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In mice, we found that deficiency in the adrenal stress response\u2014with similarities to such in patients called relative adrenal insufficiency (RAI)\u2014conferred a high risk for lethal CRS. Mice treated with CD3 antibodies were protected against lethal CRS by the production of glucocorticoids (GC) induced by the adrenal stress response in a manner dependent on the scavenger receptor B1 (SR-BI), a receptor for high-density lipoprotein (HDL). Mice with whole-body or adrenal gland-specific SR-BI deficiency exhibited impaired GC production, more severe CRS, and increased mortality in response to CD3 antibodies. Pretreatment with a low dose of GC effectively suppressed the development of CRS and rescued survival in SR-BI\u2013deficient mice without compromising T cell function through apoptosis. Our findings suggest that RAI may be a risk factor for therapy-induced CRS and that pretreating RAI patients with GC may prevent lethal CRS.<\/jats:p>","DOI":"10.1126\/scisignal.add4900","type":"journal-article","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T17:58:27Z","timestamp":1679421507000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["The adrenal stress response is an essential host response against therapy-induced lethal immune activation"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1573-7382","authenticated-orcid":true,"given":"Ling","family":"Guo","sequence":"first","affiliation":[{"name":"Saha Cardiovascular Research Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7280-9023","authenticated-orcid":true,"given":"Weinan","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH, 45229, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7837-4211","authenticated-orcid":true,"given":"Qian","family":"Wang","sequence":"additional","affiliation":[{"name":"Saha Cardiovascular Research Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Misa","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9075-1531","authenticated-orcid":true,"given":"Bin","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Cancer Biostatistics, University of Kentucky College of Medicine, Lexington, KY 40536, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4978-6177","authenticated-orcid":true,"given":"Chieko","family":"Mineo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1157-4002","authenticated-orcid":true,"given":"Philip W.","family":"Shaul","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5590-087X","authenticated-orcid":true,"given":"Jaebok","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine at St.\u00a0Louis, St.\u00a0Louis, MO 63110, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0322-6078","authenticated-orcid":true,"given":"L. 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