Search

Adverse drug reactions (ADRs) are a major obstacle to drug development, and some of these, including hypersensitivity reactions to the HIV reverse transcriptase inhibitor abacavir (ABC), are associated with HLA alleles, particularly HLA-B*57:01. However, not all [HLA-B*57:01.sup.+] patients develop ADRs, suggesting that in addition to the HLA genetic risk, other factors may influence the outcome of the response to the drug. To study HLA-linked ADRs in vivo, we generated HLA-B*57:01-Tg mice and show that, although ABC activated Tg mouse [CD8.sup.+] T cells in vitro in a HLA-B*57:01-dependent manner, the drug was tolerated in vivo. In immunocompetent Tg animals, ABC induced [CD8.sup.+] T cells with an anergy-like phenotype that did not lead to ADRs. In contrast, in vivo depletion of [CD4.sup.+] T cells prior to ABC administration enhanced DC maturation to induce systemic ABC-reactive [CD8.sup.+] T cells with an effector-like and skin-homing phenotype along with [CD8.sup.+] infiltration and inflammation in drug-sensitized skin. B7 costimulatory molecule blockade prevented [CD8.sup.+] T cell activation. These Tg mice provide a model for ABC tolerance and for the generation of HLA-B*57:01-restricted, ABC-reactive [CD8.sup.+] T cells dependent on both HLA genetic risk and immunoregulatory host factors., Introduction Adverse drug reactions (ADRs) have been defined by the World Health Organization (WHO) as noxious and unintended responses to a drug given at a dose established for the prophylaxis, [...]