Toshimi Sakurai

The effect of anti-tumor necrosis factor (TNF)-α monoclonal antibody on allergic cutaneous late phase reaction in mice

Biphasic cutaneous reaction with peak response at 1 (early phase) and 24 to 48 hour (late phase) was elicited by epicutaneous challenge with antigen in actively and passively sensitized mice. Mice were actively immunized with dinitrophenylated (DNP) ascaris antigen and challenged with dinitrofluorobenzene (DNFB). Passively sensitization was carried out by the injection of monoclonal anti-DNP-IgE antibody into mice and challenge was elicited with DNFB. Prednisolone at doses of 3 to 10 mg/kg clearly inhibited both early and late phase reactions in either sensitized mice. Monoclonal anti-tumor necrosis factor (TNF)-alpha antibody inhibited the late phase cutaneous reaction in actively sensitized mice. Anti-interleukin-5 (IL-5) monoclonal antibody has no effect on both phase reactions in either actively and passively sensitized animals. These results indicate the possible participation of TNF-alpha in allergic cutaneous late phase reaction in actively sensitized mice.

TNF-α participates in an IgE-mediated cutaneous reaction in mast cell deficient, WBB6F1-W/Wv mice

The participation of tumor necrosis factor-α (TNF-α) in a IgE-mediated cutaneous reaction in WBB6F1-W/Wv (W/Wv), mast cell deficient, mice and the effect of prednisolone on this cutaneous reaction were investigated. Mice were passively sensitized by an intravenous injection of monoclonal anti-dinitrophenol (DNP) IgE, and their ears challenged epicutaneously with dinitrofluorobenzene 24 h later. The cutaneous reaction estimated by ear thickness reached a peak 48–72h after the antigen challenge. A monoclonal anti-tumor necrosis factor (TNF)-α antibody inhibited the IgE-mediated cutaneous reaction. An increase of TNF-α mRNA was demonstrated 4h after the application of antigen by the reverse transcriptase-polymerase chain reaction. The injection of recombinant murine TNF-α induced a cutaneous reaction which peaked at 24 h in nonsensitized mice. Prednisolone at doses of 3 to 10 mg/kg clearly inhibited the IgE-mediated cutaneous reaction, however, it did not affect the expression of TNF-α-mRNA. Prednisolone at doses of 1 to 10 mg/kg clearly inhibited the TNF-α-induced cutaneous reaction.These results suggest that TNF-α plays a role in the IgE-mediated cutaneous reaction in W/Wv mice and that prednisolone inhibits the cutaneous reaction at least in part by inhibiting the action of TNF-α.

Characterization of antihistamines using biphasic cutaneous reaction in BALB/c mice

Effects of 11 histamine H1 receptor antagonists on IgE-mediated biphasic cutaneous reaction in mice were examined. The immediate phase reaction (IPR) assessed at 1 hour after antigen application was significantly inhibited by all antihistamines examined. The inhibition of IPR by cetirizine and mequitazine were potent, but those by cyproheptadine and diphenhydramine were weak. The later phase reaction (LPR) assessed at 24 hours after antigen application was inhibited by chlorpheniramine, oxatomide, ketotifen, mequitazine, emedastine, terfenadine and azelastine. The inhibition of LPR by emedastine was potent, but those by ketotifen and terfenadine were only partial. Emedastine inhibited both IPR and LPR comparably. Present results indicate that H1 receptor activation is involved in the IPR of the biphasic cutaneous reaction, and that the blockade of H1 receptors at IPR does not contribute to the attenuation of following LPR. Histamine H1 receptor antagonists inhibiting the LPR have a property distinct from H1 receptor antagonism, which may have an additional benefit for the treatment of allergic diseases.

Pharmacological studies of platelet-activating factor (PAF)-induced augmentation of response to histamine in guinea-pigs

An acute increase in airway response to histamine produced by platelet activating factor (PAF) was investigated pharmacologically in guinea-pigs. (1) The airway response to histamine (3 micrograms/kg) measured as pulmonary pressure was increased 8 min after injection of PAF at a dose of 25 ng/kg without affecting the numbers of leukocytes (macrophages, eosinophils, neutrophils and lymphocytes) in bronchoalveolar lavage fluid and airway capillary permeability. (2) To investigate the mechanism responsible for the PAF (25 ng/kg)-induced airway hyperresponsiveness to histamine, the effects of CV-3988 (a PAF-antagonist), ONO-1078 (a leukotriene (LT) antagonist), AA-861 (a 5-lipoxygenase inhibitor), indomethacin (a cyclooxygenase inhibitor), OKY-046 (a thromboxane A2 (TXA2) synthetase inhibitor) and S-1452 (a TXA2 receptor antagonist) were examined. Simultaneously, to investigate the direct antagonistic effects of these drugs on PAF-induced response, the effects of above agents on PAF (150 ng/kg) induced bronchoconstriction were examined. CV-3988 completely inhibited both reactions, while ONO-1078 and AA-861 had no effect on both reactions. OKY-046, S-1452 and indomethacin inhibited PAF-induced bronchoconstriction more potently than PAF-induced airway hyperresponsiveness. These results indicate that inflammatory response is not involved in the onset of PAF-induced acute airway hyperreactivity. Results also suggest that TXA2 but not LT may play a role in the onset of this airway hyperreactivity and the role of TXA2 in hyperreactivity is less important than in PAF-induced bronchoconstriction.

The effect of a novel thromboxane A2 (TXA2) receptor antagonist (S-1452) on the antigen-induced bronchocostriction and airway hyperresponsiveness in guinea pigs

The effect of a novel thromboxane A2 (TXA2) receptor antagonist (S-1452) on antigen-induced bronchoconstriction and airway hyperresponsiveness in guinea pigs was studied. Ketotifen was used as a reference drug. S-1452 at doses of 1 and 3 mg/kg (per oral administration, 1 h before the injection of U-46619) clearly inhibited U-46619-induced pulmonary pressure increase. Ketotifen at a dose of 10 mg/kg did not affect U-46619-induced bronchoconstriction. S-1452 at doses of 3 and 10 mg/kg and ketotifen at a dose of 10 mg/kg inhibited the antigen-induced bronchoconstriction in guinea pigs which had been passively sensitized with guinea pig IgE antibody. S-1452 at a dose of 10 mg/kg inhibited repeated antigen provocation-induced airway hyperresponsiveness in guinea pigs. The accumulation of inflammatory cells by antigen provocation in bronchial alveolar lavage fluid (BALF) was inhibited by ketotifen but not by S-1452. These results indicate the efficacy of S-1452 on antigen-induced bronchoconstriction and antigen-induced airway hyperresponsiveness in guinea pigs.