title: T-cell-mediated drug hypersensitivity: immune mechanisms and their clinical relevance.
abstract: T-cell-mediated drug hypersensitivity represents a significant proportion of immune mediated drug hypersensitivity reactions. In the recent years, there has been an increase in understanding the immune mechanisms behind T-cell-mediated drug hypersensitivity. According to hapten mechanism, drug specific T-cell response is stimulated by drug-protein conjugate presented on major histocompatibility complex (MHC) as it is presented as a new antigenic determinant. On the other hand, p-i concept suggests that a drug can stimulate T cells via noncovalent direct interaction with T-cell receptor and/or peptide-MHC. The drug binding site is quite variable and this leads to several different mechanisms within p-i concept. Altered peptide repertoire can be regarded as an 'atypical' subset of p-i concept since the mode of the drug binding and the binding site are essentially identical to p-i concept. However, the intracellular binding of abacavir to HLA-B(*)57:01 additionally results in alteration in peptide repertoire. Furthermore the T-cell response to altered peptide repertoire model is only shown for abacavir and HLA-B(*)57:01 and therefore it may not be generalised to other drug hypersensitivity. Danger hypothesis has been postulated to play an important role in drug hypersensitivity by providing signal 2 but its experimental data is lacking at this point in time. Furthermore, the recently described allo-immune response suggests that danger signal may be unnecessary. Finally, in view of these new understanding, the classification and the definition of type B adverse drug reaction should be revised.
authors.affiliation: Department of Clinical Immunology and Allergy, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Yun
authors.affiliation: Department of Clinical Immunology and Allergy, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: Fenfen
authors.initials: F
authors.lastname: Cai
authors.affiliation: Department of Clinical Immunology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Lee
authors.affiliation: ADR-AC GmbH, Bern 3008, Switzerland.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Pichler
keywords: Drug hypersensitivity; HLA antigens; Haptens; Receptors, antigen, T-Cell