HLAs: Key regulators of T‐cell‐mediated drug hypersensitivity

Abstract

Adverse drug reactions (ADR) can be broadly categorised as either on-target or off-target. On-target ADRs arise as a direct consequence of the pharmacological properties of the drug and are therefore predictable and dose dependant. On-target ADRs comprise the majority (>80%) of ADRs, relate to the drug’s interaction with its known pharmacological target and are a result of a complex interplay of genetic and ecologic factors. In contrast off-target ADRs, including immune mediated ADRs (IM-ADRs), are due to unintended pharmacological interactions such as inadvertent ligation of host cell receptors or non-pharmacological interactions mediated through an adaptive immune response. IM-ADRs can be classified according to the primary immune cell involved and include B cell-mediated (Gell-Coombs type I-III reactions) and T cell-mediated (Gell-Coombs type IV or delayed hypersensitivity) reactions. IM-ADRs mediated by T cells are associated with phenotypically distinct clinical diagnoses and can vary from a mild delayed rash to a life threatening cutaneous, systemic or organ disease, such as Stephen Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and drug-induced liver disease (DILI). T-cell mediated ADRs are strongly linked to the carriage of particular HLA risk alleles which in the case of abacavir hypersensitivity and HLA-B*57:01 has led to translation into the clinic as a routine screening test. In this review, we will discuss the immunogenetics and pathogenesis of IM-ADRs and how HLA associations inform both pre-drug screening strategies and mechanistic understanding.

Dapsone‐ and nitroso dapsone‐specific activation of T cells from hypersensitive patients expressing the risk allele HLA‐B*13:01

“…Genome‐wide association studies have identified strong associations between the expression of HLA alleles and susceptibility to drug hypersensitivity . These data suggest that drugs bind selectively to the HLA protein to activate the T cells that participate in the adverse event.…”

Risks and management of antiepileptic drug induced skin reactions in the adult out-patient setting

“…HLA-A*31:01 association has been most consistently identified for CBZ induced reactions ( [12], see below). AED binding to specific parts of certain HLA molecules would then oligoclonally stimulate specific types of T cells as has been suggested in the case of the antiretroviral, abacavir induced reactivity in HLA-B*57:01 positive patients [13]. It is likely that there is also a reduction in more general T helper type 1 (Th1) function.…”

Clinical and pathogenic aspects of the severe cutaneous adverse reaction epidermal necrolysis (EN)

“…A shared binding pocket motif was identified in different HLA‐C risk alleles for nevirapine‐induced hypersensitivity 118 . Likewise, carbamazepine appeared to bind to several HLA‐B alleles sharing a conserved binding pocket 52 …”

“…2). 52,53 First, the (pro)hapten model involves intracellular processing of (a metabolite derived from) the drug, whereupon a drug‐derived peptide is covalently conjugated to an endogenous peptide. This novel (pro)hapten is presented by a HLA class I molecule and recognized by a specific TCR on the cytotoxic T‐cell membrane.…”