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We profiled 59 biopsies from patients with varying gastrointestinal (GI) aGVHD manifestations and 18 healthy controls and measured the spatial expression of 40 proteins, designated to delineate distinct epithelial cell populations of the gut, stromal cells, and immune cells. Normal duodenum was stereotypical across individuals, showing organization and zonation of epithelial, stromal, and immune cells. Patients with aGVHD exhibited increased fibrosis, alterations in crypt morphology, loss of Paneth cells, and accumulation of endocrine cells in the crypts. Homeostatic immune organization was disrupted, with a prominent reduction in immunoglobulin A\u2013secreting plasma cells. CD8 T cells were enriched only in a subset of patients, whereas others exhibited noncanonical enrichments of macrophages and neutrophils. Immune composition was correlated with the time after transplantation, with shared dynamics observed across individuals. Host cells dominated the plasma and T cell compartments in the gut for extended periods of time after transplantation, suggesting that additional players may drive aGVHD across individuals in addition to donor-derived T cells. This spatial atlas of healthy and GI aGVHD uncovers epithelial and immune dynamics across individuals, offering insights into disease pathophysiology and potential clinical applications.<\/jats:p>","DOI":"10.1126\/scitranslmed.adu6032","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T18:58:26Z","timestamp":1762369106000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":11,"title":["A spatial atlas of human gastrointestinal acute GVHD reveals epithelial and immune dynamics underlying disease pathophysiology"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5498-7766","authenticated-orcid":true,"given":"Nofar","family":"Azulay","sequence":"first","affiliation":[{"name":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2459-3061","authenticated-orcid":true,"given":"Idan","family":"Milo","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0365-431X","authenticated-orcid":true,"given":"Yuval","family":"Bussi","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3300-058X","authenticated-orcid":true,"given":"Raz","family":"Ben-Uri","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1931-706X","authenticated-orcid":true,"given":"Tal Keidar","family":"Haran","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel."},{"name":"Department of Pathology, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8605-2933","authenticated-orcid":true,"given":"Michal","family":"Eldar","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6628-1632","authenticated-orcid":true,"given":"Ofer","family":"Elhanani","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5099-3328","authenticated-orcid":true,"given":"Yotam","family":"Harnik","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8849-6615","authenticated-orcid":true,"given":"Oran","family":"Yakubovsky","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel."},{"name":"Department of General Surgery and Transplantation, Sheba Medical Center, Ramat Gan 52621, Israel."},{"name":"Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2612-8555","authenticated-orcid":true,"given":"Ido","family":"Nachmany","sequence":"additional","affiliation":[{"name":"Department of General Surgery and Transplantation, Sheba Medical Center, Ramat Gan 52621, Israel."},{"name":"Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4260-8738","authenticated-orcid":true,"given":"Tomer-Meir","family":"Salame","sequence":"additional","affiliation":[{"name":"Life Sciences Core Facility, Weizmann Institute of Science, Rehovot 7610001, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5378-3825","authenticated-orcid":true,"given":"Martin","family":"Wartenberg","sequence":"additional","affiliation":[{"name":"Institute of Tissue Medicine and Pathology (ITMP), University of Bern, Murtenstrasse 31, Bern 3008, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Bertheau","sequence":"additional","affiliation":[{"name":"UFR de M\u00e9decine, University Paris Cit\u00e9, Paris, France."},{"name":"Pathology Department, H\u00f4pital Saint Louis - 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