Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire

TLDR

Idiosyncratic adverse drug reactions are unpredictable, dose‑independent, and potentially life‑threatening, often involving immune mechanisms and strong associations with specific HLA alleles such as HLA‑B*57:01 for abacavir. The study aims to clarify how abacavir triggers drug‑specific CD8⁺ T‑cell activation and to develop in‑vitro assays that can identify other HLA‑linked hypersensitivities, thereby accelerating safer drug design. The authors established in‑vitro assays that test candidate compounds for their ability to alter the peptide repertoire presented by HLA‑B*57:01. They found that abacavir binds the F pocket of HLA‑B*57:01, reshapes its peptide specificity, and presents unique self‑peptides that elicit T‑cell responses in hypersensitive patients.

Abstract

Idiosyncratic adverse drug reactions are unpredictable, dose-independent and potentially life threatening; this makes them a major factor contributing to the cost and uncertainty of drug development. Clinical data suggest that many such reactions involve immune mechanisms, and genetic association studies have identified strong linkages between drug hypersensitivity reactions to several drugs and specific HLA alleles. One of the strongest such genetic associations found has been for the antiviral drug abacavir, which causes severe adverse reactions exclusively in patients expressing the HLA molecular variant B*57:01. Abacavir adverse reactions were recently shown to be driven by drug-specific activation of cytokine-producing, cytotoxic CD8(+) T cells that required HLA-B*57:01 molecules for their function; however, the mechanism by which abacavir induces this pathologic T-cell response remains unclear. Here we show that abacavir can bind within the F pocket of the peptide-binding groove of HLA-B*57:01, thereby altering its specificity. This provides an explanation for HLA-linked idiosyncratic adverse drug reactions, namely that drugs can alter the repertoire of self-peptides presented to T cells, thus causing the equivalent of an alloreactive T-cell response. Indeed, we identified specific self-peptides that are presented only in the presence of abacavir and that were recognized by T cells of hypersensitive patients. The assays that we have established can be applied to test additional compounds with suspected HLA-linked hypersensitivities in vitro. Where successful, these assays could speed up the discovery and mechanistic understanding of HLA-linked hypersensitivities, and guide the development of safer drugs.