Funmilola Haukamp (Hannover/ DE), Zoe Hartmann (Hannover/ DE), Prof. Andreas Pich (Hannover/ DE), Dr. Joachim Kuhn (Bad Oeynhausen/ DE), Prof. Dr. Rainer Blasczyk (Hannover/ DE), Dr. Florian Stieglitz (Hannover/ DE), Dr. Christina Bade-Döding (Hannover/ DE)
Background
Extensive clinical trials prior to license of a drug could not prevent certain cellular drug-mediated severe immune reactions. Dependent on the genotype, Carbamazepine (CBZ) hypersensitivities cause diverse clinical pictures as MPE, DRESS (HLA-A*31:01) or more fatal diseases SJS or TEN (HLA-B*15:02). Recently, the association between HLA-B*57:01 and CBZ administration could be demonstrated to result in SJS/TEN.
Methods
Genetically engineered human B-LCLs expressing sHLA-B*57:01 molecules were treated with CBZ or its metabolite carbamazepine-10,11-epoxide (EPX). The incapability of these B-LCLs to metabolize CBZ makes them an ideal system for analyzing the influence of CBZ and EPX orthogonally. HLA/drug complexes were purified and the availability of CBZ or EPX was monitored by mass spectrometry. The cellular alteration through HLA/drug interdependence was measured by full proteome analysis.
Results
The data reveal significant stronger engagement of B*57:01 to the metabolite EPX than to CBZ. Subsequent full proteome analysis of engineered B*57:01+ cells following CBZ or EPX treatment uncovered an unknown mechanism; HLA-B*57:01/EPX complexes introduced drastic proteomic alterations as the induction of inflammatory processes through the upstream kinase ERBB2 and the upregulation of NFκB and JAK/STAT pathway implying a pro-apoptotic, pro-necrotic shift in the cellular response. Simultaneously, anti-inflammatory pathways and associated effector proteins were downregulated.
Conclusion
Fundamental knowledge of drug-susceptible HLA molecules, their drug antagonist and the disequilibrium of the proteomic content will certainly facilitate personalized and safe medication.
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