Molecular Basis of Drug Recognition by Specific T–Cell Receptors

Abstract

In recent years the involvement of T cells in allergic reactions to drugs has been well established. However, several molecular aspects of drug recognition by specific T cells remain still unclear. This review will discuss the known pathways of drug presentations by antigen presenting cells, the recognition of MHC/peptide/drug complexes by specific T–cell receptors, and the activation mechanism of drug–specific T cells.

Recognition of Sulfamethoxazole and Its Reactive Metabolites by Drug-Specific CD4+ T Cells from Allergic Individuals

“…Half of all SMX-specific TCC tested responded to N-acetyl SMX, the major nontoxic metabolite of SMX excreted in human urine. These data are in keeping with our previous observations of a considerable degree of cross-reactivity of SMX-specific TCC with SMX derivatives bearing the same sulfanilamide core structure (15,16).…”

“…However, recent investigations have revealed that drugs such as lidocaine and SMX, which are considered to be chemically inert, can be recognized by drug-specific T cell clones (TCC) (11)(12)(13)(14)(15). This recognition required the continuous presence of the drug and was MHC-restricted and very rapid.…”

Drug interaction with T-cell receptors

“…This stimulation still requires the presence of MHC molecules, whereby previous investigations have shown that TCCs with selective specificity for SMX are less dependent on the type of MHC allele than TCCs able to interact with more sulfanilamides. 25,26 Our data support the p-i-concept (pharmacologic interaction with immune receptors 8 ), which implies that drugs, even if they are not haptens, can interact directly with certain TCR. 4,8 This type of drug interaction with TCR does not require covalent binding of the drug to MHC-peptide complexes, as washing removed the drug, and even fixed APC could still present the drug.…”

mRNA Expression of Multiple Cytochrome P450 Isozymes in Four Types of Cultured Skin Cells

“…These drugs, mostly low-molecular-weight compounds, are thought to become immunogenic upon binding to proteins. Most drugs are chemically inert, and their metabolic activation to form protein adducts has been proposed to be a necessary first step in the induction of an allergic reaction, especially for sensitization [2, 3]. The role of human cytochrome P450 (CYP) isozymes in the metabolic activation of these drugs is being increasingly recognized (for example, the involvement of CYP2C9 and 2C19 in phenytoin metabolism and protein-adduct formation [4]).…”