title: New genetic findings lead the way to a better understanding of fundamental mechanisms of drug hypersensitivity.
abstract: Drug hypersensitivity reactions are an important clinical problem for both health care and industry. Recent advances in genetics have identified a number of HLA alleles associated with a range of these adverse reactions predominantly affecting the skin but also other organs, such as the liver. The associations between abacavir hypersensitivity and HLA-B*57:01 and carbamazepine-induced Stevens-Johnson syndrome and HLA-B*15:02 have been implemented in clinical practice. There are many different mechanisms proposed in the pathogenesis of drug hypersensitivity reactions, including the hapten hypothesis, direct binding to T-cell receptors (the pharmacologic interaction hypothesis), and peptide-binding displacement. A problem with all the hypotheses is that they are largely based on in vitro findings, with little direct in vivo evidence. Although most studies have focused on individual mechanisms, it is perhaps more important to consider them all as being complementary, potentially occurring at the same time with the same drug in the same patient. This might at least partly account for the heterogeneity of the immune response seen in different patients. There is a need to develop novel methodologies to evaluate how the in vitro mechanisms relate to the in vivo situation and how the highly consistent genetic findings with different HLA alleles can be more consistently used for both prediction and prevention of these serious adverse reactions.
authors.affiliation: Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, United Kingdom. Electronic address: munirp@liverpool.ac.uk.
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, University of Florida, Gainesville, Fla.
authors.forename: David A
authors.initials: DA
authors.lastname: Ostrov
authors.affiliation: Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, United Kingdom.
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
mesh_terms: D002220:Carbamazepine / Q000009:adverse effects; D015224:Dideoxynucleosides / Q000009:adverse effects; D004342:Drug Hypersensitivity / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D018740:Genetic Heterogeneity; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018448:Models, Immunological; D010597:Pharmacogenetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D013262:Stevens-Johnson Syndrome / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D000099227:Abacavir
chemical_list: D002220:Carbamazepine; D015224:Dideoxynucleosides; D006680:HLA Antigens; D011948:Receptors, Antigen, T-Cell; D000099227:Abacavir
keywords: Drug hypersensitivity; HLA; crystallography; genetic polymorphisms; mechanisms