Hepatoxicity SIG (Sept 11): Understanding HLA-Associated Adverse Drug Reactions in Drug-Induced Liver Injury-Hepatoxicity SIG (Sept 11): Understanding HLA-Assoc Adv Drug Reactions1

Video Transcription

Video Summary

Dr. David Ostrov presented on the role of human leukocyte antigen (HLA) alleles in drug-induced liver injury (DILI) and related immune mechanisms. HLAs are highly polymorphic molecules key in immune response by presenting peptides to T cells. Certain HLA alleles are genetically linked to autoimmune diseases and hypersensitivity reactions to drugs like abacavir and carbamazepine. Abacavir binds stably within the peptide-binding cleft of HLA-B57, altering peptide presentation and triggering T cell responses—a model of altered peptide repertoire. Other drugs, such as carbamazepine and green tea component EGCG, may bind HLA molecules more transiently, enhancing peptide loading and potentially eliciting immune activation. Dr. Ostrov emphasized differences in peptide loading between class I and II HLAs, noting some HLAs (e.g., HLA-B3501) uniquely bind extracellular peptides and allow peptide exchange at the cell surface or in endosomal vesicles. The environmental context, such as prior pathogen exposure, likely influences individual susceptibility to immune reactions despite HLA carriage. While reactive drug moieties forming peptide adducts (haptens) are implicated, predicting HLA-drug binding and DILI risk remains complex due to factors like ordered water molecules mediating interactions that are hard to computationally model. The discussion highlighted the evolving mechanistic understanding of HLA-associated drug hypersensitivity, with implications for safer drug design and personalized risk assessment.

Keywords

HLA alleles

drug-induced liver injury

immune mechanisms

abacavir hypersensitivity

carbamazepine reaction

peptide loading

T cell activation

peptide adducts

personalized medicine