text: The p-i concept links pharmacology with immunology: It implies that drugs bind directly, as an off-target activity to immune receptors which results in various forms of T cell stimulations. P-i thus starts with an off-target pharmacological activity of the drug followed by a cascade of immunological events which always starts with T cell activation, even if the drug did not bind to the T cell itself but to an antigen presenting cell (APC).
  The drug bindings occur by non-covalent bonds (e.g. Hydrogen bonds, electrostatic interactions, van der Waals forces) to some of the highly polymorphic T cell receptors for antigen (TCR) and / or human leukocyte antigens (HLA). The binding occurs mostly on the cell surface and is labile, reversible and transient. It interacts with the crucial molecules of antigen dependent T cell activation, which may alter the self-HLA to make it look like an allo-HLA-allele, to which T cells strongly react; Some drug binding to TCR itself may – together with HLA-peptide interaction – elicit TCR-CDR signalling or alter the TCR conformation, thereby enhancing its interaction with HLA-peptide (allogeneic effect). Certain drugs may not only interact with the immune receptors on the surface but also inside the cell (endoplasmic reticulum e.g. Abacavir to HLA-B*57:01). This may cause a change of presented peptides (altered peptide model).
  The polymorphism of the immune receptors explains to a large extent the notoriously unpredictable “idiosyncrasy” of drug hypersensitivity reactions (DHR), as some of the individually distinct protein sequences may bind the drug better than others. Thereby only those individuals react to the drug which express the fitting protein sequence, e.g. a certain HLA-allele.
  Until now, only αβ TCR and HLA-class I and II proteins were described as target structures for p-i mediated drug hypersensitivity, but it is likely that other immune receptors (γδ-TCR, HLA-Class Ib, etc.) are also possible off target structures.