This study was supported by the Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Switzerland, and the Swiss National Science Foundation (grant no. 310030_149958, C.A.). All authors declare that their participation in the study did not involve factual or potential conflicts of interests.
In the context of drug hypersensitivity, our group has recently proposed a new model based on the structural features of drugs (pharmacological interaction with immune receptors; p-i concept) to explain their recognition by T cells. According to this concept, even chemically inert drugs can stimulate T cells because certain drugs interact in a direct way with T-cell receptors (TCR) and possibly major histocompatibility complex molecules without the need for metabolism and covalent binding to a carrier. In this study, we investigated whether mouse T-cell hybridomas transfected with drug-specific human TCR can be used as an alternative to drug-specific T-cell clones (TCC). Indeed, they behaved like TCC and, in accordance with the p-i concept, the TCR recognize their specific drugs in a direct, processing-independent, and dose-dependent way. The presence of antigen-presenting cells was a prerequisite for interleukin-2 production by the TCR-transfected cells. The analysis of cross-reactivity confirmed the fine specificity of the TCR and also showed that TCR transfectants might provide a tool to evaluate the potential of new drugs to cause hypersensitivity due to cross-reactivity. Recombining the ␣-and -chains of sulfanilamide-and quinolone-specific TCR abrogated drug reactivity, suggesting that both original ␣-and -chains were involved in drug binding. The TCR-transfected hybridoma system showed that the recognition of two important classes of drugs (sulfanilamides and quinolones) by TCR occured according to the p-i concept and provides an interesting tool to study drug-TCR interactions and their biological consequences and to evaluate the cross-reactivity potential of new drugs of the same class.
Ca 2؉ signals mediate the hepatic effects of numerous hormones and growth factors. Hepatic Ca 2؉ signals are elicited by the inositol trisphosphate receptor, an intracellular Ca 2؉ channel. Three isoforms of this receptor have been identified; they are expressed and regulated differently. We investigated the effect of liver fibrosis and cirrhosis on the hepatic expression of the inositol trisphosphate receptor isoforms. Two different rat models were used: bile duct ligation (fibrosis) and chronic exposure to CCl 4 /phenobarbital (cirrhosis). Messenger RNA levels were determined by ribonuclease protection assay (RPA), competitive polymerase chain reaction (PCR) followed by Southern blotting, and real-time quantitative PCR. Protein expression was assessed by Western blotting; tissue distribution was assessed by immunohistology. In control animals, isoform 2 was the predominant isoform, isoform 1 represented less than one third, and isoform 3 less than 1%. After bile duct ligation, expression of types 1 and 3 increased 1.9-and 5.7-fold, and expression of type 2 decreased 2.5-fold at the protein level. After exposure to CCl 4 /phenobarbital, expression of types 1, 2, and 3 were 2.4-, 0.9-, and 4.2-fold their expression in control animals. Type 2 was localized to the apical domain of hepatocytes, consistent with a role for Ca 2؉ signals in canalicular function. Type 3 was detectable in intrahepatic bile duct epithelial cells and not in hepatocytes, suggesting that Ca 2؉ signals may be regulated differently in these cells. Signaling through inositol trisphosphate receptor participates in the pathogenesis of cirrhosis, because this process affects the expression of its isoforms. (HEPATOLOGY 1999;30:1018-1026.)Development of cirrhosis implies not only remodeling of the liver architecture, but also dramatic changes in the functions of hepatic cells. These changes are orchestrated by a network of receptors, protein-kinases, and transducers that compose complex signaling pathways. Among them, the inositol 1,4,5-trisphosphate receptor (IP 3 R) plays a central role. 1 Numerous hormones and growth factors bind to receptors on plasma membrane to stimulate the production of inositol 1,4,5-trisphosphate (IP 3 ) and to trigger IP 3 -dependent Ca 2ϩ release through the Ca 2ϩ channel of the IP 3 R. 2 Ca 2ϩ signals regulate many cellular functions from gene expression and cellular division to metabolic pathways and cellular secretion. 1 Both hepatocytes and biliary epithelial cells demonstrate complex Ca 2ϩ signals, which rely essentially on IP 3 R, because the ryanodine receptor, another intracellular Ca 2ϩ channel, could not be detected in liver. 3 In response to hormonal stimulation, intracellular Ca 2ϩ concentration oscillates in hepatocytes and even forms Ca 2ϩ waves through the entire lobule. 4 Hepatocellular Ca 2ϩ signals start in a specific apical location and diffuse in an apical to basal manner. 5 IP 3 -dependent Ca 2ϩ signals stimulate bile canalicular contractions, an effect blocked by nitric oxide. 6 In intrahepatic bil...
Our data suggest that CM may be stimulatory for T cells either by direct binding to the MHC-TCR complex or by binding after uptake and processing by APCs. This questions the assumed inert nature of CM.
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