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Avidity determines T ‐cell reactivity in abacavir hypersensitivity

2012; Wiley; Volume: 42; Issue: 7 Linguagem: Inglês

10.1002/eji.201142159

1521-4141

Jacqueline Adam, Klara Eriksson, Benno Schnyder, Stefano Fontana, Werner J. Pichler, Daniel Yerly,

Immune Cell Function and Interaction

The antiretroviral drug abacavir (abc) elicits severe drug hypersensitivity reactions in HLA ‐ B *5701 + individuals. To understand the abc‐specific activation of CD 8 + T cells, we generated abc‐specific T ‐cell clones (abc‐ TCC s). 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 APC s did not affect TCC reactivity. Ca 2+ influx assays revealed different reactivity patterns of abc‐ TCC s. While all TCC s 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‐ TCC s were not fixed but dynamic. When TCC s 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 TCC s 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.