In contrast to allergic and pharmacological stimulations, there is no evidence that the adaptive immune system is involved. In response to a drug, inflammatory cells degranulate or produce and release a large amount of inflammatory mediators, such as leukotrienes.
Pseudo-allergic or nonallergic hypersensitivity reactions are characterized by direct drug interactions with inflammatory effector cells, in particular mast cells, basophils and eosinophils, and probably also neutrophils. Immune/allergic and pharmacological hypersensitivity reactions The final result of p-i stimulation is similar toallergic immune-mediated T cell reactions and can lead to a quite heterogeneous clinical picture. Rather, a typical feature of p-i stimulation is its restriction to T cells alone as the drugs bind to immune receptors involved in T cell activation. In pharmacological hypersensitivity, complex immune responses encompassing dendritic cell activation and subsequent stimulation of B and T cells do not occur. Drug hypersensitivity reactions (DHR) according to the p-i concept do not require the processing of a new antigenic complex and neither metabolism of the drug nor subsequent processing steps are required (table 1). Typically, drug binding to a receptor is rapid, based on noncovalent interactions and is reversible. The binding of a drug to an immune receptor follows the same rules as a drug binding to a nonimmunological receptor. Pharmacological hypersensitivity reactions according to the p-i (pharmacological interaction with immune receptor) concept are based on the noncovalent binding of drugs or metabolites to immune receptor proteins themselves (HLA or T cell receptors, TCR).
Importantly, haptens can also stimulate innate immunity and activate dendritic cells, meeting an important requirement for the induction of a novel immune response. Processing of these complexes may furthermore generate antigenic hapten-peptides which have the ability to stimulate T cells in a human leukocyte antigen (HLA)-dependent manner. These complexes have an immunostimulatory potential since they provide antigenic epitopes to B cells and immunoglobulins.
Reactions to small molecules include allergic, pharmacological (p-i) and nonallergic (‘pseudo-allergic') hypersensitivity reactions.Īllergic, immune-mediated reactions are based on the covalent binding of small chemicals to protein or peptide molecules, which generates new antigenic determinants consisting of either hapten-protein or hapten-peptide complexes. Immune reactions to proteins, which represent complete antigens per se, are not discussed here. Karger AG, Baselĭrug hypersensitivity reactions (DHR) are the result of immune interactions with small molecular compounds or proteins used as drugs. 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.
#Haptens have immunogenicity but not reactivity full#
In the sulfamethoxazole model of p-i TCR, responsive T cells likely require costimulation for full T cell activation. More importantly, the drug binding to HLA generates a drug-modified HLA, which stimulates T cells directly, like an allo-HLA. In the abacavir model of p-i HLA, the drug binding to HLA may result in alteration of the presenting peptides. Hence, the complex and diverse clinical manifestations of delayed-type hypersensitivity are caused by the functional heterogeneity of T cells. 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. 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). They are assigned the ‘pharmacological interaction with immune receptors' (p-i) concept. Such drug interactions with immune receptors may lead to T cell stimulation, resulting in clinical symptoms of delayed-type hypersensitivity. 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 interactions are a main cause of adverse side effects to drugs and are normally classified as predictable type A reactions. Some chemicals interact with other molecules than the actual target ligand, representing so-called ‘off-target' activities of drugs. hydrogen bonds, salt bridges or electrostatic interactions. Small chemicals like drugs tend to bind to proteins via noncovalent bonds, e.g.