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p-i Concept (Pharmacologycal interaction with immune receptor) The p-i concept is a concept to explain delayed appearing, T cell mediated immune reactions to small molecules like drugs. It postulates an immune-stimulatory effect of a drugs on T cells by direct binding of a small molecule to immune receptors like Human leukocyte antigen (HLA) or T-cell receptor (TCR). This corresponds to a typical [Pharmacotoxicology#Off-target_toxicity|off-taget]] activity of a drug. Such p-i reactions are considered to be involved in various drug hypersensitivity reactions. Important examples are DRESS (drug reaction with eosinophilia and systemic symptoms) or Stevens–Johnson syndrome.

Summary
Small chemicals like drugs are often designed or selected on the basis of preferential binding to proteins. If the protein is a receptor, this interaction may block interaction with the natural ligand; Rarely it may even enhance the receptor function. It occurs via noncovalent bonds, e.g. hydrogen bonds, salt bridges or electrostatic interactions. Some chemicals/drugs interact with more molecules rather than the actual target ligand, representing so called off-target activities of drugs. These of target interactions are a common cause of adverse side effects to drugs and are normally classified as predictable type A reactions.

Detailed analysis of drug-induced T cell stimulations in drug hypersensitivity reactions revealed that off-target activities also affect immune receptors such as human leukocyte antigens (HLA) or T cell receptors (TCR). These immune recptors are highly polymorphic: one estimates that in the human population >10.000 different HLA proteins (alleles) exist, whereby each individual codes for at least 14-16 different HLA class I and HLA class II alleles. which are expressed in high quatities on nucleated cells. In addition, each indiividual has an enormous repertoire of T cells, each with distinct TCR (>1.000.000 -10.000.000 different T cells with unique TCR). The polymorphism of these immune receptors enhances the probability that these proteins have a configuration which allows binding of certain chemicals/drugs.

The interaction of a drug with an immune receptor is called ’pharmacological interaction with immune receptors’ p-i concept. One can differentiate p-i HLA or p-i TCR (see below): p-i refers to drug binding to the HLA-protein; p-i TCR refers to drug binding to TCR. Both p-i stimulations result in a T cell stimulation. Of note, p-i stimulations are due to a drug-receptor interaction (= pharmacology). P-i stimulations are thus not due to formation of a new antigen, as it is the case when the drug acts as a Hapten and modifies a protein (Hapten-carrier complex). In p-i HLA, the immune stimulation of reactive T cells is elicited by modification of the HLA-peptide complex by the drug. It has similarities to an allo-like immune reaction. In p-i TCR, the stimulation occurs by enhanced affintiy for HLA-peptides or HLA-drug-peptide complexes. The exact link to different clinical manifestations of drug hypersentitivity has not yet been elucidated.

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.