Increase in inflammatory cytokine levels in abacavir stimulated mononuclear cells from HIV infected patients with abacavir hypersensitivity
Almeida, C., Martin, A., Nolan, D. and Mallal, S. (2004) Increase in inflammatory cytokine levels in abacavir stimulated mononuclear cells from HIV infected patients with abacavir hypersensitivity. In: 16th Annual Conference of the Australasian Society for HIV Medicine, 2 - 4 September 2004, Canberra, Australia
Genetic factors including MHC alleles, HLA-B*5701 and Hsp70 Hom M493T highly predispose Caucasoid abacavir recipients to hypersensitivity. Depletion of immunological CD8+ T cells abrogate an abacavir specific TNF production in cultured mono-nuclear cells suggesting a MHC class I restricted immune response to abacavir and or its haptenated derivative.
In this study, we sought to examine abacavir specific inflammatory cytokine response in cultured PBMCs from HIV infected abacavir hypersensitive (ABC HSR) (n=10), abacavir tolerant (n=8), abacavir unexposed (n=7) individuals. PBMCs were separated from heparinised whole blood by Ficoll density gradients and cryo-preserved. Abacavir was used at a fi nal concentration of 4μg/mL. Production of INF gamma, IL-2, IL-4 was measured by ELISA (Pharmingen) and TNF by flow cytometry. Abacavir stimulated inflammatory cytokine expression was also examined by microarray analysis (GEArray™Q series kit for chemiluminescent detection, SupperArray Bioscience Corp).
Abacavir stimulated INF gamma production was significantly higher in ABC HSR individuals (median 42.5 pg/μL, IQR: 1.7 to 82.95) compared to abacavir tolerant (median –9.6 pg/μL, IQR –18.1 to –1.4) or unexposed individuals (median –20.6 pg/μL, IQR –24.4 to –10.7) (P = 0.01). Intracellular TNF levels were also substantially higher in ABC HSR compared with tolerant individuals (P= 0.008). Increased mRNA expression of pro-inflammatory cytokines and chemokines occurred in response to a 24 hr abacavir stimulated mono-nuclear cells of abacavir hypersensitive individuals as determined by microarray analysis.
Inflammatory cytokine levels are significantly elevated in patients with abacavir hypersensitivity thereby influencing the pathophysiology of this reaction. These data suggest that an abacavir specific immunological response in vitro may be useful as clinical diagnostic marker and may help to clarify the immunological mechanisms involved in the development of abacavir HSR.
|Publication Type:||Conference Paper|
|Murdoch Affiliation:||Centre for Clinical Immunology and Biomedical Statistics|
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