Drug hypersensitivity and eosinophilia: The decisive role of p‐i stimulation

Abstract

AbstractEosinophilia is a common finding in drug hypersensitivity reactions (DHR). Its cause is unclear, as neither antigen/allergen‐driven inflammation nor clonal expansion is involved. Most delayed‐DHRs are due to p‐i (pharmacologic interaction of drugs with immune receptors). These are off‐target activities of drugs with immune receptors that result in various types of T‐cell stimulation, some of which involve excessive IL‐5 production. Functional and phenotypic studies of T‐cell clones and their TCR‐transfected hybridoma cell lines revealed that some p‐i‐induced drug stimulations occur without CD4/ CD8 co‐receptor engagement. The CD4/CD8 co‐receptors link Lck (lymphocyte‐specific protein tyrosine kinase) and LAT (linker for activation of T cells) to the TCR. Alteration of Lck or LAT can result in a TCR signalosome with enhanced IL‐5 production. Thus, if a more affine TCR‐[drug/peptide/HLA] interaction allows bypassing the CD4 co‐receptor, a modified Lck/LAT activation may lead to a TCR signalosome with elevated IL‐5 production. This “IL‐5‐TCR‐signalosome” hypothesis could also explain eosinophilia in superantigen or allo‐stimulation (graft‐versus‐host disease), in which evasion of CD4/CD8 co‐receptors has also been described. It may open new therapeutic possibilities in certain eosinophilic diseases by directly targeting the IL‐5‐TCR signalosome.