{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T01:00:01Z","timestamp":1768525201059,"version":"3.49.0"},"posted":{"date-parts":[[2025,8,11]]},"group-title":"Immunology","reference-count":30,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH\/NIAID","award":["1R21AI101932"],"award-info":[{"award-number":["1R21AI101932"]}]},{"name":"NIH\/NCI","award":["1P01CA148600"],"award-info":[{"award-number":["1P01CA148600"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  2-Methoxyestradiol (2ME2, Panzem) is an endogenous metabolite that is well-tolerated in phase I\/II clinical trials for variety of tumors. The plasma levels of 2ME2 may increase up to 1,000-fold during pregnancy and correlate temporally with the remission of rheumatoid arthritis (RA) and multiple sclerosis (MS) symptoms. The anti-inflammatory properties of 2ME2 were recently established in the mouse model of MS, and the mechanism of action is the ability of 2ME2 to inhibit lymphocyte proliferation, cytokine production and T cell polarization. Herein, we have demonstrated that 2ME2 treatment can significantly reduce the mortality and morbidity associated with graft-versus-host disease (GVHD). There is a lower number of donor-derived CD4\n                  <jats:sup>+<\/jats:sup>\n                  and CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells in the peripheral lymph node and Peyer\u2019s patches of 2ME2-treated mice compared to control recipients. Moreover, 2ME2 exposure can significantly decrease the production of IFN-\u03b3 and IL-2 in donor-derived CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cells and serum in GVHD mice. However, 2ME2 treatment has no effect on the differentiation of CD8\n                  <jats:sup>+<\/jats:sup>\n                  effector T cells in vivo and their cytolytic activity remains intact. Furthermore, 2ME2 therapy is effective in preventing GVHD while preserving graft-versus leukemia (GVL) activity in mice. Our findings indicate that 2ME2 could be a novel and effective treatment for GVHD patients.\n                <\/jats:p>","DOI":"10.1101\/2025.08.11.667504","type":"posted-content","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T06:30:15Z","timestamp":1754980215000},"source":"Crossref","is-referenced-by-count":0,"title":["2-Methoxyestradiol Treatment Prevents Graft-versus-Host Disease While Preserving Graft-versus-Leukemia Effect in Mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0968-3015","authenticated-orcid":false,"given":"Dan","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4534-2042","authenticated-orcid":false,"given":"Roland","family":"Bassett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4314-5037","authenticated-orcid":false,"given":"Richard E.","family":"Champlin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1196-1715","authenticated-orcid":false,"given":"Jeffrey J.","family":"Molldrem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0459-4112","authenticated-orcid":false,"given":"Tak W.","family":"Mak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4291-4057","authenticated-orcid":false,"given":"Qing","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025081313351074000_2025.08.11.667504v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/35077251"},{"key":"2025081313351074000_2025.08.11.667504v1.2","unstructured":"Sale, GE . The Pathology of Organ Transplantation. London, Stoneham: Butterworth Publishers, Inc. 1990. p.229\u2013260."},{"key":"2025081313351074000_2025.08.11.667504v1.3","unstructured":"Ferrara JLM , Antin JH . The Pathophysiology of graft-versus-host disease. In: Thomas ED , Blume KG , Forman SJ , eds. Hematopoietic Cell Transplantation. Blackwell Scientific Publications, Boston. 1994. p.305\u201315."},{"issue":"Suppl","key":"2025081313351074000_2025.08.11.667504v1.4","first-page":"S102","article-title":"Graft-versus-host disease: state of the science","volume":"1","year":"2013","journal-title":"Biol Blood Marrow Transplant"},{"key":"2025081313351074000_2025.08.11.667504v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2010.05.019"},{"key":"2025081313351074000_2025.08.11.667504v1.6","unstructured":"Fowler DH , and Gress RE . 1997. Graft-versus-host disease as a Th1-type process: regulation by donor cells of Th2 cytokine phenotype. In: Ferrara JLM , Deeg HJ , Burakoff SJ , eds. Graft-vs.-Host Disease. New York: Marcel Dekker Inc. p.479\u2013500."},{"key":"2025081313351074000_2025.08.11.667504v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/nri2000"},{"key":"2025081313351074000_2025.08.11.667504v1.8","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-12-290403"},{"key":"2025081313351074000_2025.08.11.667504v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/nri3226"},{"key":"2025081313351074000_2025.08.11.667504v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/nri3212"},{"issue":"13","key":"2025081313351074000_2025.08.11.667504v1.11","first-page":"3691","article-title":"2-Methoxyestradiol inhibits proliferation and induces apoptosis independently of estrogen receptors alpha and beta","volume":"62","year":"2002","journal-title":"Cancer Res"},{"key":"2025081313351074000_2025.08.11.667504v1.12","doi-asserted-by":"publisher","DOI":"10.1023\/A:1026543018478"},{"key":"2025081313351074000_2025.08.11.667504v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2007.05.005"},{"key":"2025081313351074000_2025.08.11.667504v1.14","doi-asserted-by":"publisher","DOI":"10.1530\/acta.0.1030282"},{"key":"2025081313351074000_2025.08.11.667504v1.15","doi-asserted-by":"publisher","DOI":"10.1210\/en.2006-0964"},{"key":"2025081313351074000_2025.08.11.667504v1.16","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-007-0072-5"},{"key":"2025081313351074000_2025.08.11.667504v1.17","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1386.021"},{"key":"2025081313351074000_2025.08.11.667504v1.18","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780400120"},{"key":"2025081313351074000_2025.08.11.667504v1.19","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2474-10-46"},{"key":"2025081313351074000_2025.08.11.667504v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2008.01.016"},{"key":"2025081313351074000_2025.08.11.667504v1.21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1215558110"},{"key":"2025081313351074000_2025.08.11.667504v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2011.02.007"},{"key":"2025081313351074000_2025.08.11.667504v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2009.08.013"},{"key":"2025081313351074000_2025.08.11.667504v1.24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.002865"},{"key":"2025081313351074000_2025.08.11.667504v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2012.05.014"},{"key":"2025081313351074000_2025.08.11.667504v1.26","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0b013e3181fb0486"},{"key":"2025081313351074000_2025.08.11.667504v1.27","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-07-294785"},{"key":"2025081313351074000_2025.08.11.667504v1.28","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-10-312751"},{"key":"2025081313351074000_2025.08.11.667504v1.29","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802212"},{"key":"2025081313351074000_2025.08.11.667504v1.30","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-4095"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.08.11.667504","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:19:19Z","timestamp":1768468759000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.08.11.667504"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,11]]},"references-count":30,"URL":"https:\/\/doi.org\/10.1101\/2025.08.11.667504","relation":{},"subject":[],"published":{"date-parts":[[2025,8,11]]},"subtype":"preprint"}}