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The delayed onset and the association with HLA variants are characteristic of an immunological mechanism. The objective of this study was to generate clozapine-specific T cell clones (TCC) and characterize pathways of T cell activation and cross-reactivity with clozapine metabolites and olanzapine. TCC were established and characterized by culturing PBMCs from healthy donors and patients with a history of clozapine-induced agranulocytosis. Modeling was used to explore the drug\u2013HLA binding interaction. Global TCC protein changes were profiled by mass spectrometry. Six well-growing clozapine-responsive CD4+ and CD8+ TCC were used for experiments; activation of TCC required APC, with clozapine interacting directly at therapeutic concentrations with several HLA-DR molecules. TCC were also activated with N-desmethylclozapine and olanzapine at supratherapeutic concentrations. Marked changes in TCC protein expression profiles were observed when clozapine treatment was compared with olanzapine and the medium control. Docking of the compounds into the HLA-DRB1*15:01 and HLA-DRB1*04:01 binding clefts revealed that clozapine and olanzapine bind in a similar conformation to the P4\u2013P6 peptide binding pockets, whereas clozapine N-oxide, which did not activate the TCC, bound in a different conformation. TCC secreted Th1, Th2, and Th22 cytokines and effector molecules and expressed TCR V\u03b2 5.1, 16, 20, and 22 as well as chemokine receptors CXCR3, CCR6, CCR4, and CCR9. Collectively, these data show that clozapine interacts at therapeutic concentrations with HLA-DR molecules and activates human CD4+ T cells. Olanzapine only activates TCC at supratherapeutic concentrations.<\/jats:p>","DOI":"10.4049\/jimmunol.2000646","type":"journal-article","created":{"date-parts":[[2020,9,28]],"date-time":"2020-09-28T20:00:22Z","timestamp":1601323222000},"page":"2375-2390","source":"Crossref","is-referenced-by-count":16,"title":["Characterization of Clozapine-Responsive Human T Cells"],"prefix":"10.1093","volume":"205","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1873-4032","authenticated-orcid":false,"given":"Monday O","family":"Ogese","sequence":"first","affiliation":[{"name":"Medical Research Council Centre for Drug Safety Science, Department Molecular and Clinical Pharmacology, University of Liverpool , Liverpool L69 3GE ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4085-6367","authenticated-orcid":false,"given":"Adam","family":"Lister","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Drug Safety Science, Department Molecular and Clinical Pharmacology, University of Liverpool , Liverpool L69 3GE ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3730-1136","authenticated-orcid":false,"given":"Rosalind E","family":"Jenkins","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Drug Safety Science, Department Molecular and Clinical Pharmacology, University of Liverpool , Liverpool L69 3GE ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7774-2075","authenticated-orcid":false,"given":"Xiaoli","family":"Meng","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Drug Safety Science, Department Molecular and Clinical Pharmacology, University of Liverpool , Liverpool L69 3GE ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2801-9817","authenticated-orcid":false,"given":"Ana","family":"Alfirevic","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Drug Safety Science, Department Molecular and Clinical Pharmacology, University of Liverpool , Liverpool L69 3GE ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Douglas","sequence":"additional","affiliation":[{"name":"Cheshire and Wirral Partnership National Health Service Foundation Trust , Chester CH2 1BQ ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Mcloughlin","sequence":"additional","affiliation":[{"name":"Cheshire and Wirral Partnership National Health Service Foundation Trust , Chester CH2 1BQ ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7254-6307","authenticated-orcid":false,"given":"Edward","family":"Silva","sequence":"additional","affiliation":[{"name":"Mersey Care National Health Service Foundation Trust, Rathbone Low Secure Unit, Rathbone Hospital , Liverpool L13 4AW ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8384-824X","authenticated-orcid":false,"given":"B Kevin","family":"Park","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Drug Safety Science, Department Molecular and Clinical Pharmacology, University of Liverpool , Liverpool L69 3GE ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7534-7266","authenticated-orcid":false,"given":"Munir","family":"Pirmohamed","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Drug Safety Science, Department Molecular and Clinical Pharmacology, University of Liverpool , Liverpool L69 3GE ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean J","family":"Naisbitt","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Drug Safety Science, Department Molecular and Clinical Pharmacology, University of Liverpool , Liverpool L69 3GE ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,11,1]]},"reference":[{"key":"2025030417505452000_r1","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/S0140-6736(09)60995-8","article-title":"Schizophrenia","volume":"374","author":"van Os","year":"2009","journal-title":"Lancet"},{"key":"2025030417505452000_r2","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1097\/MOH.0000000000000391","article-title":"Clozapine-induced agranulocytosis\/granulocytopenia: mechanisms and monitoring","volume":"25","author":"Wici\u0144ski","year":"2018","journal-title":"Curr. 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