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To determine the molecular mechanisms of T cell stimulation by staphylococcal enterotoxin A (SEA), we examined the expression of T cell receptor (TcR) V beta on the T cells from four strains of mice stimulated in vitro with SEA, using flow cytometric analysis for the number of T cells bearing V beta 3, V beta 6, V beta 8, V beta 11 and RNA blotting analysis for the amount of transcripts of V beta 1, V beta 5 and V beta 12. The number of T cell blasts bearing V beta 1, V beta 3, V beta 1 or V beta 12 were increased in the T cell blasts proliferating in vitro in response to SEA in C57BL/6 mice. In AKR/J mice, which contain few V beta 11- or V beta 12-bearing T cells due to a tolerance to the self-MHC class II IE-antigens, T cells bearing V beta 1 or V beta 3 responded to SEA. SEA enriched only V beta 1-bearing T cells in BALB/c mice carrying Mls-2a which lack Mls-1a-reactive V beta 3-bearing T cells as well as V beta 11- and V beta 12-bearing T cells. In spite of the presence of V beta 1-bearing T cells, C3H/He T cells exhibited a very low responsiveness to SEA. T cell repertoires skewed by clonal deletion of self-reactive T cells may in part account for the different sensitivity to SEA among the different strains. A tolerance to SEA can be established in C57BL/6 mice which have been primed i.v. with SEA and treated i.p. with 200 mg/kg of cyclophosphamide 2 days later. All mature T cells bearing V beta 3 or V beta 11 were virtually abolished in the periphery of tolerant mice. These results suggest that most T cells reactive to SEA bear V beta 1, V beta 3, V beta 11 or V beta 12 and that clonal deletion of mature T cells reactive to SEA may account for the cellular mechanisms for cyclophosphamide-induced tolerance to SEA.

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A camptothecin derivative, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), shows a potent antitumour activity in experimental tumour models and in clinical trials. However, CPT-11 induced early diarrhoea and vomiting at high dose levels in clinical studies and showed an acetylcholine-like action on the guinea-pig ileum and trachea. In the present study, we investigated the activities of camptothecin derivatives in inhibiting acetylcholinesterase (AChE) and in binding to muscarinic acetylcholine receptors (AChR). CPT-11 inhibited AChE and binding of the specific ligand to AChR with respective 50% inhibition concentrations of 0.2 and 5 microM. These inhibitions were induced by camptothecin derivatives having an amino group at the C-10 position (or the C-4 position of hexacyclic derivatives), but were not or were only slightly induced by the others. Early defecation and vomiting in dogs were observed after intravenous injection of DU-6596 and DU-6888, two hexacyclic derivatives having the aminomethyl group at the C-4 position, and of CPT-11. DU-6174, however, which has a hydroxy group at this position, induced no early defecation and little vomiting. Plasma concentrations of CPT-11, DU-6596 and DU-6888 after intravenous treatment at doses causing such early adverse effects were maintained for 1 h or longer at levels sufficient to inhibit AChE. These results suggest that the inhibition of AChE by camptothecin derivatives with an amino group at the C-10 position (or the C-4 position) relates to the early defecation or diarrhoea and vomiting.

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