Interaction of Small Molecules with Specific Immune Receptors: The p-i Concept and its Consequences
Werner J. Pichler and Stephen Watkins
Affiliation: ADR-AC GmbH, Holligenstr. 91, 3008 Bern, Switzerland.
Drugs may stimulate the immune system by forming stable new antigenic complexes consisting of the drug or
drug metabolite which is covalently bound to a protein or peptide (hapten-carrier complex). Both, B- and T-cell immunity
may arise, the latter directed to hapten modified peptides presented by HLA molecules. Beside this immunological
stimulation, drugs can also stimulate the immune system through binding by non-covalent bonds to proteins like immune
receptors. This so-called “pharmacological interaction with immune receptors” concept (“p-i concept”) may occur with
HLA or TCR molecules themselves (p-i HLA or p-i TCR), and not the immunogenic peptide. It is a type of “off-target”
activity of the drug on immune receptors, but more complex as various cell types, cell interactions and functionally
different T cells are involved. In this review the conditions which lead to activation of T cells by p-i are discussed:
important factors for a functional consequence of drug binding is the location of binding (p-i HLA or p-i TCR); the exact
site within these immune receptors; the affinity of binding and the finding that p-i HLA can stimulate the immune system
like an allo-allele. The p-i concept is able to solve some puzzles of drug hypersensitivity reactions and are a basis to better
treat and potentially avoid drug hypersensitivity reactions. Moreover, the p-i concept shows that in contrast to previous
beliefs small molecules do interact with immune receptors with functional consequence. But these interactions are not
based on “immune recognition”, are at odds with some immunological concepts, but may nevertheless open new
possibilities to understand and even treat immune reactions.
Keywords: Alloreactivity, hapten, p-i concept, p-i HLA, p-i TCR.
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