title: Avidity determines T-cell reactivity in abacavir hypersensitivity.
abstract: The antiretroviral drug abacavir (abc) elicits severe drug hypersensitivity reactions in HLA-B*5701(+)  individuals. To understand the abc-specific activation of CD8(+)  T cells, we generated abc-specific T-cell clones (abc-TCCs). Abc reactivity could not be linked to the metabolism and/or processing of the drug, since abc metabolizing enzymes were not expressed in immune cells and inhibition of the proteasome in APCs did not affect TCC reactivity. Ca(2+)  influx assays revealed different reactivity patterns of abc-TCCs. While all TCCs reacted to abc presented on HLA-B*5701 molecules, a minority also reacted immediately to abc in solution. Titration experiments showed that the ability to react immediately to abc correlated significantly with the TCR avidity of the T cells. Modifications of soluble abc concentrations revealed that the reactivity patterns of abc-TCCs were not fixed but dynamic. When TCCs with an intermediate TCR avidity were stimulated with increasing abc concentrations, they showed an accelerated activation kinetic. Thus, they reacted immediately to the drug, similar to the reaction of TCCs of high avidity. The observed immediate activation and the noninvolvement of the proteasome suggest that, in contrast to haptens, abc-specific T-cell stimulation does not require the formation of covalent bonds to produce a neo-antigenic determinant.
authors.affiliation: Clinic for Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, Switzerland.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Adam
authors.forename: Klara K
authors.initials: KK
authors.lastname: Eriksson
authors.forename: Benno
authors.initials: B
authors.lastname: Schnyder
authors.forename: Stefano
authors.initials: S
authors.lastname: Fontana
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Pichler
authors.forename: Daniel
authors.initials: D
authors.lastname: Yerly
mesh_terms: D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000276:immunology; D000915:Antibody Affinity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000032:analysis / Q000276:immunology; D002999:Clone Cells; D015224:Dideoxynucleosides / Q000009:adverse effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000209:etiology* / Q000276:immunology*; D015235:HLA-B Antigens / Q000276:immunology*; D006801:Humans; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation; D020543:Proteome / Q000276:immunology; D018709:Statistics, Nonparametric; D000099227:Abacavir
chemical_list: D019380:Anti-HIV Agents; D002118:Calcium; D015224:Dideoxynucleosides; D015235:HLA-B Antigens; D020543:Proteome; D000099227:Abacavir; C484830:HLA-B*57:01 antigen