Immune responses to abacavir in antigen-presenting cells from hypersensitive patients
- 1 June 2007
- journal article
- basic science
- Published by Ovid Technologies (Wolters Kluwer Health) in AIDS
- Vol. 21 (10), 1233-1244
- https://doi.org/10.1097/qad.0b013e3280119579
Abstract
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 heterogenous 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 TcRαβ 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.Keywords
This publication has 43 references indexed in Scilit:
- Peptides chaperoned by heat-shock proteins are a necessary and sufficient source of antigen in the cross-priming of CD8+ T cellsNature Immunology, 2005
- Toll-like receptor signallingNature Reviews Immunology, 2004
- Association of genetic variations in HLA-B region with hypersensitivity to abacavir in some, but not all, populationsPharmacogenomics, 2004
- HSP70 Peptide Binding Mutants Separate Antigen Delivery from Dendritic Cell StimulationImmunity, 2004
- Presentation of Exogenous Antigens on Major Histocompatibility Complex (MHC) Class I and MHC Class II Molecules Is Differentially Regulated during Dendritic Cell MaturationThe Journal of Experimental Medicine, 2003
- Indirect activation of naïve CD4+ T cells by dendritic cell–derived exosomesNature Immunology, 2002
- Abacavir Hypersensitivity ReactionClinical Infectious Diseases, 2002
- Novel Signal Transduction Pathway Utilized by Extracellular HSP70Online Journal of Public Health Informatics, 2002
- Rab4 and Rab7 Define Distinct Nonoverlapping Endosomal CompartmentsOnline Journal of Public Health Informatics, 1996
- Hepatitis B virus small surface antigen particles are processed in a novel endosomal pathway for major histocompatibility complex class I‐restricted epitope presentationEuropean Journal of Immunology, 1995