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.

Multiple Drug Hypersensitivity

“…This massive, drug-induced proliferation in a 6- to 7-day culture is reminiscent of proliferations observed in mixed leukocyte reactions. This would be consistent with the allo-immune hypothesis of DHR which postulates that severe DHR are due to p-i stimulations resulting in allo-like immune stimulations [32,45]. It hypothesizes that drug binding to HLA modifies the HLA-peptide complex and makes it look like an allo-HLA structure, which then elicits a strong, polyclonal T-cell stimulation.…”

“…A high percentage of PD1+, CD38+ circulating T cells has also been found in other chronic diseases such as graft-versus-host disease [45] and chronic herpes virus infections [35,36]. In the latter it was linked to a reduced life span of the affected persons [46].…”

“…The MDH might thus correspond to a chronic graft-versus-host disease-like stimulation. Indeed, the CD4+, CD25 dim , CD38+, and PD-1+ T cells found in MDH are also found in chronic graft-versus-host disease [45]. …”

HLA and Delayed Drug-Induced Hypersensitivity

“…The p-i concept claims that drugs induce DDAR without binding to a carrier and without forming a hapten-carrier complex [27,31,32]. This model therefore posits that a drug can directly stimulate T cells and, consequently, generate a specific immune response without needing to be previously processed or metabolized [27,31,32].…”

“…This model therefore posits that a drug can directly stimulate T cells and, consequently, generate a specific immune response without needing to be previously processed or metabolized [27,31,32]. …”