{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T23:59:02Z","timestamp":1778716742026,"version":"3.51.4"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T00:00:00Z","timestamp":1673222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The use of allogeneic hematopoietic cell transplantation (allo-HCT) for treating hematological disorders is increasing, but the development of graft-versus-host disease (GvHD) remains a major cause of morbidity and mortality. The use of post-transplant cyclophosphamide (CY) has significantly improved outcomes following allo-HCT, but complications of viral reactivation due to delayed immune reconstitution or relapse remain. Other laboratories are evaluating the potential benefit of lowering the dose of CY given post-transplant, whereas our laboratory has been focusing on whether partially replacing CY with another DNA alkylating agent, bendamustine (BEN) may be advantageous in improving outcomes with allo-HCT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we utilized a xenogeneic GvHD (xGvHD) model in which immunodeficient NSG mice are infused with human peripheral blood mononuclear cells (PBMCs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We show that a lower dose of CY (25 mg\/kg) given on days +3 and +4 or CY (75 mg\/kg) given on only day +3 post-PBMC infusion is not sufficient for improving survival from xGvHD, but can be improved with the addition of BEN (15 mg\/kg) on day +4 to day +3 CY (75 mg\/kg). CY\/BEN treated mice when combined with cyclosporine A (CSA) (10mg\/kg daily from days +5 to +18 and thrice weekly thereafter), had improved outcomes over CY\/CY +CSA treated mice. Infiltration of GvHD target organs was reduced in both CY\/CY and CY\/BEN treatment groups versus those receiving no treatment. CY\/CY +CSA mice exhibited more severe xGvHD at day 10, marked by decreased serum albumin and increased intestinal permeability. CY\/BEN treated mice had reductions in na\u00efve, effector memory and Th17 polarized T cells. RNAseq analysis of splenocytes isolated from CY\/CY and CY\/BEN treated animals revealed increased gene set enrichment in multiple KEGG pathways related to cell migration, proliferation\/differentiation, and inflammatory pathways, among others with CY\/BEN treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Together, we illustrate that the use of CY\/BEN is safe and shows similar control of xGvHD to CY\/CY, but when combined with CSA, survival with CY\/BEN is significantly prolonged compared to CY\/CY.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1045710","type":"journal-article","created":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T08:10:00Z","timestamp":1673251800000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Partially replacing cyclophosphamide with bendamustine in combination with cyclosporine A improves survival and reduces xenogeneic 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