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

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 HLAlinked 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.3D structure | small molecule | binding site A bacavir is a nucleoside analog that suppresses HIV replication. In approximately 8% of recipients, abacavir is associated with significant immune-mediated drug hypersensitivity, which is strongly associated with the presence of the HLA-B*57:01 allele (1, 2). Three complementary models for the mechanism of immune-mediated severe adverse drug reactions have traditionally been discussed (3, 4). The hapten (or prohapten) model states that drugs and their metabolites are too small to be immunogenic on their own, but rather act like haptens and modify certain self-proteins in the host that lead to immune recognition of the resulting hapten-self-peptide complexes as de novo antigens (5-7). The pharmacologic interaction with immune receptors (p-i) model states that drugs can induce the formation of HLA-drug complexes that can activate T-cell immune responses directly without requiring a specific peptide ligand (8). The danger model, which is in principle compatible with other models, states that danger signals other than the drug itself (e.g., chemical, physical, or viral stress) are required to overcome immune tolerance barriers that otherwise suppress drug hypersensitivity reactions (7).None of these existing models provides a convincing mechanism explaining how abacav...

Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury

“…6,[25][26][27][28] In contrast, flucloxacillin does not alter peptide binding to HLA-B*57:01, 28 which supports our hypothesis that functional flucloxacillin antigens derive from naturally processed drug-protein conjugates. Flucloxacillin-responsive CD8þ clones from patients with liver injury and HLA-B*57:01-positive volunteers were not stimulated with abacavir.…”

Mechanisms involved in the Abacavir-mediated hypersensitivity syndrome

“…Furthermore, ABC binding also appears to impact the C, D and E but not the B pocket of HLA-B*57:01, in line with unchanged anchor preferences at position 2 of peptides eluted from HLA-B*57:01 in the presence of ABC. These data are consistent with two other recent reports in which changes from conventional anchors to Isoleucine, Leucine (and Valine) containing peptides were observed in HLA-B*57:01 molecules derived from cells cultured in the presence of ABC [7,8].…”

Development and partial validation of a mouse model for predicting drug hypersensitivity reactions

“…abacavir/HLA-B*5701, allopurinol/HLA-B*5801, and carbamazepine HLA-B*1502 (Aihara, 2011;Wei et al, 2012). Recent studies have demonstrated that, in the case of abacavir, binding of abacavir to the peptide binding cleft of the HLA can alter the peptide repertoire presented to T-cells, which can result in an allogenic-like reaction (Illing et al, 2012;Norcross et al, 2012;Ostrov et al, 2012). Interestingly, binding of abacavir appears to be restricted to HLA-B*5701, since the peptide repertoire of the closely related HLA-B*5801 was not found to be modified by abacavir.…”