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Thomas Kaever, Imir G Metushi, Rebecca Pavlos, John Sidney, David A Ostrov, Soren Buus, Alec Redwood, Alessandro Sette, Donald F Hunt, Elizabeth J Phillips, Bjoern Peters, Using MHC Binding Assays to Investigate HLA-Dependent Drug Directed Immune Responses, The Journal of Immunology, Volume 198, Issue Supplement_1, May 2017, Page 55.42, https://doi.org/10.4049/jimmunol.198.Supp.55.42
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Abstract
Immune mediated adverse drug reactions (IM-ADRs) pose a significant risk to human health, and have been shown to be linked to specific human leukocyte antigen (HLA) alleles. Hypersensitivity syndrome induced by abacavir, the strongest such genetic association found to date, is driven by drug-specific activation of cytokine producing, cytotoxic CD8+ T cells exclusively found in individuals expressing the HLA-B*57:01 allele variant. We have previously shown that abacavir interacts with the peptide binding cleft of the HLA-B*57:01 molecule, thus increasing the affinity of certain self-peptides generating an altered self-peptide repertoire. In MHC binding studies a second drug, acyclovir, also revealed a dose dependent increase in affinity for peptides that contain small, hydrophobic residues at the C terminus. Peptide elution studies performed in the presence of acyclovir showed an elevated number of endogenously bound peptides with a C-terminal isoleucine. Accordingly, we concluded that acyclovir acts by the same mechanism as abacavir, albeit at a lesser magnitude. Our data showed a maximum increase of affinity of 2.5-fold for acyclovir, when the effect of abacavir was as high as 1000-fold. Acyclovir is not known to cause IM-ADRs. We concluded that the moderate effect of acyclovir on binding affinity was not sufficient to cause a hypersensitivity reaction. Here we applied the same screening strategies to four compounds that are involved in IM-ADRs with strong known HLA association, to determine if drug specific effects of these molecules could be observed. While no effect as striking as that for abacavir could be detected, several notable changes in repertoire were associated with the presence of these compounds.
