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Immune suppressive small molecule and protein-based therapeutics targeting donor anti-host immune cells are currently used for GVHD prophylaxis and treatment. Even with these therapies, aGVHD progresses to life-threatening steroid-refractory aGVHD (SR-aGVHD) in up to 50% of cases and is a risk factor for the subsequent development of debilitating chronic GVHD. To improve aGVHD-related outcomes, donor graft engineering techniques and adoptive transfer of immune modulatory cells have been explored. Highly rigorous donor graft T-cell depletion approaches have revealed that mitigation of aGVHD can be accompanied by slow immune recovery post-allo-HCT and reduction in anti-microbial and anti-leukemia responses resulting in increased relapse and infection rates, respectively. Recent T-cell separation techniques allowing for precision graft engineering by selectively eliminating aGVHD-causing T-cells (eg, na\u00efve T-cells) without loss of T-cells with beneficial functions and retaining and\/or enriching immune regulatory populations (eg, regulatory T-cells (Tregs) or myeloid-derived suppressor cells) have been tested and will continue to improve. Clinical cell-based regulatory therapies have been employed for targeting SR-aGVHD, particularly mesenchymal stem cells (MSCs) and more recently, Tregs. In this review, we summarize aGVHD pathophysiology, highlight newly discovered aGVHD mechanisms, and discuss current and emerging cellular and graft manipulation approaches for aGVHD prevention and treatment.<\/jats:p>","DOI":"10.1093\/stmcls\/sxaf009","type":"journal-article","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T08:25:26Z","timestamp":1742718326000},"source":"Crossref","is-referenced-by-count":5,"title":["Cellular therapies for the prevention and treatment of acute graft-versus-host disease"],"prefix":"10.1093","volume":"43","author":[{"given":"Daniel","family":"Peltier","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Herman B. Wells Center for Pediatric Research, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine , Indianapolis, IN 46202 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Van","family":"Anh Do-Thi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Herman B. Wells Center for Pediatric Research, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine , Indianapolis, IN 46202 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy","family":"Devos","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Hospitals Leuven and Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven , Leuven 3000 ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9608-9841","authenticated-orcid":false,"given":"Bruce R","family":"Blazar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota , Minneapolis, MN 55455 ,","place":["United 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