Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions

Abstract

Adverse drug reactions (ADRs) remain associated with significant mortality. Delayed hypersensitivity reactions (DHRs) that occur greater than 6 h following drug administration are T-cell mediated with many severe DHRs now associated with human leukocyte antigen (HLA) risk alleles, opening pathways for clinical prediction and prevention. However, incomplete negative predictive value (NPV), low positive predictive value (PPV), and a large number needed to test (NNT) to prevent one case have practically prevented large-scale and cost-effective screening implementation. Additional factors outside of HLA contributing to risk of severe T-cell-mediated DHRs include variation in drug metabolism, T-cell receptor (TCR) specificity, and, most recently, HLA-presented immunopeptidome-processing efficiencies via endoplasmic reticulum aminopeptidase (ERAP). Active research continues toward identification of other highly polymorphic factors likely to impose risk. These include those previously associated with T-cell-mediated HLA-associated infectious or auto-immune disease such as Killer cell immunoglobulin-like receptors (KIR), epistatically linked with HLA class I to regulate NK- and T-cell-mediated cytotoxic degranulation, and co-inhibitory signaling pathways for which therapeutic blockade in cancer immunotherapy is now associated with an increased incidence of DHRs. As such, the field now recognizes that susceptibility is not simply a static product of genetics but that individuals may experience dynamic risk, skewed toward immune activation through therapeutic interventions and epigenetic modifications driven by ecological exposures. This review provides an updated overview of current and proposed genetic factors thought to predispose risk for severe T-cell-mediated DHRs.

Development of mouse models with restricted HLA-B∗57:01 presentation for the study of flucloxacillin-driven T-cell activation and tolerance in liver injury

“…A number of drugs have been described to interact with different HLA alleles and lead to hypersensitivity reactions. 31 The development of HLA transgenic animal models is critical to elucidate the mechanisms driving immune-mediated drug hypersensitivity reactions (including FLX-DILI). Here, we characterize FLX immune reactivity in existing and novel HLA-B*57:01 Tg strains and discuss tolerogenic mechanisms that may contribute to restrict drug-responsive CD8 + T cells.…”

Unravelling the Proteomics of HLA-B*57:01+ Antigen Presenting Cells during Abacavir Medication

“…Due to the extraordinary specificity of AHS and the occurrence of the HLA-B*57:01 genotype, exploiting the mechanism of ABC-induced ADR would guide towards a deeper comprehension of HLA-mediated ADRs. The low PPV for many HLA-associated ADRs indicate that not solely the occurrence of the respective HLA risk allele, but also the involvement of other patient-specific factors might contribute to the development of type B ADRs [39].…”

In Vitro Monitoring of Human T Cell Responses to Skin Sensitizing Chemicals—A Systematic Review

“…However, if chemical-induced epitopes are formed inefficiently and if this is combined with the rarity of antigen-specific T cells, the detection of T cell activation may become virtually impossible. In addition, epitopes may form in an HLA allele-restricted manner, which is less well investigated for sensitizing chemicals that are not used as drugs [ 68 , 69 , 70 , 71 , 72 ].…”

“…Binding via p-i has often been reported in the context of HLA allele-associated drug hypersensitivities [ 68 , 69 , 70 , 71 , 72 , 73 , 74 ]. Arguably, the most prominent example is abacavir binding to the F-pocket of HLA-B*57:01, which conceals a carboxy-terminal tryptophan important for peptide anchoring.…”