Evolving models of the immunopathogenesis of T cell-mediated drug allergy: The role of host, pathogens, and drug response

Abstract

Immune-mediated (IM) adverse drug reactions (ADRs) are an underrecognized source of preventable morbidity, mortality, and cost. Increasingly, genetic variation in the HLA loci is associated with risk of severe reactions, highlighting the importance of T-cell immune responses in the mechanisms of both B cell-mediated and primary T cell-mediated IM-ADRs. In this review we summarize the role of host genetics, microbes, and drugs in IM-ADR development; expand on the existing models of IM-ADR pathogenesis to address multiple unexplained observations; discuss the implications of this work in clinical practice today; and describe future applications for preclinical drug toxicity screening, drug design, and development.

Keywords: Abacavir; Stevens-Johnson syndrome; T-cell receptor; adverse drug reaction; allopurinol; altered peptide; carbamazepine; drug reaction with eosinophilia and systemic symptoms; hapten; heterologous immunity; human herpesvirus; human leukocyte antigen; major histocompatibility complex; p-i; pharmacogenetics; pharmacogenomics; toxic epidermal necrolysis.