Applications of Immunopharmacogenomics: Predicting, Preventing, and Understanding Immune-Mediated Adverse Drug Reactions

Abstract

Adverse drug reactions (ADRs) are a significant health care burden. Immune-mediated adverse drug reactions (IM-ADRs) are responsible for one-fifth of ADRs but contribute a disproportionately high amount of that burden due to their severity. Variation in human leukocyte antigen ( HLA) genes has emerged as a potential preprescription screening strategy for the prevention of previously unpredictable IM-ADRs. Immunopharmacogenomics combines the disciplines of immunogenomics and pharmacogenomics and focuses on the effects of immune-specific variation on drug disposition and IM-ADRs. In this review, we present the latest evidence for HLA associations with IM-ADRs, ongoing research into biological mechanisms of IM-ADRs, and the translation of clinical actionable biomarkers for IM-ADRs, with a focus on T cell-mediated ADRs.

Keywords: Stevens-Johnson syndrome; adverse drug reaction; human leukocyte antigen; immunopharmacogenomics; pharmacogenomics; toxic epidermal necrolysis.

Figure 1:

ADRs can be classified as either Type A (on target effects) or Type B (off target effects). Both types of ADRs can exhibit concentration dependent relationships with development and severity of the ADR. Type A reactions relate to the known primary therapeutic action of the drug (e.g. bleeding related to warfarin) whereas Type B reactions relate to mechanisms not directly related to the drugs intended pharmacological action. Off target reactions can occur without a direct immunological effect and have an immunological phenotype (e.g. non-IgE mediated mast-cell activation with fluoroquinolones. Off target reactions can also be immune-mediated, associated with immunological memory, and either dose dependent (T-cell-mediated reactions as in abacavir hypersensitivity) or non-dose dependent (IgE-mediated recognition and amplification of small amounts of antigen as in penicillin anaphylaxis). ADME indicates absorption, distribution, metabolism, and excretion; ADR, adverse drug reaction; HLA, human leukocyte antigen; PD, pharmacodynamics; PK, pharmacokinetics; PKC, protein kinase C; VKORC1, vitamin K epoxide reductase.

Figure 2:

Proposed immunopathogenesis for T-cell-mediated ADRs: a) the hapten/prohapten model stipulates that drugs form covalent bonds with endogenous peptides, which are processed by antigen-presenting cells, presented on MHC molecules, and trigger a T-cell response; b) the pharmacological-interaction model proposes that a drug binds directly to receptors such as TCR or HLA triggering an immune response; c) the altered peptide repertoire model stipulates that the drug forms noncovalent bonds within the MHC binding pocket, altering the MHC such that endogenous peptides bind and trigger an immune response. HLA indicates human leukocyte antigen; MHC, major histocompatibility complex; TCR, T-cell receptor.

Figure 3:

Pathogenic mechanisms for drug-induced SJS/TEN and DRESS. SJS/TEN primarily involves the epidermis. The drug likely interacts with HLA protein on keratinocytes, which act as antigen presenting cells to active CD8⁺ cytotoxic T-cells. Drug-specific CD8⁺ cytotoxic T-cells accumulate within blisters and release perforin and granzyme B that kills keratinocytes. CD8⁺ T-cells, NK cells, and NKT cells are also triggered to secrete granulysin, which is cytotoxic and the most powerful mediator of keratinocyte death. DRESS primarily involves the dermis. DRESS is characterized by a lymphocytic infiltrate of T-cells into the dermis and release of TNF-alpha and IFN-gamma. DRESS is also associated with replication of human herpesviruses, which have an unclear role in pathogenesis. APC indicates antigen presenting cell; CTL, cytotoxic lymphocyte; DC, dendritic cell; DRESS, drug reaction with eosinophilia and systemic symptoms; NK, natural killer cell; NKT, natural killer T-cell; SJS, Stevens-Johnson Syndrome; TCR, T-cell receptor; TEN; toxic epidermal necrolysis.

Figure 4:

Integrated “omics” approaches to drive personalized medicine in IM-ADRs. Approaches for prevention and treatment of IM-ADRs will include multiple omics platforms that link genomic, epigenomic, transcriptomic, metabolomic and other biological data. There is an opportunity to leverage this comprehensive “omic” data to estimate disease risk, facilitate rapid and accurate diagnosis, and predict the safety and efficacy of therapeutic interventions. Aggregation of this data is also likely to garner critical insights into the pathogenesis of IM-ADRs and lead to novel therapeutic interventions.