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Immune responses to abacavir in antigen-presenting cells from hypersensitive patients.
Martin, Annalise M; Almeida, Coral-Ann; Cameron, Paul; Purcell, Anthony W; Nolan, David; James, Ian; McCluskey, James; Phillips, Elizabeth; Landay, Alan; Mallal, Simon.
Afiliação
  • Martin AM; Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Western Australia 6000, Australia.
AIDS ; 21(10): 1233-44, 2007 Jun 19.
Article em En | MEDLINE | ID: mdl-17545699
OBJECTIVES: A potentially life-threatening hypersensitive reaction accompanies the use of HIV nucleoside analogue abacavir (ABC) in 4-8% of Caucasian individuals. HLA-B*5701 and Hsp70 493T alleles have been shown to predict susceptibility to this hypersensitivity. DESIGN AND METHODS: This study was undertaken to provide a mechanistic understanding of the highly significant genetic association of HLA Class I and Hsp70 alleles with ABC hypersensitivity. RESULTS: In this study an ABC-induced localization of intracellular HSP70 to endosomal vesicles of antigen-presenting cells was demonstrated. This ABC-stimulated redistribution of endogenous HSP70 was substantially higher in the genetically homogenous HLA-B*5701, Hsp70 493T ABC-hypersensitive individuals and ABC-naive individuals in comparison with the heterogeneous tolerant patients (P = 0.023). Increased expression of HSP70 was also detected in the hypersensitive group as measured by flow cytometry (P = 0.032). Blocking of HSP70 and HSP70 cell surface receptors CD14 and TLR2 abrogated ABC-stimulated HSP70 redistribution in sensitized individuals to basal levels (P < 0.004). In addition, the use of TcRalphabeta and HLA-B57/58 antibodies also ablated the expression of HSP70. Cells expressing the activation markers CD40 were increased after ABC stimulation in the hypersensitive patients (P = 0.006). ABC-stimulated interferon-gamma levels were higher in hypersensitive patients in comparison with ABC-tolerant individuals with a mean of 123.54 versus 0 pg/ml (P = 0.001). CONCLUSION: The present data indicates that ABC stimulates an innate immune response and activates antigen-presenting cells via the endogenous HSP70-mediated Toll-like receptor pathway in genetically susceptible individuals potentially initiating the immuno-pathological hypersensitive response.
Assuntos
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Base de dados: MEDLINE Assunto principal: Didesoxinucleosídeos / Inibidores da Transcriptase Reversa / Hipersensibilidade a Drogas / Células Apresentadoras de Antígenos Idioma: En Ano de publicação: 2007 Tipo de documento: Article
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Base de dados: MEDLINE Assunto principal: Didesoxinucleosídeos / Inibidores da Transcriptase Reversa / Hipersensibilidade a Drogas / Células Apresentadoras de Antígenos Idioma: En Ano de publicação: 2007 Tipo de documento: Article