{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T06:11:16Z","timestamp":1779343876599,"version":"3.51.4"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation, characterized by donor T-cell-mediated immune responses against the host. This condition significantly impacts patient quality of life, and it is associated with mortality, particularly when the gastrointestinal tract is affected. This study investigated the potential therapeutic synergy between umbilical cord-derived mesenchymal stromal cells (UC-MSCs), known for their immunomodulatory potential, and Vedolizumab (VDZ), a gut-specific \u03b14\u03b27 integrin antagonist that prevents lymphocyte trafficking to intestinal tissues. Our results demonstrate that UC-MSCs maintain an unaltered immunophenotype and low \u03b14\u03b27 expression in the presence of VDZ, even under inflammatory conditions. Moreover, VDZ exposure did not modify UC-MSC immunomodulatory functions, IDO expression, or susceptibility to peripheral blood mononuclear cell-mediated lysis. In an NSG mouse model of aGvHD, single-agent therapies showed limited effects on survival, whereas combined VDZ and UC-MSCs highlighted the critical importance of optimizing administration windows and dosing schedules. Although no clear synergistic therapeutic benefits were observed in this model, the absence of toxicity or mutual inhibition establishes a favorable safety profile for the combination of VDZ and UC-MSCs as rescue therapy for steroid-refractory aGvHD. These findings also provide a rationale for exploring this combination in a prophylactic setting, preventing gastrointestinal aGvHD by limiting early lymphocyte trafficking while preserving systemic immune regulation.<\/jats:p>","DOI":"10.3389\/fcell.2026.1836978","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T05:44:24Z","timestamp":1779342264000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Assessment of Vedolizumab and UC-MSC interaction and therapeutic potential in acute graft-versus-host-disease"],"prefix":"10.3389","volume":"14","author":[{"given":"Anna","family":"Merlo","sequence":"first","affiliation":[{"name":"Advanced Cellular Therapy Laboratory, Haematology Unit","place":["Vicenza, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serena","family":"Zilio","sequence":"additional","affiliation":[{"name":"Veneto Institute of Oncology, IOV \u2013 IRCCS, Immunology and Molecular Oncology Diagnostics","place":["Padua, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Bernardi","sequence":"additional","affiliation":[{"name":"Advanced Cellular Therapy Laboratory, Haematology Unit","place":["Vicenza, Italy"]},{"name":"Veneto Institute of Oncology, IOV \u2013 IRCCS, Immunology and Molecular Oncology Diagnostics","place":["Padua, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Catanzaro","sequence":"additional","affiliation":[{"name":"Advanced Cellular Therapy Laboratory, Haematology Unit","place":["Vicenza, Italy"]},{"name":"Veneto Institute of Oncology, IOV \u2013 IRCCS, Immunology and Molecular Oncology Diagnostics","place":["Padua, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa","family":"Galla","sequence":"additional","affiliation":[{"name":"Advanced Cellular Therapy Laboratory, Haematology Unit","place":["Vicenza, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Zocca","sequence":"additional","affiliation":[{"name":"Advanced Cellular Therapy Laboratory, Haematology Unit","place":["Vicenza, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivia","family":"Marini","sequence":"additional","affiliation":[{"name":"Advanced Cellular Therapy Laboratory, Haematology Unit","place":["Vicenza, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Piccoli","sequence":"additional","affiliation":[{"name":"Advanced Cellular Therapy Laboratory, Haematology Unit","place":["Vicenza, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Tosetto","sequence":"additional","affiliation":[{"name":"Transplant Program, Haematology Unit","place":["Vicenza, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weisha","family":"Qi","sequence":"additional","affiliation":[{"name":"Veneto Institute of Oncology, IOV \u2013 IRCCS, Immunology and Molecular Oncology Diagnostics","place":["Padua, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilaria","family":"Marigo","sequence":"additional","affiliation":[{"name":"Veneto Institute of Oncology, IOV \u2013 IRCCS, Immunology and Molecular Oncology Diagnostics","place":["Padua, Italy"]},{"name":"Department of Surgery, Oncology and Gastroenterology, University of Padua","place":["Padua, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Elice","sequence":"additional","affiliation":[{"name":"Advanced Cellular Therapy Laboratory, Haematology Unit","place":["Vicenza, Italy"]},{"name":"Transplant Program, Haematology Unit","place":["Vicenza, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Astori","sequence":"additional","affiliation":[{"name":"Advanced Cellular Therapy Laboratory, Haematology Unit","place":["Vicenza, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1093\/stcltm\/szae061","article-title":"Cryopreserved apoptotic mesenchymal stromal cells retain functional efficacy in suppressing an allergic inflammation in a murine model","volume":"13","author":"Amison","year":"2024","journal-title":"Stem Cells Transl. Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1186\/s12967-020-02625-0","article-title":"Logistics of an advanced therapy medicinal product during COVID-19 pandemic in Italy: successful delivery of mesenchymal stromal cells in dry ice","volume":"30","author":"Astori","year":"2020","journal-title":"J. Transl. Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1500","DOI":"10.1038\/s41409-022-01741-3","article-title":"Therapy response of glucocorticoid-refractory acute GVHD of the lower intestinal tract","volume":"57","author":"Biovasco","year":"2022","journal-title":"Bone Marrow Transpl."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1016\/j.jcyt.2017.08.004","article-title":"Umbilical cord mesenchymal stromal cell transplantations: a systemic analysis of clinical trials","volume":"19","author":"Can","year":"2017","journal-title":"Cytotherapy"},{"key":"B5","doi-asserted-by":"publisher","first-page":"786","DOI":"10.3109\/14653249.2011.563294","article-title":"Minimally manipulated whole human umbilical cord is a rich source of clinical-grade human mesenchymal stromal cells expanded in human platelet lysate","volume":"13","author":"Capelli","year":"2011","journal-title":"Cytotherapy"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2277","DOI":"10.1038\/s41591-024-03016-4","article-title":"Vedolizumab for the prevention of intestinal acute GVHD after allogeneic hematopoietic stem cell transplantation: a randomized phase 3 trial","volume":"30","author":"Chen","year":"2024","journal-title":"Nat. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3531","DOI":"10.1016\/j.ymthe.2023.10.004","article-title":"Apoptosis in mesenchymal stromal cells activates an immunosuppressive secretome predicting clinical response in Crohn's disease","volume":"31","author":"Cheung","year":"2023","journal-title":"Mol. Ther."},{"key":"B8","doi-asserted-by":"publisher","first-page":"e06036","DOI":"10.1016\/j.heliyon.2021.e06036","article-title":"A flow cytometric assay for the quantification of MSC lysis by peripheral blood mononucleated cells","volume":"7","author":"Chieregato","year":"2021","journal-title":"Heliyon"},{"key":"B9","doi-asserted-by":"publisher","first-page":"4093","DOI":"10.1182\/blood-2012-01-403196","article-title":"IFNgammaR signaling mediates alloreactive T-cell trafficking and GVHD","volume":"120","author":"Choi","year":"2012","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells. The International society for cellular therapy position statement","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"key":"B11","doi-asserted-by":"publisher","first-page":"4009","DOI":"10.1182\/blood-2005-06-2339","article-title":"L-selectin and beta7 integrin on donor CD4 T cells are required for the early migration to host mesenteric lymph nodes and acute colitis of graft-versus-host disease","volume":"106","author":"Dutt","year":"2005","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1046\/j.1365-2141.2000.01986.x","article-title":"Mesenchymal progenitor cells in human umbilical cord blood","volume":"109","author":"Erices","year":"2000","journal-title":"Br. J. Haematol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1897","DOI":"10.1182\/blood.2025028553","article-title":"Remestemcel-L-rknd (Ryoncil): the first approved cellular therapy for steroid-refractory acute GVHD","volume":"146","author":"Etra","year":"2025","journal-title":"Blood"},{"key":"B14","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.bbmt.2016.10.009","article-title":"Targeting integrin alpha4beta7 in steroid-refractory intestinal graft-versus-host disease","volume":"23","author":"Floisand","year":"2017","journal-title":"Biol. Blood Marrow Transpl."},{"key":"B15","doi-asserted-by":"publisher","first-page":"eaam7828","DOI":"10.1126\/scitranslmed.aam7828","article-title":"Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation","volume":"9","author":"Galleu","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1007\/s12185-025-03955-9","article-title":"Vedolizumab for prevention of lower-GI acute GVHD in the Japanese subgroup analysis of the phase 3 GRAPHITE study","volume":"12","author":"Goto","year":"2025","journal-title":"Int. J. Hematol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"619","DOI":"10.3389\/fimmu.2019.00619","article-title":"Comparison of mesenchymal stromal cells from different origins for the treatment of graft-vs.-Host-disease in a humanized mouse model","volume":"10","author":"Gregoire","year":"2019","journal-title":"Front. Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1111\/tan.12497","article-title":"Insights into the pathogenesis of GvHD: what mice can teach us about man","volume":"85","author":"Hulsdunker","year":"2015","journal-title":"Tissue Antigens"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1182\/blood.2023020073","article-title":"Novel developments in the prophylaxis and treatment of acute GVHD","volume":"142","author":"Jamy","year":"2021","journal-title":"Blood"},{"key":"B20","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.jcyt.2013.10.012","article-title":"Optimization of the therapeutic efficacy of human umbilical cord blood-mesenchymal stromal cells in an NSG mouse xenograft model of graft-versus-host disease","volume":"16","author":"Jang","year":"2014","journal-title":"Cytotherapy"},{"key":"B21","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1038\/s41423-023-01022-z","article-title":"Current perspectives on mesenchymal stromal cell therapy for graft versus host disease","volume":"20","author":"Kadri","year":"2023","journal-title":"Cell Mol. Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"761616","DOI":"10.3389\/fimmu.2021.761616","article-title":"Mesenchymal stromal cells for the treatment of graft versus host disease","volume":"12","author":"Kelly","year":"2021","journal-title":"Front. Immunol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.1038\/leu.2011.108","article-title":"Mesenchymal stromal cell 'licensing': a multistep process","volume":"25","author":"Krampera","year":"2011","journal-title":"Leukemia"},{"key":"B24","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1016\/j.bbmt.2020.01.018","article-title":"A phase 3, single-arm, prospective study of Remestemcel-L, Ex Vivo culture-expanded adult human mesenchymal stromal cells for the treatment of pediatric patients who failed to respond to steroid treatment for acute graft-versus-host disease","volume":"26","author":"Kurtzberg","year":"2020","journal-title":"Biol. Blood Marrow Transpl."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1016\/S0140-6736(04)16104-7","article-title":"Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells","volume":"363","author":"Le Blanc","year":"2004","journal-title":"Lancet"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1025350","DOI":"10.3389\/fimmu.2022.1025350","article-title":"Vedolizumab for acute gastrointestinal graft-versus-host disease: a systematic review and meta-analysis","volume":"13","author":"Li","year":"2022","journal-title":"Front. Immunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1576","DOI":"10.1158\/0008-5472.CAN-13-1656","article-title":"Mesenchymal stem cells use IDO to regulate immunity in tumor microenvironment","volume":"74","author":"Ling","year":"2014","journal-title":"Cancer Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"612830","DOI":"10.3389\/fcell.2021.612830","article-title":"Vedolizumab: potential mechanisms of action for reducing pathological inflammation in inflammatory bowel diseases","volume":"9","author":"Luzentales-Simpson","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"631353","DOI":"10.3389\/fimmu.2021.631353","article-title":"Metabolic reprogramming of GMP grade cord tissue-derived mesenchymal stem cells enhances their suppressive potential in GVHD","volume":"12","author":"Mendt","year":"2021","journal-title":"Front. Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1038\/ni879","article-title":"Peyer's patch is the essential site in initiating murine acute and lethal graft-versus-host reaction","volume":"4","author":"Murai","year":"2003","journal-title":"Nat. Immunol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"E39","DOI":"10.1002\/ajh.25678","article-title":"The \u03b14\u03b27 blockade with vedolizumab is effective in prevention of graft vs. host disease using a xenogeneic mouse model","volume":"95","author":"Palaniyandi","year":"2020","journal-title":"Am. J. Hematol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1182\/blood-2003-03-0957","article-title":"LPAM (alpha 4 beta 7 integrin) is an important homing integrin on alloreactive T cells in the development of intestinal graft-versus-host disease","volume":"103","author":"Petrovic","year":"2004","journal-title":"Blood"},{"key":"B33","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1124\/jpet.109.153973","article-title":"The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases","volume":"330","author":"Soler","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B34","doi-asserted-by":"publisher","first-page":"100249","DOI":"10.1016\/j.eclinm.2019.100249","article-title":"Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: an updated systematic review and meta-analysis","volume":"19","author":"Thompson","year":"2020","journal-title":"EclinicalMedicine"},{"key":"B35","volume-title":"Product Monograph, Entyvio\u00ae Vedolizumab","author":"Vedolizumab","year":"2016"},{"key":"B36","doi-asserted-by":"publisher","first-page":"842","DOI":"10.4161\/mabs.26392","article-title":"In vitro assessment of the effects of vedolizumab binding on peripheral blood lymphocytes","volume":"5","author":"Wyant","year":"2013","journal-title":"MAbs"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2167","DOI":"10.1056\/NEJMra1609337","article-title":"Acute graft-versus-host disease\u2014biologic process, prevention, and therapy","volume":"377","author":"Zeiser","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1800","DOI":"10.1056\/NEJMoa1917635","article-title":"Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease","volume":"382","author":"Zeiser","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"4279","DOI":"10.1091\/mbc.e02-02-0105","article-title":"Human adipose tissue is a source of multipotent stem cells","volume":"13","author":"Zuk","year":"2002","journal-title":"Mol. Biol. Cell"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1836978\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T05:44:25Z","timestamp":1779342265000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1836978\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,21]]},"references-count":39,"alternative-id":["10.3389\/fcell.2026.1836978"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1836978","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,21]]},"article-number":"1836978"}}