Characterization of Clozapine-Responsive Human T Cells

• DOI: 10.4049/jimmunol.2000646
• Publication Date: 2020-09-28T20:00:22Z
• Authors: Monday O Ogese; Adam Lister; Rosalind E Jenkins; Xiaoli Meng; Ana Alfirevic; Lisa Douglas; Rachel Mcloughlin; Edward Silva; B Kevin Park; Munir Pirmohamed; Dean J Naisbitt
• Keywords: Adult; Male; 0303 health sciences; T-Lymphocytes; HLA-DR Antigens; Cross Reactions; Middle Aged; Lymphocyte Activation; Clone Cells; 3. Good health; 03 medical and health sciences; Cytokines; Humans; Female; Clozapine

Abstract Use of the atypical antipsychotic clozapine is associated with life-threatening agranulocytosis. The delayed onset and association HLA variants are characteristic an immunological mechanism. objective this study was to generate clozapine-specific T cell clones (TCC) characterize pathways activation cross-reactivity metabolites olanzapine. TCC were established characterized by culturing PBMCs from healthy donors patients a history clozapine-induced Modeling used explore drug–HLA binding interaction. Global protein changes profiled mass spectrometry. Six well-growing clozapine-responsive CD4+ CD8+ for experiments; required APC, interacting directly at therapeutic concentrations several HLA-DR molecules. also activated N-desmethylclozapine olanzapine supratherapeutic concentrations. Marked in expression profiles observed when treatment compared medium control. Docking compounds into HLA-DRB1*15:01 HLA-DRB1*04:01 clefts revealed that bind similar conformation P4–P6 peptide pockets, whereas N-oxide, which did not activate TCC, bound different conformation. secreted Th1, Th2, Th22 cytokines effector molecules expressed TCR Vβ 5.1, 16, 20, 22 as well chemokine receptors CXCR3, CCR6, CCR4, CCR9. Collectively, these data show interacts activates human cells. Olanzapine only