhd, tnfrsf25, cd25

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