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      Azacytidine mitigates experimental sclerodermic chronic graft-versus-host disease

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          Abstract

          Background

          Previous studies have demonstrated that regulatory T cells (Tregs) play a protective role in the pathogenesis of chronic graft-versus-host disease (cGVHD). Tregs constitutively express the gene of the transcription factor Foxp3 whose CNS2 region is heavily methylated in conventional CD4 + T cells (CD4 +Tconvs) but demethylated in Tregs.

          Methods

          Here, we assessed the impact of azacytidine (AZA) on cGVHD in a well-established murine model of sclerodermic cGVHD (B10.D2 (H-2d) → BALB/cJ (H-2d)).

          Results

          The administration of AZA every 48 h from day +10 to day +30 at the dose of 0.5 mg/kg or 2 mg/kg mitigated chronic GVHD. Further, AZA-treated mice exhibited higher blood and thymic Treg frequencies on day +35, as well as higher demethylation levels of the Foxp3 enhancer and the IL-2 promoter in splenocytes at day +52. Interestingly, Tregs from AZA-treated mice expressed more frequently the activation marker CD103 on day +52. AZA-treated mice had also lower counts of CD4 +Tconvs and CD8 + T cells from day +21 to day +35 after transplantation, as well as a lower proportion of CD4 +Tconvs expressing the Ki67 antigen on day +21 demonstrating an anti-proliferating effect of the drug on T cells.

          Conclusions

          Our results indicate that AZA prevented sclerodermic cGVHD in a well-established murine model of cGVHD. These data might serve as the basis for a pilot study of AZA administration for cGVHD prevention in patients at high risk for cGVHD.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13045-016-0281-2) contains supplementary material, which is available to authorized users.

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          Most cited references45

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          Simple method of estimating severity of pulmonary fibrosis on a numerical scale.

          A continuous numerical scale for determining the degree of fibrosis in lung specimens was devised for correlation with other pulmonary variables such as lung function tests or mineral burden. Grading was scored on a scale from 0 to 8, using the average of microscope field scores. The system allows fibrosis to be measured in small samples of tissue (1 cm) which can provide a detailed description of the changes in a lung, currently not possible with most existing methods.
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            Advances in graft-versus-host disease biology and therapy.

            Allogeneic haematopoietic stem cell transplantation is used to treat a variety of disorders, but its efficacy is limited by the occurrence of graft-versus-host disease (GVHD). The past decade has brought impressive advances in our understanding of the role of stimulatory and suppressive elements of the adaptive and innate immune systems from both the donor and the host in GVHD pathogenesis. New insights from basic immunology, preclinical models and clinical studies have led to novel approaches for prevention and treatment. This Review highlights the recent advances in understanding the pathophysiology of GVHD and its treatment, with a focus on manipulations of the immune system that are amenable to clinical application.
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              Long-term survival and late deaths after allogeneic hematopoietic cell transplantation.

              Allogeneic hematopoietic cell transplantation (HCT) is curative but is associated with life-threatening complications. Most deaths occur within the first 2 years after transplantation. In this report, we examine long-term survival in 2-year survivors in the largest cohort ever studied. Records of 10,632 patients worldwide reported to the Center for International Blood and Marrow Transplant Research who were alive and disease free 2 years after receiving a myeloablative allogeneic HCT before 2004 for acute myelogenous or lymphoblastic leukemia, myelodysplastic syndrome, lymphoma, or severe aplastic anemia were reviewed. Median follow-up was 9 years, and 3,788 patients had been observed for 10 or more years. The probability of being alive 10 years after HCT was 85%. The chief risk factors for late death included older age and chronic graft-versus-host disease (GVHD). For patients who underwent transplantation for malignancy, relapse was the most common cause of death. The greatest risk factor for late relapse was advanced disease at transplantation. Principal risk factors for nonrelapse deaths were older age and GVHD. When compared with age, sex, and nationality-matched general population, late deaths remained higher than expected for each disease, with the possible exception of lymphoma, although the relative risk generally receded over time. The prospect for long-term survival is excellent for 2-year survivors of allogeneic HCT. However, life expectancy remains lower than expected. Performance of HCT earlier in the course of disease, control of GVHD, enhancement of immune reconstitution, less toxic regimens, and prevention and early treatment of late complications are needed.
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                Author and article information

                Contributors
                +32-4-366 72 01 , f.baron@ulg.ac.be
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                1756-8722
                4 July 2016
                4 July 2016
                2016
                : 9
                : 53
                Affiliations
                [ ]Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I3, Laboratory of Hematology, University of Liège, Liège, Belgium
                [ ]GIGA-R, Department of Pathology, University of Liège, Liège, Belgium
                [ ]GIGA-R, Animal care unit, University of Liège, Liège, Belgium
                [ ]Department of Medicine, Division of Hematology, CHU of Liège, Liège, Belgium
                [ ]Translational Immunology Laboratory, VIB, Leuven, Belgium
                [ ]Department of Microbiology and Immunology, KU Leuven-University of Leuven, Leuven, Belgium
                [ ]Department of Hematology, University of Liège, CHU Sart-Tilman, 4000 Liège, Belgium
                Article
                281
                10.1186/s13045-016-0281-2
                4932697
                27377819
                068a9219-f09f-48d7-afc7-df518734c9ba
                © Fransolet et al. 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 1 April 2016
                : 21 June 2016
                Funding
                Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/501100002661, Fonds De La Recherche Scientifique - FNRS;
                Funded by: Leon Fredericq fund
                Funded by: Anti-Cancer Center ULg
                Funded by: Fonds Wetenschappelijk Onderzoek – Vlaanderen
                Funded by: Belgian Foundation Against Cancer
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Oncology & Radiotherapy
                aza,azacytidine,decitabine,dac,treg,regulatory t cells,gvhd,graft-versus-host disease,chronic graft-versus-host disease,sclerodermic graft-versus-host disease

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