title: Drug Hypersensitivity: How Drugs Stimulate T Cells via Pharmacological Interaction with Immune Receptors.
abstract: Small chemicals like drugs tend to bind to proteins via noncovalent bonds, e.g. hydrogen bonds, salt bridges or electrostatic interactions. Some chemicals interact with other molecules than the actual target ligand, representing so-called 'off-target' activities of drugs. Such interactions are a main cause of adverse side effects to drugs and are normally classified as predictable type A reactions. Detailed analysis of drug-induced immune reactions revealed that off-target activities also affect immune receptors, such as highly polymorphic human leukocyte antigens (HLA) or T cell receptors (TCR). Such drug interactions with immune receptors may lead to T cell stimulation, resulting in clinical symptoms of delayed-type hypersensitivity. They are assigned the 'pharmacological interaction with immune receptors' (p-i) concept. Analysis of p-i has revealed that drugs bind preferentially or exclusively to distinct HLA molecules (p-i HLA) or to distinct TCR (p-i TCR). P-i reactions differ from 'conventional' off-target drug reactions as the outcome is not due to the effect on the drug-modified cells themselves, but is the consequence of reactive T cells. Hence, the complex and diverse clinical manifestations of delayed-type hypersensitivity are caused by the functional heterogeneity of T cells. In the abacavir model of p-i HLA, the drug binding to HLA may result in alteration of the presenting peptides. More importantly, the drug binding to HLA generates a drug-modified HLA, which stimulates T cells directly, like an allo-HLA. In the sulfamethoxazole model of p-i TCR, responsive T cells likely require costimulation for full T cell activation. These findings may explain the similarity of delayed-type hypersensitivity reactions to graft-versus-host disease, and how systemic viral infections increase the risk of delayed-type hypersensitivity reactions.
authors.affiliation: ADR-AC GmbH, Bern, Switzerland.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Pichler
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Adam
authors.forename: Stephen
authors.initials: S
authors.lastname: Watkins
authors.forename: Natascha
authors.initials: N
authors.lastname: Wuillemin
authors.forename: James
authors.initials: J
authors.lastname: Yun
authors.forename: Daniel
authors.initials: D
authors.lastname: Yerly
mesh_terms: D004342:Drug Hypersensitivity / Q000276:immunology*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D006680:HLA Antigens; D011948:Receptors, Antigen, T-Cell