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Activating interactions of sulfanilamides with T cell receptors

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2013
Author Watkins Stephan Pichler WJ,
Project Investigating the primary immune response against drugs in humans
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Original article (peer-reviewed)

Journal Open Journal of Immunology
Volume (Issue) 3(3)
Page(s) 139 - 157
Title of proceedings Open Journal of Immunology

Open Access

URL http://www.scirp.org/journal/oji/
Type of Open Access Website

Abstract

Activation and expansion of drug reactive T cells are key features in drug hypersensitivity reactions. Drugs may interact directly with im- mune receptors such as the human leukocyte antigens (HLA) or the T-cell receptors (TCR) it- self, the pharmacological interaction [p-i] con- cept. To analyze whether the drug sulfameth- oxazole (SMX) interacts directly with the TCR and thereby contributing to signaling and T cell activation, we analyze two SMX specific T cell clones (TCC “1.3” and “H13”). Proliferation to SMX and 11 related sulfanilamides, Ca++ influx in drug stimulated T-cells and the inhibitory ef- fect of non-reactive sulfanilamides on SMX sti- mulation were analyzed. In silico docking of SMX and related sulfanilamide to the TCR were used to identify possible drug binding sites, and correlated to in vitro data to find the correct docking. In Ca++ influx assays, reactions oc- curred as early as 14 sec after adding SMX to TCC and APC. The broadly reactive clone (“H13”) was stimulated by 5 additional sulfanilamide, while one TCC (“1.3”) was reactive exclusively with SMX but not other sulfanilamides. Compe- tition experiments with sulfanilamide inhibited SMX induced Ca++ influx and proliferation of the TCC 1.3 in a dose dependent way. Docking ex- periments with SMX and related sulfanilamides confirmed and explained the in vitro data as docking localized binding sites for SMX and the 5 stimulating sulfanilamides on the CDR2β do- main of the clone H13, while the 6 non-stimula- tory SA failed to bind. In TCC 1.3, SMX could be docked on the CDR3α of the TCR. The other, non-stimulatory but inhibitory SA could also be docked to the same site. The combined analysis of in vitro and in silico data show that sulfa- nilamide can bind directly to TCRs. It shows that TCR, like other receptors, appear to be reame- nable to manipulations by small molecules.
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