Figure 1.

Proposed models of T-cell receptor (TCR), major histocompatability complex (MHC), drug interactions: In the hapten/prohapten model (i) a drug (e.g., penicillin) binds covalently to an endogenous peptide (e.g., albumin), forming a new molecule. Antigen presenting cells process and present it as short peptide fragments within the MHC binding cleft, some of which (peptide A) include drug epitopes (purple pentagon). If recognized by a TCR, a drug-specific immune response can ensue. In the pharmacological-interaction (P-I) model (ii) the drug binds non-covalently to certain MHC molecules or TCRs, stimulating specific TCR and thus generating drug-reactive T-cells. In the altered peptide repertoire model (iii) a drug (e.g., abacavir) binds non-covalently to the binding pocket of a MHC molecule (e.g. HLA-B*57:01), altering its conformation and allowing a new array of self-peptides (peptide B) to stably occupy it and stimulate T-cells. This can lead to drug-induced activation of autoimmunity (e.g., abacavir hypersensitivity reaction.) Adapted from Pavlos et al.¹⁷⁵