Recognition of local anesthetics by alphabeta+ T cells.
Patients with drug allergy show a specific immune response to drugs. Chemically nonreactive drugs like, for example, local anesthetics are directly recognized by alphabeta+ T cells in an HLA-DR restricted way, as neither drug metabolism nor protein processing is required for T cell stimulation. In this study we identified some of the structural requirements that determine cross-reactivity of T cells to local anesthetics, with the aim to improve the molecular basis for the selection of alternatives in individuals sensitized to a certain local anesthetic and to better understand presentation and T cell recognition of these drugs. Fifty-five clones (52 lidocaine specific, three mepivacaine specific from two allergic donors) were analyzed. Stimulatory compounds induced a down-regulation of the T cell receptor, demonstrating that these non-peptide antigens are recognized by the T cell receptor 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 ester local anesthetics, OH- and desalkylated metabolites) were used to identify structural requirements for T cell recognition. Each of the four clones examined in detail was uniquely sensitive to changes in the structures of the local anesthetic: clone SFT24, i.e., did not recognize any of the tested OH- or desalkylated metabolites, while the clone OFB2 proliferated to all OH-metabolites and other differently modified molecules. The broadly reactive clone OFB2 allowed us to propose a model, suggesting that the structure of the amine side chain of local anesthetics is essential for recognition by the T cell receptor.
Zanni
M P
MP
Institute of Immunology and Allergology, Inselspital, Bern, Switzerland.
von Greyerz
S
S
Hari
Y
Y
Schnyder
B
B
Pichler
W J
WJ
D000779:Anesthetics, Local / Q000276:immunology*; D002460:Cell Line; D002999:Clone Cells / Q000276:immunology; D003429:Cross Reactions / Q000276:immunology; D004342:Drug Hypersensitivity / Q000276:immunology; D000939:Epitopes; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D007114:Immunization; D008012:Lidocaine / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex / Q000502:physiology; D008619:Mepivacaine / Q000276:immunology / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology