{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:23:54Z","timestamp":1790634234223,"version":"4.1.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2020,6,1]],"date-time":"2020-06-01T00:00:00Z","timestamp":1590969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute (NCI), National Institutes of Health","doi-asserted-by":"publisher","award":["CA164178"],"award-info":[{"award-number":["CA164178"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM008704"],"award-info":[{"award-number":["GM008704"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI0077363"],"award-info":[{"award-number":["AI0077363"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Bispecific T cell engagers have demonstrated clinical efficacy; however, their use can be accompanied by severe toxicity. Mechanistic understanding of these toxicities is limited by a lack of suitable immunocompetent preclinical models. In this study, we describe an immunocompetent mouse tumor model that exhibits bispecific T cell engager\u2013induced toxicity and recapitulates key features similar to those in human cytokine release syndrome. In this study, toxicity occurred between the second and fourth injections of an NK Group 2D bispecific T cell engager protein. Symptoms were transient, peaking 3\u20134 h after treatment and resolving by 8 h. Mice developed weight loss, elevated plasma cytokines, a significant reduction in spleen white pulp, and lymphocyte infiltration in the liver. Systemic cellular immune changes also occurred; notably, an increase in CD8+ T cell activation, an increase in myeloid cells in the blood, and a population of Ly-6Cint monocytes (CD11b+Ly-6G\u2212F4\/80\u2212) emerged in the liver and spleens of bispecific protein\u2013treated mice. IFN-\u03b3 was primarily produced by CD8+ T cells in the spleen and was required for the observed changes in both T cell and myeloid populations. Rag deficiency, IFN-\u03b3 deficiency, or depletion of either CD4+ or CD8+ T cells prevented toxicity, whereas perforin deficiency, GM-CSF deficiency, or modulation of the myeloid population through clodronate-mediated depletion showed a partial abrogation of toxicity. Together, these findings reveal that T cell activation by a bispecific T cell engager leads to changes in the host myeloid cell population, both of which contribute to treatment induced toxicity in immunocompetent mice.<\/jats:p>","DOI":"10.4049\/jimmunol.1901401","type":"journal-article","created":{"date-parts":[[2020,4,15]],"date-time":"2020-04-15T19:35:21Z","timestamp":1586979321000},"page":"2973-2983","source":"Crossref","is-referenced-by-count":18,"title":["Toxicity Induced by a Bispecific T Cell\u2013Redirecting Protein Is Mediated by Both T Cells and Myeloid Cells in Immunocompetent Mice"],"prefix":"10.1093","volume":"204","author":[{"given":"Claire","family":"Godbersen-Palmer","sequence":"first","affiliation":[{"name":"Center for Synthetic Immunity, Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon, NH 03756"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany A","family":"Coupet","sequence":"additional","affiliation":[{"name":"Center for Synthetic Immunity, Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon, NH 03756"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2224-5979","authenticated-orcid":false,"given":"Zakaria","family":"Grada","sequence":"additional","affiliation":[{"name":"Department of Pathology, Dartmouth\u2013Hitchcock Medical Center , Lebanon, NH 03756"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2688-7781","authenticated-orcid":false,"given":"Samuel C","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Synthetic Immunity, Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon, NH 03756"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3976-5847","authenticated-orcid":false,"given":"Charles L","family":"Sentman","sequence":"additional","affiliation":[{"name":"Center for Synthetic Immunity, Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Lebanon, NH 03756"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,6,1]]},"reference":[{"key":"2025030417511971900_r1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-2776(06)90001-7","article-title":"Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity","volume":"90","author":"Smyth","year":"2006","journal-title":"Adv. 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