Characterization of Clozapine-Responsive Human T Cells

Collapse authors list.
Ogese, Monday O ORCID: 0000-0002-1873-4032, Lister, Adam, Jenkins, Rosalind E, Meng, Xiaoli ORCID: 0000-0002-7774-2075, Alfirevic, Ana ORCID: 0000-0002-2801-9817, Douglas, Lisa, Mcloughlin, Rachel, Silva, Edward, Park, B Kevin, Pirmohamed, Munir ORCID: 0000-0002-7534-7266 et al (show 1 more authors) and Naisbitt, Dean J (2020) Characterization of Clozapine-Responsive Human T Cells JOURNAL OF IMMUNOLOGY, 205 (9). 2375-+. ISSN 0022-1767, 1550-6606

Text Ogese et al. V1.docx - Author Accepted Manuscript Download (141kB)

Abstract

Use of the atypical antipsychotic clozapine is associated with life-threatening agranulocytosis. The delayed onset and the association with HLAvariants are characteristic of an immunological mechanism. The objective of this study was to generate clozapinespecific 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-HLA 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-P6 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 Vβ 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.

Item Type:	Article
Uncontrolled Keywords:	T-Lymphocytes, Clone Cells, Humans, Clozapine, HLA-DR Antigens, Cytokines, Lymphocyte Activation, Cross Reactions, Adult, Middle Aged, Female, Male
Depositing User:	Symplectic Admin
Date Deposited:	15 Oct 2020 10:28
Last Modified:	16 Jun 2026 14:09
DOI:	10.4049/jimmunol.2000646
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3104265
Disclaimer:	The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate.