Comparison of alemtuzumab, anti-thymocyte globulin, and post-transplant cyclophosphamide for graft-versus-host disease and graft-versus-leukemia in murine models
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...
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| Veröffentlicht in: | PloS one 2021-01, Vol.16 (1), p.e0245232 |
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| creator | Mashima, Kiyomi Oh, Iekuni Fujiwara, Ken Izawa, Junko Takayama, Norihito Nakano, Hirofumi Kawasaki, Yasufumi Minakata, Daisuke Yamasaki, Ryoko Morita, Kaoru Ashizawa, Masahiro Yamamoto, Chihiro Hatano, Kaoru Sato, Kazuya Ohmine, Ken Fujiwara, Shin-Ichiro Ohno, Nobuhiko Kanda, Yoshinobu |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0245232 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0245232</identifier><identifier>PMID: 33428661</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Alemtuzumab - therapeutic use ; Anatomy ; Animal models ; Animals ; Antibodies ; Antilymphocyte Serum - therapeutic use ; Antithymocyte globulin ; Biology ; Biology and life sciences ; Comparative analysis ; Computed tomography ; Cyclophosphamide ; Cyclophosphamide - therapeutic use ; Disease Models, Animal ; Drug therapy ; Editing ; Experiments ; Female ; Globulins ; Graft versus host disease ; Graft versus host reaction ; Graft vs Host Disease - drug therapy ; Graft vs Host Disease - etiology ; Graft vs Host Disease - prevention & control ; Grafting ; Hematology ; Hematopoietic Stem Cell Transplantation - adverse effects ; Hematopoietic stem cells ; Histology ; Humans ; Immunosuppressive agents ; Immunotherapy ; Leukemia ; Luciferin ; Lymphocytes ; Lymphocytes T ; Lymphoma ; Medical imaging ; Medical research ; Medicine ; Medicine and Health Sciences ; Methodology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Monoclonal antibodies ; Research and Analysis Methods ; Severity of Illness Index ; Sodium salts ; Stem cell transplantation ; Stem cells ; Substrates ; Targeted cancer therapy ; Thymocytes ; Transplantation ; Transplants & implants ; Tumor Burden ; Viruses</subject><ispartof>PloS one, 2021-01, Vol.16 (1), p.e0245232</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Mashima et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 Mashima et al 2021 Mashima et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-474e332fe0c24e642bcbae9dbbce0262d5f91fa42896bf030de37b999866a3e83</citedby><cites>FETCH-LOGICAL-c758t-474e332fe0c24e642bcbae9dbbce0262d5f91fa42896bf030de37b999866a3e83</cites><orcidid>0000-0002-4736-3285</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799789/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799789/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33428661$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Palaniyandi, Senthilnathan</contributor><creatorcontrib>Mashima, Kiyomi</creatorcontrib><creatorcontrib>Oh, Iekuni</creatorcontrib><creatorcontrib>Fujiwara, Ken</creatorcontrib><creatorcontrib>Izawa, Junko</creatorcontrib><creatorcontrib>Takayama, Norihito</creatorcontrib><creatorcontrib>Nakano, Hirofumi</creatorcontrib><creatorcontrib>Kawasaki, Yasufumi</creatorcontrib><creatorcontrib>Minakata, Daisuke</creatorcontrib><creatorcontrib>Yamasaki, Ryoko</creatorcontrib><creatorcontrib>Morita, Kaoru</creatorcontrib><creatorcontrib>Ashizawa, Masahiro</creatorcontrib><creatorcontrib>Yamamoto, Chihiro</creatorcontrib><creatorcontrib>Hatano, Kaoru</creatorcontrib><creatorcontrib>Sato, Kazuya</creatorcontrib><creatorcontrib>Ohmine, Ken</creatorcontrib><creatorcontrib>Fujiwara, Shin-Ichiro</creatorcontrib><creatorcontrib>Ohno, Nobuhiko</creatorcontrib><creatorcontrib>Kanda, Yoshinobu</creatorcontrib><title>Comparison of alemtuzumab, anti-thymocyte globulin, and post-transplant cyclophosphamide for graft-versus-host disease and graft-versus-leukemia in murine models</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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.</description><subject>Adult</subject><subject>Alemtuzumab - therapeutic use</subject><subject>Anatomy</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antilymphocyte Serum - therapeutic use</subject><subject>Antithymocyte globulin</subject><subject>Biology</subject><subject>Biology and life sciences</subject><subject>Comparative analysis</subject><subject>Computed tomography</subject><subject>Cyclophosphamide</subject><subject>Cyclophosphamide - therapeutic use</subject><subject>Disease Models, Animal</subject><subject>Drug therapy</subject><subject>Editing</subject><subject>Experiments</subject><subject>Female</subject><subject>Globulins</subject><subject>Graft versus host disease</subject><subject>Graft versus host reaction</subject><subject>Graft vs Host Disease - drug therapy</subject><subject>Graft vs Host Disease - etiology</subject><subject>Graft vs Host Disease - prevention & control</subject><subject>Grafting</subject><subject>Hematology</subject><subject>Hematopoietic Stem Cell Transplantation - adverse effects</subject><subject>Hematopoietic stem cells</subject><subject>Histology</subject><subject>Humans</subject><subject>Immunosuppressive agents</subject><subject>Immunotherapy</subject><subject>Leukemia</subject><subject>Luciferin</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Lymphoma</subject><subject>Medical imaging</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Methodology</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Monoclonal antibodies</subject><subject>Research and Analysis Methods</subject><subject>Severity of Illness Index</subject><subject>Sodium 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Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mashima, Kiyomi</au><au>Oh, Iekuni</au><au>Fujiwara, Ken</au><au>Izawa, Junko</au><au>Takayama, Norihito</au><au>Nakano, Hirofumi</au><au>Kawasaki, Yasufumi</au><au>Minakata, Daisuke</au><au>Yamasaki, Ryoko</au><au>Morita, Kaoru</au><au>Ashizawa, Masahiro</au><au>Yamamoto, Chihiro</au><au>Hatano, Kaoru</au><au>Sato, Kazuya</au><au>Ohmine, Ken</au><au>Fujiwara, Shin-Ichiro</au><au>Ohno, Nobuhiko</au><au>Kanda, Yoshinobu</au><au>Palaniyandi, Senthilnathan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comparison of alemtuzumab, anti-thymocyte globulin, and post-transplant cyclophosphamide for graft-versus-host disease and graft-versus-leukemia in murine models</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2021-01-11</date><risdate>2021</risdate><volume>16</volume><issue>1</issue><spage>e0245232</spage><pages>e0245232-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>33428661</pmid><doi>10.1371/journal.pone.0245232</doi><tpages>e0245232</tpages><orcidid>https://orcid.org/0000-0002-4736-3285</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2021-01, Vol.16 (1), p.e0245232 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2476828946 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adult Alemtuzumab - therapeutic use Anatomy Animal models Animals Antibodies Antilymphocyte Serum - therapeutic use Antithymocyte globulin Biology Biology and life sciences Comparative analysis Computed tomography Cyclophosphamide Cyclophosphamide - therapeutic use Disease Models, Animal Drug therapy Editing Experiments Female Globulins Graft versus host disease Graft versus host reaction Graft vs Host Disease - drug therapy Graft vs Host Disease - etiology Graft vs Host Disease - prevention & control Grafting Hematology Hematopoietic Stem Cell Transplantation - adverse effects Hematopoietic stem cells Histology Humans Immunosuppressive agents Immunotherapy Leukemia Luciferin Lymphocytes Lymphocytes T Lymphoma Medical imaging Medical research Medicine Medicine and Health Sciences Methodology Mice Mice, Inbred NOD Mice, SCID Monoclonal antibodies Research and Analysis Methods Severity of Illness Index Sodium salts Stem cell transplantation Stem cells Substrates Targeted cancer therapy Thymocytes Transplantation Transplants & implants Tumor Burden Viruses |
| title | Comparison of alemtuzumab, anti-thymocyte globulin, and post-transplant cyclophosphamide for graft-versus-host disease and graft-versus-leukemia in murine models |
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