T cell activation in drug allergies

The frequency of drug allergies due to a specific immunological reaction is estimated to be 15% of all drug-induced side effects. The pathomechanism of such allergies depends on the type of drug and various patient-related factors. They have been elucidated only in a few cases. According to current concepts, drugs or their metabolites have to be recognized by T cells to elicit an allergic reaction. Indeed, T cell sensitization has been demonstrated by experimental studies in various drug allergies using both lymphocyte transfer mation rests and skin patch tests. For T cell recognition, an antigen has to be presented by an APC on the MHC. Most drug and drug metabolites have a low molecular weight and gain their immunogenicity by binding to a carrier protein. Different ways of hapten presentation have been proposed: the hapten binds covalently to a serum or cellular protein, which is subsequently processed and presented as a modified protein; the hapten alters antigen processing, which leads to the presentation of cryptic peptide; the hapten binds in a direct and extracellular way to a preexisting MHC peptide complex. Specific restimulation of peripheral blood mononuclear cells in primary cultures of drug-allergic patients with the relevant drug leads to an activation of CD4(+) and CD8(+) T-cells. In the peripheral blood of patients with hypersensitivity syndrome, also an in vive activation of CD4(+) and CD8(+) T-cells has been described, which correlated to the clinical course. Most drug-specific T cell clones have an alpha beta(+) TCR. However, few lidocaine-specific T cell clones with gamma delta(+) TCR have been described recently. Analysis of V beta chains of TCRs in primary cultures of drug-allergic patients revealed either oligoclonal or polyclonal patterns, depending on the patient and the drug. The cytokine production of drug-specific T cells revealed a variable pattern. Occasionally, a high IL-5 production was seen. Recently, a drug-specific, MHC-restricted, T cell-mediated cytotoxicity in CD4(+) and CD8(+) T-cell clones could be shown. Our data show that in drug allergies T cells are crucial for the initiation and also for the effector phase of a drug-specific immune response. This would have implications for the development of new diagnostic methods and for the search of a sensitizing potential of a novel drug.