text: The p-i concept represents an alternative explanation of immune stimulation by drugs in DHR. It implies that no formation of a new antigen (hapten-protein complex) is needed to elicit an immune activation: T cells are stimulated by the drug binding to immune receptors directly, which leads to conformational changes of HLA and/or TCR as well as to signalling by the TCR-CD3 complex: The p-i concept was created and formulated by Prof. emeritus Werner J. Pichler in early 2000, based on studies with drug specific T cell clones, derived from patients with DHR. The underlying investigations were performed by various PhD students in Pichler's research group at the Inselspital/University of Bern in Bern, Switzerland. The essential, initial finding was that T cells from patients with DH showed a specific reaction to the incriminated drug in vitro (proliferation, cytotoxicity, cytokine release), and that this drug dependent stimulation of immune cells relied on labile (=non-covalent) binding of drugs to cell surface proteins, namely on antigen presenting cells and T cells, which were present in the cell culture.
  That a non-covalent, and drug binding was sufficient for T cell stimulation was shown by three main findings  underlying the lability of drug bindings: washing the cells in the cell culture (APCs, T cells) effectively removed the drugs, and the cells could not be stimulated any longer; This means that the drug was binding in a labile way, which was possible with the inert, parent compound; Transformation to a reactive metabolite was not needed to elicit a reaction:  blocking processing or metabolism by drugs did not interfere with reactivity and even fixing the antigen presenting cells by glutaraldehyde failed to eliminate T cell reactivity; And lastly by the speed of reaction: the reaction occurred within minutes, before metabolism could happen; addition of the drug to the cell culture containing drug reactive T cells resulted in a Ca influx in drug specific T cells within less than a minute.
  Over the years this p-i concept could be confirmed by many functional and structural studies including crystallography which localized the precise region of the immune receptor (HLA-B*57:01, TCRVβ20, etc.), to which a particular drug binds. Since crucial and highly sensitive molecules of T cell activation are targeted, complex and highly variable immunological consequences can develop: different types of T cells are activated to a variable degree, leading in inflammatory consequences with a highly polymorphic clinical picture of acute symptoms, followed by different late appearing complications.