ABSTRACT
Mast cells are the most prominent effector cells of Type 1 hypersensitivity immune responses. CYC116 [4-(2-amino-4-methyl-1,3-thiazol-5-yl)-N-[4-(morpholin-4-yl)phenyl] pyrimidin-2-amine] is under development to be used as an anti-cancer drug, but the inhibitory effects of CYC116 on the activation of mast cells and related allergy diseases have not reported as of yet. In this study, we demonstrated, for the first time, that CYC116 inhibited the degranulation of mast cells by antigen stimulation (IC₅₀, ∼1.42 µM). CYC116 also inhibited the secretion of pro-inflammatory cytokines including TNF-α (IC₅₀, ∼1.10 µM), and IL-6 (IC₅₀, ∼1.24 µM). CYC116 inhibited the mast cell-mediated allergic responses, passive cutaneous anaphylaxis (ED50, ∼22.5 mg/kg), and passive systemic anaphylaxis in a dose-dependent manner in laboratory experiments performed on mice. Specifically, CYC116 inhibited the activity of Fyn in mast cells and inhibited the activation of Syk and Syk-dependent signaling proteins including LAT, PLCγ, Akt, and MAP kinases. Our results suggest that CYC116 could be used as an alternative therapeutic medication for mast cell-mediated allergic disorders, such as atopic dermatitis and allergic rhinitis.
Subject(s)
Animals , Mice , Anaphylaxis , Cytokines , Dermatitis, Atopic , Hypersensitivity , Interleukin-6 , Mast Cells , Passive Cutaneous Anaphylaxis , Phosphotransferases , Rhinitis, AllergicABSTRACT
Se estima que niños alérgicos desarrollen tolerancia oral durante los primeros años de vida con una dieta de eliminación de lácteos. Determinar el tiempo de desarrollo de tolerancia oral a la proteína de leche de vaca, características clínicas y laboratorio. Estudio prospectivo, seguimiento durante 10 años, de niños con alergia a proteína de leche de vaca. Se indicó dieta de eliminación por 4 semanas con posterior reto. Se solicitó IgE total y específica. Se registro edad y tiempo de dieta al confirmarse la tolerancia. 81 niños, 33/81(40,74%) femeninos y 48/81(59,25%) masculinos, edad promedio de diagnóstico 6,22 meses(rango <1-42). Alergia no mediada IgE 32/81 (39,50%) y alergia mediada IgE 49/81 (60,49%); IgE específica para leche de vaca positivo en 55/81 (67,90%). Diagnóstico por respuesta positiva a la dieta de eliminación en 62/81 (76,54%) y con reto en 19/81 (23,45%). Desarrollaron tolerancia después de 12-18m con dieta, 21/32 (65,62%) con alergia no IgE a los 1,6 años y 23/49 (46,93%) con alergia IgE a los 2,13 años. Los niños restantes toleraron entre 19-24m, a los 2,35 y 2,80 años para la alergia no IgE e IgE respectivamente. Después de 36m, continuaron sin tolerar 5 niños entre ambos grupos con progreso a alergia alimentaria múltiple. El diagnóstico de alergia puede basarse en la respuesta positiva a la dieta de eliminación de lácteos, el reto es necesario en casos inciertos y la tolerancia se alcanza a una edad más temprana en niños con alergia no mediada IgE
It is estimated that allergic children develop oral tolerance in the early years of life with a dairy elimination diet. To determine the time development of oral tolerance to cow's milk protein, clinical and laboratory. A prospective study followed for 10 years, children allergic to cow's milk protein. He said elimination diet for 4 weeks after challenge. Was requested total IgE and specific. Age and time was recorded to confirm diet tolerance. 81 children, 33/81 (40.74%) were female and 48/81 (59.25%) male, average age at diagnosis 6.22 months (range <1-42). IgE-mediated allergy is not 32/81 (39.50%) and IgE-mediated allergy 49/81 (60.49%) specific IgE to cow's milk positive in 55/81 (67.90%). Diagnosis by positive response to the elimination diet in 62/81 (76.54%) and challenge in 19/81 (23.45%). Tolerance developed after 12-18m with diet, 21/32 (65.62%) with non-IgE allergy to 1.6 years and 23/49 (46.93%) with IgE allergy to 2.13 years. The remaining children tolerated between 19-24m, to the 2.35 and 2.80 years for non-IgE allergy and IgE, respectively. After 36m, continued without tolerating 5 children between the two groups with multiple food allergy progress. The diagnosis of allergy can be based on positive response to milk elimination diet, the challenge is necessary in uncertain cases and tolerance is reached at an earlier age in children with IgE mediated allergy is not
Subject(s)
Female , Infant , Breast-Milk Substitutes , Food Hypersensitivity , Hypersensitivity, Immediate/diagnosis , Hypersensitivity, Immediate/pathology , Milk Hypersensitivity/diagnosis , Milk Hypersensitivity/pathology , Allergy and Immunology , Child Nutrition Sciences , Gastroenterology , PediatricsABSTRACT
Scutellariae Radix (Scu.), one of the immune-regulatory substances, is recognized to play the role in the metabolic process of inflammation, allergy and immunity. It has been traditionally used in the Oriental medicine to treat inflammatory bowel diseases (IBD). The purpose of this study was to evaluate the effects of water extracts of Scutellariae Radix on the spleen lymphocyte immune function in the Balb/c female mice treated with dextran sodium sulfate (DSS) to induce colitis. Water extract of Scutellariae Radix (100 mg/kg) and sulfasalazine (50 mg/kg) were administrated orally for 2 weeks of experimental period. Mice were divided into three experimental groups randomly: DSS group (5% DSS was ad libitum for 5 days) as control group, DSS + Scu. (water extracts of Scutellariae Radix for 2 weeks after 5% DSS was ad libitum for 5 days) as experimental group, and DSS + Sulfasalazine group (Sulfasalazine for 2 weeks after 5% DSS was ad libitum for 5 days) as positive control group. Levels of Ig A, Ig E, CD4(+), CD8(+), TNF-alpha and other cytokines were measured. Treatment of DSS for 5 days induced bowel inflammation and the treatment with Scu. water exteract and sulfasalazine significantly recovered the damage. The length of intestine of DSS group was significantly shorter than that of other groups. The serum and fecal concentration of Ig A of SS + Scu group was higher than those of DSS group. The contents of CD4(+) T cells was higher in the DSS + Scu. group than the other groups and CD8(+) T cells was the lowest in DSS + Sulfasalazine group. The Ig A level of cultured supernatant of spleen lymphocyte was the highest, while the Ig E level was the lowest in SS + Scu group. The concentration of TNF-alpha, cytokine secreted from the Th1 cell in the supernatant spleen lymphocyte, was the highest in the DSS group and the lowest in the DSS + Scu. group. The concentration of IFN-gamma and lL-12 was lower in the DSS + Scu. group than those of the other groups. The concentration of IL-4 in the supernatant of spleen lymphocyte was the lowest in the DSS + Scu. group but IL-10 was not significantly different. Based on these findings, water extract of Scutellariae Radix exhibited the inhibitory effect via IL-4 production thereby inhibited the production of Ig E and strengthened immune system, and alleviated injury in DSS-induced colitis mice model.