Recognition of local anesthetics by alpha beta(+) T cells

Patients with drug allergy show a specific immune response to drugs. Chemic ally nonreactive drugs Like, for example, local anesthetics are directly re cognized by alpha beta(+) T cells in an HLA-DR restricted way, as neither d rug metabolism nor protein processing is required for T cell stimulation. I n this study we identified some of the structural requirements that determi ne cross-reactivity of T cells to local anesthetics, with the aim to improv e the molecular basis for the selection of alternatives in individuals sens itized to a certain local anesthetic and to better understand presentation and T cell recognition of these drugs. Fifty-five clones (52 lidocaine spec ific, three mepivacaine specific from two allergic donors) were analyzed. S timulatory compounds induced a downregulation of the T cell receptor, demon strating that these non-peptide antigens are recognized by the T cell recep tor itself. A consistent cross-reactivity between lidocaine and mepivacaine was found, as all except one lidocaine specific clone proliferated to both drugs tested. Sixteen chemically related local anesthetics (including este r local anesthetics, OH- and desalkylated metabolites) were used to identif y structural requirements for T cell recognition. Each of the four clones e xamined in detail was uniquely sensitive to changes in the structures of th e local anesthetic: clone SFT24, i.e., did not recognize any of the tested OH- or desalkylated metabolites, while the clone OFB2 proliferated to all O H-metabolites and other differently modified molecules. The broadly reactiv e clone OFB2 allowed us to propose a model, suggesting that the structure o f the amine side chain of local anesthetics is essential for recognition by the T cell receptor.