concanavalin-a and Pruritus

TS-022, {4-[(1R, 2S, 3R, 5R)-5-Chloro-2-((S)-3-cyclohexyl-3-hydroxyprop-1-ynyl)-3-hydroxycyclopentyl] butylthio} acetic acid monohydrate, inhibits ADP-induced platelet aggregation, an effect significantly antagonized, as in the case of prostaglandin D(2) by the prostanoid DP(1) receptor antagonist (BW A868C). TS-022 is a prostanoid DP(1) receptor agonist, originally developed as a novel anti-pruritic drug for patients with atopic dermatitis. We examined the effects of TS-022 on experimental pruritus, cutaneous barrier disruption, and atopic dermatitis and in in vitro immune function tests. Topically applied TS-022 significantly suppressed scratching in skin-lesioned NC/Nga mice from a concentration of 2.5 nM, and this scratch-suppressive activity was significantly antagonized by BW A868C. Tacrolimus (FK-506) and dexamethasone, used as reference drugs for atopic dermatitis, also exhibited suppressive effects against scratching, but only at concentrations of 125 and 25,000 microM. TS-022 applied topically, once a day for 2 days, significantly accelerated repair of the cutaneous barrier disruption caused by mechanical scratching, from concentrations of 2.5 nM. This acceleration of repair of the disrupted cutaneous barrier by this drug was also significantly antagonized by BW A868C. FK-506 and dexamethasone showed no beneficial effects on the repair of the disrupted cutaneous barrier. Repeated topical application of 2.5 microM of TS-022 and 12.5 microM of FK-506 once a day for 6 weeks significantly improved the skin inflammation scores in the NC/Nga mice. In regard to the effects of TS-022 in vitro, the inhibitory activity of TS-022 against concanavalin A-induced cytokine production by splenocytes was marginal as compared with that of FK-506 or dexamethasone. These results suggest that the beneficial therapeutic effects of TS-022 in NC/Nga mice with atopic dermatitis are mediated by its suppressive effect on scratching and its effect of accelerating repair of the disrupted cutaneous barrier, both effects being attributable to its prostanoid DP(1) receptor agonistic activity.

Topics: Acetates; Animals; Antipruritics; Concanavalin A; Cyclohexanes; Cytokines; Dermatitis, Atopic; Dexamethasone; Humans; Hydantoins; Immunosuppressive Agents; Inflammation; Male; Mice; Platelet Aggregation; Prostaglandin D2; Pruritus; Receptors, Immunologic; Receptors, Prostaglandin; Skin; Sulfhydryl Compounds; Tacrolimus; Wound Healing

The etiology of atopic pruritus is unclear and seems mostly histamine-independent. In order to investigate non-mast cells as possible sources of pruritogenic agents, peripheral blood mononuclear cells from 12 atopic eczema patients and 12 controls were incubated in vitro for 24 h with phytohemagglutinin or concanavalin A (both at 10 micrograms/ml) or with medium alone, and each subject was tested with his own cell supernatants and lysates by prick testing and by application on tape-stripped skin. Histamine (0.1%) and substance P (500 microM) were tested in comparison, and reactions were observed for up to 24 h. Cell supernatants were also analysed for their contents of several cytokines. Lymphocyte cell extracts or supernatants failed to cause symptoms in controls but induced whealing in 6 and itching in 3 patients on prick testing within 5 min, lasting for 30 min in 2 patients and persisting for 6 h in 1 patient. Histamine caused itching in all controls and in 7 patients within 5 min on prick testing, with decreasing reactivity at later times. Substance P yielded results with lower values. With all three types of test reagents, fewer subjects reacted on tape stripped skin. High levels of interleukins 2 and 6, low levels of interferon and no detectable levels of interleukin 4 and tumour necrosis factor were measured in stimulated cell supernatants and extracts, with even lower levels in subjects exhibiting skin reactivity. These findings thus provide evidence that as yet unidentified mononuclear cell products may be involved in whealing and itching associated with atopic eczema.

Topics: Adult; Cells, Cultured; Concanavalin A; Cytokines; Dermatitis, Atopic; Histamine; Humans; Leukocytes, Mononuclear; Mitogens; Phytohemagglutinins; Pruritus; Substance P