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  • Review Article
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Genetic aspects of immune-mediated adverse drug effects

Nature Reviews Drug Discovery volume 4, pages 59–69 (2005)Cite this article

Key Points

  • Adverse drug effects are an important cause of morbidity and mortality, which account for up to 5% of all hospital admissions. Immune-mediated adverse drug effects (IMADEs), although they are uncommon with some drug classes (for example, β-lactam-containing penicillin and cephalosporin derivatives), can occur in up to 10% of patients who are at risk.

  • IMADEs can affect many tissues and organs, including the skin, lungs, liver and kidneys. Although they are usually mild (for example, minor rashes), IMADEs can be severe and can lead to organ failure or life-threatening anaphylaxis.

  • Although the precise links are undefined, it is clear that genetic factors are important risk factors for IMADEs. Genetic polymorphisms have been identified in several biological systems that contribute to IMADEs, including drug-metabolizing enzymes, major histocompatibility complex antigens and immune receptors.

  • Important advances are beginning to be made in our understanding of the role of genetic polymorphisms as risk factors. The association between mutations in the gene for arylamine N-acetyltransferase and hypersensitivity to sulphonamides, sulphasalazine and dapsone, and between expression of the HLA-B*5701 phenotype and hypersensitivity to abacavir in HIV patients, are examples of areas in which these advances are beginning to bear fruit.

  • Because of their rarity, the study of the genetics of IMADEs is difficult. Moreover, owing to the inherent differences among species, models that are conducted in wild-type rodents have limited predictive value for humans.

  • It is anticipated that the growing catalogue of polymorphisms, coupled with advances in in silico modelling and the availability of increasingly sophisticated transgenic-rodent test systems, will improve the diagnosis and prediction of IMADEs, and, ultimately, the discovery and development of drugs with a markedly decreased risk of causing them.

Abstract

Adverse drug effects (ADEs) are of great importance in medicine and account for up to 5% of all hospital admissions. ADEs can arise from several mechanisms and a wide range of drugs can cause immune-mediated ADEs (IMADEs). For a drug to elicit an IMADE, it must be both immunogenic (that is, able to sensitize the immune system) and antigenic (that is, able to evoke a response from a sensitized immune system). Unlike protein therapeutics, small-molecule drugs (or xenobiotics) are usually neither immunogenic nor antigenic. IMADEs are therefore the result of complex interactions between drug-metabolizing enzymes, immune sensitization and immune effectors. The genetic aspects of this interplay are discussed in this review.

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Figure 1: Formation of drug haptens.
Figure 2: Generation of immune effectors.
Figure 3: The Coombs and Gell classification of hypersensitivity reactions.

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Acknowledgements

This work was supported by Centocor Inc.

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Authors and Affiliations

  1. Department of Toxicology and Investigational Pharmacology, Director of Experimental Pathology, Centocor Inc., 200 Great Valley Parkway, Malvern, 19355, Pennsylvania, USA

    Peter J. Bugelski

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  1. Peter J. Bugelski
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DATABASES

Entrez Gene

CYP1B1

CYP2A6

CYP2C9

CYP2C19

CYP2D6

CYP2E1

IFN-g

IL-2

IL-4

IL-5

IL-6

IL-9

IL-10

IL-13

IL-31

NAT2

SOCS3

OMIM

Hashimoto thyroiditis

rheumatoid arthritis

Stevens–Johnson syndrome

systemic lupus erythematosus

type I diabetes mellitus

FURTHER INFORMATION

The Louisiana State University Library Toxicology Internet Resources page

The Society of Toxicology

The United States Food and Drug Administration

Glossary

XENOBIOTIC

This term is used to differentiate chemical drugs from protein therapeutics. They are generally polycyclic hydrocarbons that contain one or more nitrogen atoms, either as part of one or more of their rings, or as part of their side chains.

HAPTEN

The designation given to a small molecule that is by itself non-immunogenic, but, when covalently linked to a protein, is able to elicit an immune response.

DRUG-METABOLIZING ENZYMES

Enzymes that use xenobiotics as substrates for a wide range of chemical reactions. These include oxidations, reductions and conjugations. Metabolic enzymes can both activate and detoxify xenobiotic drugs. In immune-mediated adverse drug effects, metabolic enzymes often allow xenobiotics to act as haptens.

CYTOCHROME P450

An important family of monooxygenases that mediate the metabolism of xenobiotics

MAJOR HISTOCOMPATIBILITY COMPLEX

(MHC). Originally named because they function as transplantation antigens, MHC molecules have a crucial role in antigen presentation, and serve as accessory binding proteins for both T-helper and T-killer cells.

ANTIGEN

An entity that is able to bind antibodies or T-cell receptors and elicit an immune response. Not all antigens are immunogens (that is, they are not all able to perform the de novo activation of an immune response). In immune-mediated adverse drug effects, although the parent xenobiotic drugs can function as antigens, they must often be covalently bound to proteins (see haptens) for full antigenicity.

CLONES

Exact copies of a single progenitor cell. The clonal expansion of T and B cells is crucial in mounting an immune response.

CYTOKINE

Protein hormones that act on cells of the immune system. Interleukins are cytokines that are released by leukocyte cells, which serve as crucial factors that drive and direct immune responses.

ANTIBODY SUBCLASS

Antibodies are produced as five subclasses: immunoglobulin M (IgM), IgG, IgE, IgD and IgA. These differ in their heavy chains and, therefore, in their Fc receptor interactions. In immune-mediated adverse drug effects, IgE is important in mediating allergic (type I) reactions, whereas IgM and IgG are important effectors in type II, III and IV reactions.

CHEMOKINES

Non-peptide and small peptide molecules that are able to mediate the migration of inflammatory cells from blood vessels to the site of inflammation.

T-HELPER CELL

The subclass of T lymphocytes that mediates the expansion and direction of immune responses.

KILLER CELL

The subclass of T lymphocytes that mediate damage to cells or tissues. Killer cells are important effector cells in delayed-type hypersensitivity reactions. They also act as suppressor cells to downregulate immune responses.

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Bugelski, P. Genetic aspects of immune-mediated adverse drug effects. Nat Rev Drug Discov 4, 59–69 (2005). https://doi.org/10.1038/nrd1605

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