{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T02:33:37Z","timestamp":1789785217554,"version":"4.0.1"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T00:00:00Z","timestamp":1706918400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T00:00:00Z","timestamp":1706918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["ZU 377\/4-1"],"award-info":[{"award-number":["ZU 377\/4-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["ID 375876048 \u2013 TRR 241 B08"],"award-info":[{"award-number":["ID 375876048 \u2013 TRR 241 B08"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003042","name":"Else Kr\u00f6ner-Fresenius-Stiftung","doi-asserted-by":"publisher","award":["2021_CS.23"],"award-info":[{"award-number":["2021_CS.23"]}],"id":[{"id":"10.13039\/501100003042","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Despite promising preclinical and earlier clinical data, a recent phase III trial on the anti-\u03b27 integrin antibody etrolizumab in Crohn\u2019s disease (CD) did not reach its primary endpoint. The mechanisms leading to this outcome are not well understood. Here we characterize the \u03b27<jats:sup>+<\/jats:sup> T cell compartment from patients with CD in comparison to cells from individuals without inflammatory bowel disease. By flow cytometric, transcriptomic and functional profiling of circulating T cells, we find that triple-integrin-expressing (\u03b14<jats:sup>+<\/jats:sup>\u03b27<jats:sup>+<\/jats:sup>\u03b21<jats:sup>hi<\/jats:sup>) T cells have the potential to home to the gut despite \u03b14\u03b27 blockade and have a specific cytotoxic signature. A subset of triple-integrin-expressing cells readily acquires \u03b1E expression and could be co-stimulated via E-Cadherin-\u03b1E\u03b27 interactions in vitro. Etrolizumab-s fails to block such\u00a0\u03b1E\u03b27 signalling at high levels of T cell stimulation. Consistently, in CD patients treated with etrolizumab, T cell activation correlates with cytotoxic signatures. Collectively, our findings might add one important piece to the puzzle to explain phase III trial results with etrolizumab, while they also highlight that \u03b1E\u03b27 remains an interesting target for future therapeutic approaches in inflammatory bowel disease.<\/jats:p>","DOI":"10.1038\/s41467-024-45352-6","type":"journal-article","created":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T14:02:35Z","timestamp":1706968955000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Etrolizumab-s fails to control E-Cadherin-dependent co-stimulation of highly activated cytotoxic T cells"],"prefix":"10.1038","volume":"15","author":[{"given":"Maximilian","family":"Wiendl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Dedden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Juan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Schweda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva-Maria","family":"Paap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0938-5800","authenticated-orcid":false,"given":"Karen A.-M.","family":"Ullrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonie","family":"Hartmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Wieser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Vitali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imke","family":"Atreya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja M.","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"G\u00fcnther","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8556-8433","authenticated-orcid":false,"given":"Raja","family":"Atreya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4344-1474","authenticated-orcid":false,"given":"Markus F.","family":"Neurath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0888-2784","authenticated-orcid":false,"given":"Sebastian","family":"Zundler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,3]]},"reference":[{"key":"45352_CR1","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1016\/j.immuni.2019.03.017","volume":"50","author":"M Friedrich","year":"2019","unstructured":"Friedrich, M., Pohin, M. & Powrie, F. Cytokine networks in the pathophysiology of inflammatory bowel disease. Immunity 50, 992\u20131006 (2019).","journal-title":"Immunity"},{"key":"45352_CR2","doi-asserted-by":"publisher","first-page":"2652","DOI":"10.1056\/NEJMra2002697","volume":"383","author":"JT Chang","year":"2020","unstructured":"Chang, J. T. Pathophysiology of inflammatory bowel diseases. N. Engl. J. Med. 383, 2652\u20132664 (2020).","journal-title":"N. Engl. J. Med."},{"key":"45352_CR3","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/s41572-020-0156-2","volume":"6","author":"G Roda","year":"2020","unstructured":"Roda, G. et al. Crohn\u2019s disease. Nat. Rev. Dis. Primers. 6, 22 (2020).","journal-title":"Nat. Rev. Dis. Primers."},{"key":"45352_CR4","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1056\/NEJMoa1215739","volume":"369","author":"WJ Sandborn","year":"2013","unstructured":"Sandborn, W. J. et al. Vedolizumab as induction and maintenance therapy for Crohn\u2019s disease. N. Engl. J. Med. 369, 711\u2013721 (2013).","journal-title":"N. Engl. J. Med."},{"key":"45352_CR5","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1056\/NEJMoa1215734","volume":"369","author":"BG Feagan","year":"2013","unstructured":"Feagan, B. G. et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 369, 699\u2013710 (2013).","journal-title":"N. Engl. J. Med."},{"key":"45352_CR6","doi-asserted-by":"publisher","first-page":"1280","DOI":"10.1056\/NEJMoa2033617","volume":"385","author":"WJ Sandborn","year":"2021","unstructured":"Sandborn, W. J. et al. Ozanimod as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 385, 1280\u20131291 (2021).","journal-title":"N. Engl. J. Med."},{"key":"45352_CR7","doi-asserted-by":"publisher","first-page":"1688","DOI":"10.1136\/gutjnl-2018-317977","volume":"68","author":"S Zundler","year":"2019","unstructured":"Zundler, S. et al. Immune cell trafficking and retention in inflammatory bowel disease: mechanistic insights and therapeutic advances. Gut 68, 1688\u20131700 (2019).","journal-title":"Gut"},{"key":"45352_CR8","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.immuni.2004.08.011","volume":"21","author":"M Iwata","year":"2004","unstructured":"Iwata, M. et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527\u2013538 (2004).","journal-title":"Immunity"},{"key":"45352_CR9","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/B978-0-12-386960-9.00006-X","volume":"86","author":"M Iwata","year":"2011","unstructured":"Iwata, M. & Yokota, A. Retinoic acid production by intestinal dendritic cells. Vitam. Horm. 86, 127\u2013152 (2011).","journal-title":"Vitam. Horm."},{"key":"45352_CR10","first-page":"97","volume":"151","author":"M Briskin","year":"1997","unstructured":"Briskin, M. et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am. J. Pathol. 151, 97\u2013110 (1997).","journal-title":"Am. J. Pathol."},{"key":"45352_CR11","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1038\/s41590-019-0415-0","volume":"20","author":"MF Neurath","year":"2019","unstructured":"Neurath, M. F. Targeting immune cell circuits and trafficking in inflammatory bowel disease. Nat. Immunol. 20, 970\u2013979 (2019).","journal-title":"Nat. Immunol."},{"key":"45352_CR12","doi-asserted-by":"publisher","first-page":"1936","DOI":"10.1136\/gutjnl-2016-312439","volume":"66","author":"S Zundler","year":"2017","unstructured":"Zundler, S. et al. Blockade of \u03b1E\u03b27 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo. Gut 66, 1936\u20131948 (2017).","journal-title":"Gut"},{"key":"45352_CR13","doi-asserted-by":"publisher","first-page":"100381","DOI":"10.1016\/j.xcrm.2021.100381","volume":"2","author":"B Dai","year":"2021","unstructured":"Dai, B. et al. Dual targeting of lymphocyte homing and retention through \u03b14\u03b27 and \u03b1E\u03b27 inhibition in inflammatory bowel disease. Cell Rep. Med. 2, 100381 (2021).","journal-title":"Cell Rep. Med."},{"key":"45352_CR14","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/S2468-1253(21)00369-1","volume":"7","author":"M Agrawal","year":"2022","unstructured":"Agrawal, M. & Verstockt, B. Etrolizumab for ulcerative colitis: beyond what meets the eye. Lancet Gastroenterol. Hepatol. 7, 2\u20134 (2022).","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"45352_CR15","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/S2468-1253(22)00303-X","volume":"8","author":"WJ Sandborn","year":"2023","unstructured":"Sandborn, W. J. et al. Etrolizumab as induction and maintenance therapy in patients with moderately to severely active Crohn\u2019s disease (BERGAMOT): a randomised, placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol. Hepatol. 8, 43\u201355 (2023).","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"45352_CR16","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/S0140-6736(14)60661-9","volume":"384","author":"S Vermeire","year":"2014","unstructured":"Vermeire, S. et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 384, 309\u2013318 (2014).","journal-title":"Lancet"},{"key":"45352_CR17","first-page":"1191","volume":"12","author":"R Ichikawa","year":"2018","unstructured":"Ichikawa, R. et al. AlphaE integrin expression is increased in the ileum relative to the colon and unaffected by inflammation. J. Crohns Colitis 12, 1191\u20131199 (2018).","journal-title":"J. Crohns Colitis"},{"key":"45352_CR18","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1097\/MIB.0000000000001029","volume":"23","author":"S Zundler","year":"2017","unstructured":"Zundler, S. et al. The \u03b14\u03b21 homing pathway is essential for ileal homing of Crohn\u2019s disease effector T cells in vivo. Inflamm. Bowel Dis. 23, 379\u2013391 (2017).","journal-title":"Inflamm. Bowel Dis."},{"key":"45352_CR19","doi-asserted-by":"publisher","first-page":"436","DOI":"10.3389\/fcimb.2020.00436","volume":"10","author":"P Chen","year":"2020","unstructured":"Chen, P. et al. CD103 promotes the pro-inflammatory response of gastric resident CD4+ T cell in helicobacter pylori-positive gastritis. Front. Cell Infect. Microbiol. 10, 436 (2020).","journal-title":"Front. Cell Infect. Microbiol."},{"key":"45352_CR20","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1158\/0008-5472.CAN-12-2569","volume":"73","author":"K Franciszkiewicz","year":"2013","unstructured":"Franciszkiewicz, K. et al. CD103 or LFA-1 engagement at the immune synapse between cytotoxic T cells and tumor cells promotes maturation and regulates T-cell effector functions. Cancer Res. 73, 617\u2013628 (2013).","journal-title":"Cancer Res."},{"key":"45352_CR21","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1158\/0008-5472.CAN-10-2457","volume":"71","author":"A Le Floc'h","year":"2011","unstructured":"Le Floc'h, A. et al. Minimal engagement of CD103 on cytotoxic T lymphocytes with an E-cadherin-Fc molecule triggers lytic granule polarization via a phospholipase Cgamma-dependent pathway. Cancer Res. 71, 328\u2013338 (2011).","journal-title":"Cancer Res."},{"key":"45352_CR22","doi-asserted-by":"publisher","first-page":"3417","DOI":"10.1007\/s12325-020-01366-2","volume":"37","author":"WJ Sandborn","year":"2020","unstructured":"Sandborn, W. J. et al. Etrolizumab for the treatment of ulcerative colitis and Crohn\u2019s disease: an overview of the phase 3 clinical program. Adv. Ther. 37, 3417\u20133431 (2020).","journal-title":"Adv. Ther."},{"key":"45352_CR23","first-page":"610","volume":"11","author":"CA Lamb","year":"2017","unstructured":"Lamb, C. A. et al. \u03b1E\u03b27 integrin identifies subsets of pro-inflammatory colonic CD4+ T lymphocytes in ulcerative colitis. J. Crohns Colitis. 11, 610\u2013620 (2017).","journal-title":"J. Crohns Colitis."},{"key":"45352_CR24","doi-asserted-by":"publisher","first-page":"39","DOI":"10.3389\/fphar.2019.00039","volume":"10","author":"C Lichnog","year":"2019","unstructured":"Lichnog, C. et al. Cellular mechanisms of etrolizumab treatment in inflammatory bowel disease. Front. Pharmacol. 10, 39 (2019).","journal-title":"Front. Pharmacol."},{"key":"45352_CR25","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/S2468-1253(21)00294-6","volume":"7","author":"S Danese","year":"2022","unstructured":"Danese, S. et al. Etrolizumab versus infliximab for the treatment of moderately to severely active ulcerative colitis (GARDENIA): a randomised, double-blind, double-dummy, phase 3 study. Lancet Gastroenterol. Hepatol. 7, 118\u2013127 (2022).","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"45352_CR26","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/S2468-1253(21)00298-3","volume":"7","author":"L Peyrin-Biroulet","year":"2022","unstructured":"Peyrin-Biroulet, L. et al. Etrolizumab as induction and maintenance therapy for ulcerative colitis in patients previously treated with tumour necrosis factor inhibitors (HICKORY): a phase 3, randomised, controlled trial. Lancet Gastroenterol. Hepatol. 7, 128\u2013140 (2022).","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"45352_CR27","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/S2468-1253(21)00295-8","volume":"7","author":"S Vermeire","year":"2022","unstructured":"Vermeire, S. et al. Etrolizumab for maintenance therapy in patients with moderately to severely active ulcerative colitis (LAUREL): a randomised, placebo-controlled, double-blind, phase 3 study. Lancet Gastroenterol. Hepatol. 7, 28\u201337 (2022).","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"45352_CR28","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/S2468-1253(21)00338-1","volume":"7","author":"DT Rubin","year":"2022","unstructured":"Rubin, D. T. et al. Etrolizumab versus adalimumab or placebo as induction therapy for moderately to severely active ulcerative colitis (HIBISCUS): two phase 3 randomised, controlled trials. Lancet Gastroenterol. Hepatol. 7, 17\u201327 (2022).","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"45352_CR29","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1093\/ecco-jcc\/jjx049","volume":"11","author":"C Smids","year":"2017","unstructured":"Smids, C. et al. The complexity of alpha E beta 7 blockade in inflammatory bowel diseases. J. Crohns Colitis 11, 500\u2013508 (2017).","journal-title":"J. Crohns Colitis"},{"key":"45352_CR30","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1093\/ecco-jcc\/jjx160","volume":"12","author":"C Smids","year":"2018","unstructured":"Smids, C. et al. Intestinal T cell profiling in inflammatory bowel disease: linking T cell subsets to disease activity and disease course. J. Crohns Colitis 12, 465\u2013475 (2018).","journal-title":"J. Crohns Colitis"},{"key":"45352_CR31","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1093\/ibd\/izz049","volume":"25","author":"B Roosenboom","year":"2019","unstructured":"Roosenboom, B. et al. Intestinal CD103+CD4+ and CD103+CD8+ T-cell subsets in the gut of inflammatory bowel disease patients at diagnosis and during follow-up. Inflamm. Bowel Dis. 25, 1497\u20131509 (2019).","journal-title":"Inflamm. Bowel Dis."},{"key":"45352_CR32","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1093\/ibd\/izy077","volume":"24","author":"M-T Binder","year":"2018","unstructured":"Binder, M.-T. et al. Similar inhibition of dynamic adhesion of lymphocytes from IBD patients to MAdCAM-1 by vedolizumab and etrolizumab-s. Inflamm. Bowel Dis. 24, 1237\u20131250 (2018).","journal-title":"Inflamm. Bowel Dis."},{"key":"45352_CR33","doi-asserted-by":"publisher","first-page":"izac137","DOI":"10.1093\/ibd\/izac137","volume":"28","author":"A Schweda","year":"2022","unstructured":"Schweda, A. et al. Etrolizumab-s does not induce residual trafficking of regulatory T cells. Inflamm. Bowel Dis. 28, izac137 (2022).","journal-title":"Inflamm. Bowel Dis."},{"key":"45352_CR34","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1136\/gutjnl-2021-324868","volume":"71","author":"E Becker","year":"2022","unstructured":"Becker, E. et al. Residual homing of \u03b14\u03b27-expressing \u03b21+PI16+ regulatory T cells with potent suppressive activity correlates with exposure-efficacy of vedolizumab. Gut 71, 1551\u20131566 (2022).","journal-title":"Gut"},{"key":"45352_CR35","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1053\/j.gastro.2015.10.041","volume":"150","author":"GW Tew","year":"2016","unstructured":"Tew, G. W. et al. Association between response to etrolizumab and expression of integrin \u03b1E and granzyme A in colon biopsies of patients with ulcerative colitis. Gastroenterology 150, 477\u2013487.e9 (2016).","journal-title":"Gastroenterology"},{"key":"45352_CR36","doi-asserted-by":"publisher","first-page":"1008456","DOI":"10.3389\/fimmu.2022.1008456","volume":"13","author":"N Hammoudi","year":"2022","unstructured":"Hammoudi, N. et al. Autologous organoid co-culture model reveals T cell-driven epithelial cell death in Crohn\u2019s disease. Front. Immunol. 13, 1008456 (2022).","journal-title":"Front. Immunol."},{"key":"45352_CR37","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1172\/JCI896","volume":"101","author":"T Lin","year":"1998","unstructured":"Lin, T. et al. Fas ligand- mediated killing by intestinal intraepithelial lymphocytes. Participation in intestinal graft-versus-host disease. J. Clin. Invest. 101, 570\u2013577 (1998).","journal-title":"J. Clin. Invest."},{"key":"45352_CR38","doi-asserted-by":"publisher","first-page":"6083","DOI":"10.4049\/jimmunol.1302238","volume":"192","author":"ML Cupi","year":"2014","unstructured":"Cupi, M. L. et al. Plasma cells in the mucosa of patients with inflammatory bowel disease produce granzyme B and possess cytotoxic activities. J. Immunol. 192, 6083\u20136091 (2014).","journal-title":"J. Immunol."},{"key":"45352_CR39","doi-asserted-by":"publisher","unstructured":"Kassir, N. et al. Exposure-response relationships of etrolizumab in patients with moderately-to-severely active ulcerative colitis. CPT Pharmacometrics Syst. Pharmacol. https:\/\/doi.org\/10.1002\/psp4.12840 (2022).","DOI":"10.1002\/psp4.12840"},{"key":"45352_CR40","doi-asserted-by":"publisher","first-page":"1320","DOI":"10.1053\/j.gastro.2017.07.047","volume":"153","author":"AN Hegazy","year":"2017","unstructured":"Hegazy, A. N. et al. Circulating and tissue-resident CD4+ T cells with reactivity to intestinal microbiota are abundant in healthy individuals and function is altered during inflammation. Gastroenterology 153, 1320\u20131337.e16 (2017).","journal-title":"Gastroenterology"},{"key":"45352_CR41","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1097\/MIB.0000000000001039","volume":"23","author":"U Kopylov","year":"2017","unstructured":"Kopylov, U. et al. Efficacy and safety of vedolizumab for induction of remission in inflammatory bowel disease\u2014the Israeli real-world experience. Inflamm. Bowel Dis. 23, 404\u2013408 (2017).","journal-title":"Inflamm. Bowel Dis."},{"key":"45352_CR42","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1038\/ajg.2016.236","volume":"111","author":"PS Dulai","year":"2016","unstructured":"Dulai, P. S. et al. The real-world effectiveness and safety of vedolizumab for moderate\u2013severe Crohn\u2019s disease: results from the US VICTORY Consortium. Am. J. Gastroenterol. 111, 1147\u20131155 (2016).","journal-title":"Am. J. Gastroenterol."},{"key":"45352_CR43","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1382-0","volume":"19","author":"FA Wolf","year":"2018","unstructured":"Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15 (2018).","journal-title":"Genome Biol."},{"key":"45352_CR44","doi-asserted-by":"publisher","first-page":"861","DOI":"10.21105\/joss.00861","volume":"3","author":"L McInnes","year":"2018","unstructured":"McInnes, L. et al. UMAP: uniform manifold approximation and projection. J Open Source Softw. 3, 861 (2018).","journal-title":"J Open Source Softw."},{"key":"45352_CR45","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-41695-z","volume":"9","author":"VA Traag","year":"2019","unstructured":"Traag, V. A., Waltman, L. & van Eck, N. J. From Louvain to Leiden: guaranteeing well-connected communities. Sci. Rep. 9, 5233 (2019).","journal-title":"Sci. Rep."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-45352-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-45352-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-45352-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T17:02:44Z","timestamp":1706979764000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-45352-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,3]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["45352"],"URL":"https:\/\/doi.org\/10.1038\/s41467-024-45352-6","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,3]]},"assertion":[{"value":"22 March 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 January 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"M.F.N. has served as an advisor for Pentax, Giuliani, MSD, Abbvie, Janssen, Takeda and Boehringer. S.Z. received speaker\u2019s fees from Takeda, Roche, Galapagos, Ferring, Lilly, Falk and Janssen. M.F.N. and S.Z. received research support from Takeda, Shire (a part of Takeda) and Roche. The other authors declare no conflicts of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1043"}}