Severe Delayed Drug Reactions: Role of Genetics and Viral Infections

Abstract

Adverse drug reactions (ADRs) are a significant source of patient morbidity and mortality and represent a major burden to health care systems and drug development. Up to 50% of such reactions are preventable. Although many ADRs can be predicted based on the on-target pharmacologic activity, ADRs arising from drug interactions with off-target receptors are recognized. Off-target ADRs include the immune-mediated ADRs (IM-ADRs) and pharmacologic drug effects. In this review, we discuss what is known about the immunogenetics and pathogenesis of IM-ADRs and the hypothesized role of heterologous immunity in the development of IM-ADRs.

Keywords: Adverse drug reaction; Drug reaction with eosinophilia and systemic symptoms; Human herpes virus; Human leukocyte antigen; Pharmacogenomics; Steven Johnson syndrome; T-cell receptor; Toxic epidermal necrolysis.

Figure 1. Classification of adverse drug reactions

Adverse drug reactions may result from either on-target or off-target interactions between the drug and cellular proteins. On-target ADRs account for ≥80% of ADRs and are generally predictable based on the drug pharmacology. Variation in the cellular processes that modulate drug absorption, distribution, metabolism, and excretion (ADME), drug transporters, target receptor expression, and drug dosing or administration errors contribute to ADRs that are primarily mediated by pharmacologic mechanisms. Off-target adverse effects account for a smaller proportion of total ADRs (≤20%) and include both immune-mediated and non-immune mediated syndromes. The non-IgE mediated mast cell activation syndrome, which phenotypically resembles anaphylaxis, has recently been shown in a murine model to result from off-target binding of drug to G-protein coupled receptors without involvement of the adaptive immune system. The immune-mediated ADRs include both B-cell and T-cell mediated reactions (Type I-IV reactions according to the Gell-Coombs schema) and are associated with immunological memory. Adapted from Peter JG, Lehloenya R, Dlamini S, et al. Severe Delayed Cutaneous and Systemic Reactions to Drugs: A Global Perspective on the Science and Art of Current Practice. J Allergy Clin Immunol Pract 2017;5(3):547–563; with permission.

Figure 2. Models of T cell activation by small molecules

Three models have been proposed to explain T-cell stimulation by small molecule pharmaceuticals. The hapten/prohapten model postulates that the drug binds covalently to peptide (either in the intracellular environment prior to peptide processing and presentation or at the cell surface) to generate a neo-antigen that stimulates a T-cell response. The p-i model proposes that a small molecule may bind to HLA in a non-covalent manner to directly stimulate T-cells. The altered peptide model postulates that a small molecule can bind non-covalently to the MHC binding cleft to alter the specificity of peptide binding. This results in the presentation of novel peptide ligands to elicit an immune response. Adapted from White KD, Chung WH, Hung SI, et al. Evolving models of the immunopathogenesis of T cell-mediated drug allergy: The role of host, pathogens, and drug response. J Allergy Clin Immunol 2015;136(2):219–34; quiz 235; with permission.

Figure 3. Generation of heterologous immune responses that may contribute to the pathogenesis of severe delayed ADRs

(A) According to the heterologous immunity model, the pathogenesis of a T-cell mediated ADR, considered over the course of an affected individual’s lifetime, can be summarized as follows: 1) A prerequisite feature of each T-cell mediated ADR is carriage of the HLA risk allele; this is necessary but not sufficient for the reaction. 2) Infection by HHV (or other pathogen) elicits a polyclonal T-cell response that contains viral infection. HHV establishes latency in the host. 3) Virus-specific memory T cells persist in the host. 4) At a subsequent time point, the subject is exposed to the offending drug. Drug-endogenous peptide-HLA epitopes are formed as described by one of three models outlined in Figure 2 and 3B. 5) Virus-specific memory T cells are cross-reactive with drug-endogenous peptide-HLA epitopes and acquire cytotoxic function directed against cells displaying drug-modified epitopes. This results in clinical IM-ADR. (B) Integration of the models of T cell activation by small molecules and heterologous immunity. In the heterologous immunity model, memory T cells are generated following pathogen exposure and reside at specific anatomic sites. These memory T cells may cross react with: 1) haptenated endogenous peptides presented in the context of the HLA risk allele, 2) drugs that bind the TCR and/or MHC in a non-covalent manner under the p-i model, or 3) an altered repertoire of endogenous peptides following drug binding to MHC. Adapted from White KD, Chung WH, Hung SI, et al. Evolving models of the immunopathogenesis of T cell-mediated drug allergy: The role of host, pathogens, and drug response. J Allergy Clin Immunol 2015;136(2):219–34; quiz 235; with permission.

Figure 3. Generation of heterologous immune responses that may contribute to the pathogenesis of severe delayed ADRs

(A) According to the heterologous immunity model, the pathogenesis of a T-cell mediated ADR, considered over the course of an affected individual’s lifetime, can be summarized as follows: 1) A prerequisite feature of each T-cell mediated ADR is carriage of the HLA risk allele; this is necessary but not sufficient for the reaction. 2) Infection by HHV (or other pathogen) elicits a polyclonal T-cell response that contains viral infection. HHV establishes latency in the host. 3) Virus-specific memory T cells persist in the host. 4) At a subsequent time point, the subject is exposed to the offending drug. Drug-endogenous peptide-HLA epitopes are formed as described by one of three models outlined in Figure 2 and 3B. 5) Virus-specific memory T cells are cross-reactive with drug-endogenous peptide-HLA epitopes and acquire cytotoxic function directed against cells displaying drug-modified epitopes. This results in clinical IM-ADR. (B) Integration of the models of T cell activation by small molecules and heterologous immunity. In the heterologous immunity model, memory T cells are generated following pathogen exposure and reside at specific anatomic sites. These memory T cells may cross react with: 1) haptenated endogenous peptides presented in the context of the HLA risk allele, 2) drugs that bind the TCR and/or MHC in a non-covalent manner under the p-i model, or 3) an altered repertoire of endogenous peptides following drug binding to MHC. Adapted from White KD, Chung WH, Hung SI, et al. Evolving models of the immunopathogenesis of T cell-mediated drug allergy: The role of host, pathogens, and drug response. J Allergy Clin Immunol 2015;136(2):219–34; quiz 235; with permission.