{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T12:22:26Z","timestamp":1784204546965,"version":"3.55.0"},"reference-count":71,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"844","funder":[{"DOI":"10.13039\/501100014255","name":"Fonds de dotation CSL Behring pour la recherche","doi-asserted-by":"publisher","award":["DAM297"],"award-info":[{"award-number":["DAM297"]}],"id":[{"id":"10.13039\/501100014255","id-type":"DOI","asserted-by":"publisher"}]},{"name":"F\u00e9d\u00e9ration Leuc\u00e9mie Espoir","award":["2020-76-03"],"award-info":[{"award-number":["2020-76-03"]}]},{"name":"SiRIC InsiTu","award":["INCa-DGOS-INSERM-ITMO Cancer_18008"],"award-info":[{"award-number":["INCa-DGOS-INSERM-ITMO Cancer_18008"]}]},{"name":"Fondation Maladies Rare Association HPN France et Aplasie","award":["2022-76-29"],"award-info":[{"award-number":["2022-76-29"]}]},{"name":"INIDEX Immuno Oncology","award":["2025-101"],"award-info":[{"award-number":["2025-101"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,4,8]]},"abstract":"<jats:p>\n                    Steroid-resistant acute graft-versus-host disease (SR-aGVHD) is the leading life-threatening complication after allogeneic hematopoietic stem cell transplantation. Therapeutic development is impeded by scarce knowledge of biological pathways leading to steroid resistance after aGVHD diagnosis. To gain insight into circulating immune cell subsets and their functions at the onset of aGVHD, we performed a single-cell deep phenotyping and transcriptome analysis on peripheral blood mononuclear cells from two cohorts of patients (discovery cohort,\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    \u00a0=\u00a053; and validation cohort,\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    \u00a0=\u00a032) with aGVHD before steroid treatment or without aGVHD. Frequencies of circulating immune subsets were not associated with steroid resistance. However, pathway analysis and inferred ligand-receptor interactions revealed major functional divergences between steroid-sensitive aGVHD (SS-aGVHD) and SR-aGVHD, suggesting that steroid resistance is an intrinsic property of immune cells before any treatment. SR-aGVHD was mainly associated with tumor necrosis factor\u2013\u03b1 (TNF-\u03b1) activation. Steroid resistance resulted from a specific cross-talk characterized by inflammasome and caspase-1 activation in monocyte subsets; by TNF-\u03b1\/TNF receptor, interleukin-1\u03b2 (IL-1\u03b2), IL-18, CCL3, and CCL4 signaling between myeloid and T cells; and by lower involvement of interferon-\u03b1 and interferon-\u03b3 signaling pathways. Immune trajectories in CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells demonstrated a direct transition from an early na\u00efve state to a highly activated one. By contrast, SS-aGVHD involved gene signatures across multiple intermediate differentiation stages during cell-to-cell transitions into CD8\n                    <jats:sup>+<\/jats:sup>\n                    T subsets. These findings provide evidence that steroid resistance is driven by intrinsic mechanisms already present at the onset of the alloimmune response, which may enable previously unknown therapeutic strategies.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.aeb7834","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T17:59:41Z","timestamp":1775671181000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Corticosteroid resistance is predetermined by early immune response dynamics at acute graft-versus-host disease onset"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9985-465X","authenticated-orcid":true,"given":"Sophie","family":"Le Grand","sequence":"first","affiliation":[{"name":"INSERM UMR 1342, Translational Immunology in Immunotherapy and Hematology, IHU Leukemia Institute Paris Saint-Louis, SIRIC InSitu, Paris Cit\u00e9 University, F-75010 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8424-2640","authenticated-orcid":true,"given":"Yannick","family":"Marie","sequence":"additional","affiliation":[{"name":"Genotyping and Sequencing Facility, Paris Brain Institute-ICM, H\u00f4pital de la Piti\u00e9-Salp\u00eatri\u00e8re, CNRS UMR 7225, INSERM U1127, Sorbonne Universit\u00e9 UM75, CS21414, 75013 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Bouteiller","sequence":"additional","affiliation":[{"name":"Genotyping and Sequencing Facility, Paris Brain Institute-ICM, H\u00f4pital de la Piti\u00e9-Salp\u00eatri\u00e8re, CNRS UMR 7225, INSERM U1127, Sorbonne Universit\u00e9 UM75, CS21414, 75013 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0405-3248","authenticated-orcid":true,"given":"Margo","family":"Fernandez","sequence":"additional","affiliation":[{"name":"INSERM UMR 1342, Translational Immunology in Immunotherapy and Hematology, IHU Leukemia Institute Paris Saint-Louis, SIRIC InSitu, Paris Cit\u00e9 University, F-75010 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7187-2340","authenticated-orcid":true,"given":"Gwendolyn","family":"Marguerit","sequence":"additional","affiliation":[{"name":"INSERM UMR 1342, Translational Immunology in Immunotherapy and Hematology, IHU Leukemia Institute Paris Saint-Louis, SIRIC InSitu, Paris Cit\u00e9 University, F-75010 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Lambert","sequence":"additional","affiliation":[{"name":"INSERM UMR 1342, Translational Immunology in Immunotherapy and Hematology, IHU Leukemia Institute Paris Saint-Louis, SIRIC InSitu, Paris Cit\u00e9 University, F-75010 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8506-2574","authenticated-orcid":true,"given":"\u00c9meline","family":"Mundwiller","sequence":"additional","affiliation":[{"name":"Genotyping and Sequencing Facility, Paris Brain Institute-ICM, H\u00f4pital de la Piti\u00e9-Salp\u00eatri\u00e8re, CNRS UMR 7225, INSERM U1127, Sorbonne Universit\u00e9 UM75, CS21414, 75013 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5542-6074","authenticated-orcid":true,"given":"\u00c9milie","family":"Robert","sequence":"additional","affiliation":[{"name":"Cryostem Consortium, Technop\u00f4le de Ch\u00e2teau Gombert, 13009 Marseille, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6222-4753","authenticated-orcid":true,"given":"R\u00e9gis","family":"Peffault de Latour","sequence":"additional","affiliation":[{"name":"INSERM UMR 1342, Translational Immunology in Immunotherapy and Hematology, IHU Leukemia Institute Paris Saint-Louis, SIRIC InSitu, Paris Cit\u00e9 University, F-75010 Paris, France."},{"name":"Cryostem Consortium, Technop\u00f4le de Ch\u00e2teau Gombert, 13009 Marseille, France."},{"name":"Hematology Transplantation, Saint-Louis Hospital, Assistance Publique des H\u00f4pitaux de Paris, 75010 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e9rard","family":"Soci\u00e9","sequence":"additional","affiliation":[{"name":"INSERM UMR 1342, Translational Immunology in Immunotherapy and Hematology, IHU Leukemia Institute Paris Saint-Louis, SIRIC InSitu, Paris Cit\u00e9 University, F-75010 Paris, France."},{"name":"Hematology Transplantation, Saint-Louis Hospital, Assistance Publique des H\u00f4pitaux de Paris, 75010 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9568-3358","authenticated-orcid":true,"given":"Nicolas","family":"Vallet","sequence":"additional","affiliation":[{"name":"Hematology and Cell Therapy Department, University Hospital of Tours, Inserm U1069 N2Cox, 37000 Tours, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4553-3065","authenticated-orcid":true,"given":"David","family":"Michonneau","sequence":"additional","affiliation":[{"name":"INSERM UMR 1342, Translational Immunology in Immunotherapy and Hematology, IHU Leukemia Institute Paris Saint-Louis, SIRIC InSitu, Paris Cit\u00e9 University, F-75010 Paris, France."},{"name":"Hematology Transplantation, Saint-Louis Hospital, Assistance Publique des H\u00f4pitaux de Paris, 75010 Paris, 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