The modification of the self-HLA, of TCR, or of the TCR-peptide-HLA complex by non-covalent, bindings of drugs is a reversible, transient process, whose effect is highly dependent on the affinity of drug-protein interactions. The drug can bind first to the HLA-peptide complex (p-i HLA) or the TCR complex (p-i TCR). Sometimes the drug may be trapped in between TCR and HLA.
P-i HLA is often linked with a striking HLA-association of the DHR (shown for abacavir, carbamazepine, allopurinol, dapson, vancomycin etc.), since the drug binds to a certain HLA-allele with higher affinity than to other HLA-molecules. P-i TCR is less investigated. Drug binding to certain parts of the TCR Vβ chains may be sufficient for full activation, if interaction with HLA-peptide complexes is possible; other p-i TCR bindings may require additional T cell activation (e.g. by viral infection) to lead to clinical symptoms.
The in vitro analysis of p-i using drug specific T cell clones (TCC) or TCR-transfected cell lines generated from patients with DH revealed a strong stimulation: A high level of T cell mediated cytotoxicity, a broad spectrum of secreted cytokines and polyclonality was observed; The p-i stimulation was unorthodox: some CD4+ T cells were uncharacteristically reacting to HLA-class I or CD8+ T cells to HLA-class II drug presentation or did not show strict HLA restriction, and some TCC were polyspecific (the reactive T cell clones reacted with various peptides): Altogether, the picture emerged that p-i induced T cell stimulations have features of allo-like immune stimulations (allo-stimulation).