{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T10:14:19Z","timestamp":1761560059882,"version":"3.37.3"},"reference-count":28,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T00:00:00Z","timestamp":1610323200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004031","name":"Jichi Medical University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004031","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Graft-versus-host disease is a major complication after allogeneic hematopoietic stem cell transplantation for hematological malignancies. Immunosuppressive drugs, such as anti-thymocyte globulin, alemtuzumab, and post-transplant cyclophosphamide, have been used to prevent graft-versus-host disease in HLA-mismatched haploidentical hematopoietic stem cell transplantation. Here, we investigated whether these drugs could ameliorate graft-versus-host disease without diminishing the graft-versus-leukemia effect by using a xenogeneic transplanted graft-versus-host disease\/graft-versus-leukemia model. Anti-thymocyte globulin treatment diminished graft-versus-host disease symptoms, completely depleted the infiltration of inflammatory cells in the liver and intestine, and led to prolonged survival. By contrast, improvement after post-transplant cyclophosphamide treatment remained minimal. Alemtuzumab treatment modestly prolonged survival despite an apparent decrease of Tregs. In the graft-versus-leukemia model, 1.5 to 2.0 mg\/kg of anti-thymocyte globulin and 0.6 to 0.9 mg\/kg of alemtuzumab reduced graft-versus-host disease with minimal loss of graft-versus-leukemia effect. Mice treated with 400 mg\/kg of post-transplant cyclophosphamide did not develop graft-versus-host disease or leukemia, but it was difficult to evaluate the graft-versus-leukemia effect due to the sensitivity of A20 cells to cyclophosphamide. Although the current settings provide narrow optimal therapeutic windows, further studies are warranted to maximize the benefits of each immunosuppressant.<\/jats:p>","DOI":"10.1371\/journal.pone.0245232","type":"journal-article","created":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T20:51:34Z","timestamp":1610484694000},"page":"e0245232","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Comparison of alemtuzumab, anti-thymocyte globulin, and post-transplant cyclophosphamide for graft-versus-host disease and graft-versus-leukemia in murine models"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4736-3285","authenticated-orcid":true,"given":"Kiyomi","family":"Mashima","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iekuni","family":"Oh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken","family":"Fujiwara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junko","family":"Izawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norihito","family":"Takayama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirofumi","family":"Nakano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasufumi","family":"Kawasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Minakata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryoko","family":"Yamasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaoru","family":"Morita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Ashizawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chihiro","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaoru","family":"Hatano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuya","family":"Sato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken","family":"Ohmine","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin-Ichiro","family":"Fujiwara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nobuhiko","family":"Ohno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshinobu","family":"Kanda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,1,11]]},"reference":[{"key":"pone.0245232.ref001","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1038\/s41409-018-0387-y","article-title":"Post-transplantation cyclophosphamide-based haploidentical versus Atg-based unrelated donor allogeneic stem cell transplantation for patients younger than 60 years with hematological malignancies: a single-center experience of 209 patients.","volume":"54","author":"T Pagliardini","year":"2018","journal-title":"Bone Marrow Transplant."},{"key":"pone.0245232.ref002","doi-asserted-by":"crossref","first-page":"401","DOI":"10.3324\/haematol.2016.151779","article-title":"Post-transplant cyclophosphamide versus anti-thymocyte globulin as graft- versus-host disease prophylaxis in haploidentical transplant","volume":"102","author":"A Ruggeri","year":"2017","journal-title":"Haematologica"},{"key":"pone.0245232.ref003","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1111\/ejh.13085","article-title":"Alemtuzumab vs anti-thymocyte globulin in patients transplanted from an unrelated donor after a reduced intensity conditioning","volume":"101","author":"M Robin","year":"2018","journal-title":"Eur J Haematol"},{"key":"pone.0245232.ref004","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1016\/j.bbmt.2018.04.016","article-title":"Comprehensive analysis of the activation and proliferation kinetics and effector functions of human lymphocytes, ad antigen presentation capacity of antigen-presenting cells in xenogeneic graft-versus-host disease","volume":"24","author":"Y Kawasaki","year":"2018","journal-title":"Biol Blood Marrow Transplant"},{"key":"pone.0245232.ref005","doi-asserted-by":"crossref","first-page":"3697","DOI":"10.4049\/jimmunol.1402785","article-title":"Regulation of pulmonary graft-versus-host disease by IL-26+CD26+CD4 T lymphocytes","volume":"194","author":"K Ohnuma","year":"2015","journal-title":"J Immunol"},{"issue":"3","key":"pone.0245232.ref006","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1267\/ahc.19035","article-title":"Differential localization and invasion of tumor cells in mouse models of human and murine leukemias","volume":"53","author":"K Mashima","journal-title":"Acta Histochem Cytochem. 2020"},{"key":"pone.0245232.ref007","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/bmt.2012.244","article-title":"Investigation of the freely available easy-to-use software 'EZR' for medical statistics.","volume":"48","author":"Y Kanda","year":"2013","journal-title":"Bone Marrow Transplant"},{"issue":"3","key":"pone.0245232.ref008","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1111\/ejh.13204","article-title":"Haploidentical transplantation using low-dose alemtuzumab: Comparison with haploidentical transplantation using low-dose thymoglobulin","volume":"102","author":"S Kako","year":"2019","journal-title":"Eur J Haematol"},{"issue":"8","key":"pone.0245232.ref009","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.1182\/blood-2005-05-2146","article-title":"Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched\/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation","volume":"107","author":"DP Lu","year":"2006","journal-title":"Blood"},{"issue":"15","key":"pone.0245232.ref010","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1002\/cncr.30540","article-title":"Optimal dose of rabbit thymoglobulin in conditioning regimens for unmanipulated, haploidentical, hematopoietic stem cell transplantation: Long-term outcomes of a prospective randomized trial","volume":"123","author":"YJ Chang","year":"2017","journal-title":"Cancer"},{"issue":"11","key":"pone.0245232.ref011","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1182\/blood.2019000487","article-title":"Posttransplant cyclophosphamide vs antithymocyte globulin in HLA-mismatched unrelated donor transplantation","volume":"134","author":"G Battipaglia","year":"2019","journal-title":"Blood"},{"key":"pone.0245232.ref012","article-title":"Post-transplant cyclophosphamide for GVHD prophylaxis compared to ATG-based prophylaxis in unrelated donor transplantation","author":"R Bail\u00e9n","year":"2020","journal-title":"Ann Hematol"},{"issue":"7","key":"pone.0245232.ref013","doi-asserted-by":"crossref","first-page":"e505","DOI":"10.1016\/S2352-3026(20)30181-2","article-title":"Anti-thymocyte globulin for GVHD: one dose does not fit all","volume":"7","author":"R Admiraal","year":"2020","journal-title":"Lancet Haematol"},{"issue":"3","key":"pone.0245232.ref014","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/s41409-019-0643-9","article-title":"Personalizing rabbit anti-thymocyte globulin therapy for prevention of graft-versus-host disease after allogeneic hematopoietic cell transplantation: is there an optimal dose?","volume":"55","author":"T Shichijo","year":"2020","journal-title":"Bone Marrow Transplant."},{"issue":"12","key":"pone.0245232.ref015","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.1016\/j.bbmt.2017.08.007","article-title":"Low-Dose Antithymocyte Globulin for Graft-versus-Host-Disease Prophylaxis in Matched Unrelated Allogeneic Hematopoietic Stem Cell Transplantatio.","volume":"23","author":"A Bryant","year":"2017","journal-title":"Biol Blood Marrow Transplant"},{"issue":"1","key":"pone.0245232.ref016","doi-asserted-by":"crossref","DOI":"10.1111\/tid.12822","article-title":"No indication of increased infection rates using low-dose alemtuzumab instead of anti-thymocyte globulin as graft-versus-host disease prophylaxis before allogeneic stem cell transplantation","volume":"20","author":"T Neumann","year":"2018","journal-title":"Transpl Infect Dis"},{"issue":"9","key":"pone.0245232.ref017","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1038\/s41409-020-0813-9","article-title":"Dual T-cell depletion with ATG and PTCy for peripheral blood reduced intensity conditioning allo-HSCT results in very low rates of GVHD","volume":"55","author":"M Salas","year":"2020","journal-title":"Bone Marrow Transplant."},{"key":"pone.0245232.ref018","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1080\/14653240510018145","article-title":"Therapeutic potential of CD4+ CD25+ regulatory T cells in allogeneic transplantation","volume":"7","author":"JL Cohen","year":"2005","journal-title":"Cytotherapy"},{"key":"pone.0245232.ref019","doi-asserted-by":"crossref","first-page":"2844","DOI":"10.1681\/ASN.2006050422","article-title":"A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+Foxp3+ regulatory T cells","volume":"17","author":"M Lopez","year":"2006","journal-title":"J Am Soc Nephrol"},{"key":"pone.0245232.ref020","doi-asserted-by":"crossref","first-page":"3675","DOI":"10.1182\/blood-2008-01-130146","article-title":"Rabbit ATG but not horse ATG promotes expansion of functional CD4+ CD25highFOXP3+ regulatory T cells in vitro","volume":"111","author":"X Feng","year":"2008","journal-title":"Blood"},{"key":"pone.0245232.ref021","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s10875-011-9599-2","article-title":"Anti-T lymphocyte globulin (ATG) induces generation of regulatory T cells, at least part of them express activated CD44.","volume":"32","author":"O Shimony","year":"2012","journal-title":"J Clin Immunol"},{"key":"pone.0245232.ref022","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.clim.2006.05.006","article-title":"CD52 is a novel costimulatory molecule for induction of CD4+ regulatory T cells","volume":"120","author":"T Watanabe","year":"2006","journal-title":"Clin Immunol"},{"key":"pone.0245232.ref023","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1002\/psp4.12224","article-title":"Pharmacokinetics of monoclonal antibodies.","volume":"6","author":"JT Ryman","year":"2017","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"pone.0245232.ref024","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1111\/j.1365-2125.2007.02914.x","article-title":"Population pharmacokinetics-pharmacodynamics of alemtuzumab (Campath) in patients with chronic lymphocytic leukaemia and its link to treatment response.","volume":"64","author":"DR Mould","year":"2007","journal-title":"Br J Clin Pharmacol"},{"key":"pone.0245232.ref025","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1182\/blood-2015-07-659672","article-title":"Alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following alemtuzumab, fludarabine, and melphalan RIC HCT","volume":"127","author":"RA Marsh","year":"2016","journal-title":"Blood"},{"issue":"3","key":"pone.0245232.ref026","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1128\/AAC.3.3.407","article-title":"In vitro microassay for biological activity of cyclophosphamide metabolite","volume":"3","author":"D Laux","year":"1973","journal-title":"Antimicrob Agents Chemother"},{"key":"pone.0245232.ref027","doi-asserted-by":"crossref","first-page":"3080","DOI":"10.1182\/blood-2010-05-286856","article-title":"Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution","volume":"116","author":"R Chakraverty","year":"2010","journal-title":"Blood"},{"key":"pone.0245232.ref028","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1007\/s12185-011-0802-2","article-title":"Alemtuzumab for the prevention and treatment of graft-versus-host disease","volume":"93","author":"J Kanda","year":"2011","journal-title":"Int J Hematol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0245232","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,12]],"date-time":"2021-01-12T20:51:49Z","timestamp":1610484709000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0245232"}},"subtitle":[],"editor":[{"given":"Senthilnathan","family":"Palaniyandi","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,1,11]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0245232","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2021,1,11]]}}}