舌下脱敏治疗对哮喘患儿外周血2型固有淋巴细胞及相关细胞因子的免疫调节作用
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摘要
目的研究舌下脱敏治疗(SLIT)对尘螨致敏儿童哮喘的疗效及其对外周血2型固有淋巴细胞(ILC2)及白介素(IL)-13的表达水平,进一步明确其作用及治疗机制。方法选择2016年2月至2017年1月苏北人民医院哮喘专病门诊就诊的轻中度哮喘患者40例,所有患儿入组时(基线)均已接受抗哮喘药物治疗3个月。按照不同治疗方案分为SLIT组20例,采用抗哮喘药物联合SLIT;药物组20例,仅采用抗哮喘药物治疗。统计2组患者在基线、半年、1年后的哮喘症状评分(TASS)、用药评分(TMS)外周血ILC2表达量及ILC2表达的细胞因子IL-13的水平。采用t检验比较TASS、TMS及外周血ILC2组间及不同时间点的差异,比较外周血IL-13组间及基线和治疗半年后的差异,采用秩和检验比较外周血IL-13治疗1年后的组间差异。结果 (1)SLIT组TASS评分在基线、治疗半年后及治疗1年后分别为(1.95±0.69)分、(1.10±0.60)分及(0.70±0.66)分,治疗后TASS低于基线时,差异具有统计学意义(P=0.01;P=0.001);药物组TASS评分在基线、治疗半年后及治疗1年后分别为(2.25±0.76)分、(1.75±0.52)分及(1.10±0.64)分,治疗后TASS低于基线时,差异具有统计学意义(P=0.03;P <0.001),治疗后SLIT组TASS低于药物组,组间比较差异均有统计学差异(t=1.79,P=0.08;t=2.32,P=0.03)。(2)SLIT组在基线、治疗半年、治疗1年后TMS分别为(2.10±0.72)分、(1.50±0.51)分及(0.70±0.57)分,治疗后TMS低于基线时,差异具有统计学意义(P=0.003;P <0.001);药物组在基线、治疗半年、治疗1年后TMS分别为(2.20±0.83)分、(1.55±0.61)分及(1.20±0.62)分,治疗后TMS低于基线时,差异具有统计学意义(P=0.004;P=0.12);治疗1年后SLIT组TMS低于药物组,组间差异具有统计学意义(t=2.66,P=0.01)。(3)SLIT组ILC2表达量在基线、治疗半年后、1年后分别为(2.96±0.30)%、(2.47±0.20)%和(2.05±0.19)%,治疗后ILC2表达量低于基线时,差异均具有统计学意义(P均<0.001);药物组ILC2表达量在基线、治疗半年后、1年后分别为(2.94±0.26)%、(2.87±0.27)%和(2.28±0.21)%;治疗1年后ILC2表达量低于基线时,差异具有统计学意义(P <0.001),治疗后SLIT组ILC2表达量低于药物组,差异均具有统计学意义(t=5.36,P <0.001;t=3.73,P <0.001)(4)SLIT组IL-13水平在基线、治疗半年后、1年后分别为(21.67±1.13)%、(20.34±1.03)%和(18.17±1.33)%,治疗后IL-13水平低于基线时,差异均具有统计学意义(P均<0.001);药物组IL-13水平在基线、治疗半年后、1年后分别为(21.99±0.83)%,(21.83±0.81)%和(19.08±0.63)%;治疗1年后IL-13水平低于基线时,差异具有统计学意义(P <0.001),治疗后SLIT组IL-13水平低于药物组,差异均具有统计学意义(t=5.05,P <0.01;Z=2.76,P=0.01)。结论抗哮喘药物治疗联合SLIT可减少哮喘药物使用。SLIT可抑制哮喘患儿外周血ILC2表达并下调细胞分泌细胞因子IL-13水平。
Objective To investigate the effect of sublingual immunotherapy(SLIT) on the expression of type 2 innate lymphocytes(ILC2) and the level of cytokine IL-13 in peripheral blood of children with miteinduced allergic asthma, in order to further clarify the mechanism of SLIT in asthma. Methods Forty children with mild to moderate mite-induced allergic asthma were chosen from the Department of Respiratory Medicine in Northern Jiangsu People′s Hospital from February 2016 to January 2017. All children were sensitized to Dermatophagoides Farianae and/or Dermatophagoides Pteronyssinus and have received anti-asthma drug therapy for 3 months. The children were equally divided into two groups to receive either SLIT combined with antiasthma drug(SLIT group) or anti-asthma drug alone(drug group). Total asthma symptoms score(TASS) and total medications score(TMS) of the two groups were compared at baseline, the end of 6 months of treatment and the end of one year of treatment. The expression of ILC2 and the level of cytokine IL-13 secreted by ILC2 in peripheral blood of the two groups were also compared at the above three time points. For data with homogeneity of variance(age, TASS, TMS, the expression of ILC2 and the level of cytokine IL-13), one-way analysis of variance was used for comparisons. The t-test was used to compare the differences in TASS, TMS and peripheral blood ILC2 between groups and different time points, as well as the differences in peripheral blood IL-13 between groups and between those at baseline and the end of 6 months of treatment. The rank sum test was used to compare peripheral blood IL-13 at the end of one year treatment between groups. Results The TASS in the SLIT group were(1.95±0.69),(1.10±0.60) and(0.70±0.66) at baseline, the end of 6 months of treatment and the end of one year of treatment,respectively; posttreatment TASS were significantly lower than that at baseline(P=0.01; P=0.001). The TASS of the drug group were(2.25±0.76),(1.75±0.52) and(1.10±0.64) at baseline, half a year after treatment and one year after treatment, respectively; posttreatment TASS were significantly lower than that at baseline(P=0.03;P < 0.001). After treatment, the TASS in the SLIT group were significantly lower than those in the drug group(t=1.79, P=0.08; t=2.32, P=0.03). In the SLIT group, TMS were(2.10±0.72),(1.50±0.51) and(0.70±0.57) at baseline, half a year of treatment and one year after treatment, respectively; posttreatment TMS were significantly lower than that at baseline(P=0.003; P < 0.001). TMS of the drug group at baseline, treatment for half a year and one year after treatment were(2.20±0.83),(1.55±0.61) and(1.20±0.62) score, respectively; posttreatment TMS were significantly lower than that at baseline(P=0.004; P=0.12). After one year of treatment, TMS in the SLIT group was significantly lower than that in the drug group(t=2.66, P=0.01). The expression of ILC2 in the SLIT group was(2.96±0.30)%,(2.47±0.20)% and(2.05±0.19)% at baseline, half a year after treatment and one year later, respectively; posttreatment expression of ILC2 was significantly lower than that at baseline(P< 0.001). The expression of ILC2 in the drug group was(2.94±0.26)%,(2.87±0.27)% and(2.28±0.21)% at baseline, half a year after treatment and one year later, respectively; ILC2 expression at one year of treatment was significantly lower than that at baseline(P < 0.001). After treatment, the expression of ILC2 in the SLIT group was significantly lower than that in the drug group(t=5.36, P < 0.001; t=3.73, P < 0.001). IL-13 levels in the SLIT group were(21.67±1.13)%,(20.34±1.03)% and(18.17±1.33) % at baseline, half a year after treatment and one year later, respectively; posttreatment IL-13 levels were significantly lower than that at baseline(P < 0.001).The levels of IL-13 in the drug group were(21.99±0.83)%,(21.83±0.81)% and(19.08±0.63)% at baseline, half a year after treatment and one year later, respectively; IL-13 level at one year of treatment was significantly lower than that at baseline(P < 0.001). After treatment, IL-13 levels in the SLIT group were significantly lower than those in the drug group(t=5.05, P < 0.01; Z=2.76, P=0.01). Conclusion Drug therapy combined with SLIT can significantly reduce drug use. SLIT can significantly reduce the percentage of ILC2 in peripheral blood of children with asthma, and down-regulate the level of cytokine IL-13.
Objective To investigate the effect of sublingual immunotherapy(SLIT) on the expression of type 2 innate lymphocytes(ILC2) and the level of cytokine IL-13 in peripheral blood of children with miteinduced allergic asthma, in order to further clarify the mechanism of SLIT in asthma. Methods Forty children with mild to moderate mite-induced allergic asthma were chosen from the Department of Respiratory Medicine in Northern Jiangsu People′s Hospital from February 2016 to January 2017. All children were sensitized to Dermatophagoides Farianae and/or Dermatophagoides Pteronyssinus and have received anti-asthma drug therapy for 3 months. The children were equally divided into two groups to receive either SLIT combined with antiasthma drug(SLIT group) or anti-asthma drug alone(drug group). Total asthma symptoms score(TASS) and total medications score(TMS) of the two groups were compared at baseline, the end of 6 months of treatment and the end of one year of treatment. The expression of ILC2 and the level of cytokine IL-13 secreted by ILC2 in peripheral blood of the two groups were also compared at the above three time points. For data with homogeneity of variance(age, TASS, TMS, the expression of ILC2 and the level of cytokine IL-13), one-way analysis of variance was used for comparisons. The t-test was used to compare the differences in TASS, TMS and peripheral blood ILC2 between groups and different time points, as well as the differences in peripheral blood IL-13 between groups and between those at baseline and the end of 6 months of treatment. The rank sum test was used to compare peripheral blood IL-13 at the end of one year treatment between groups. Results The TASS in the SLIT group were(1.95±0.69),(1.10±0.60) and(0.70±0.66) at baseline, the end of 6 months of treatment and the end of one year of treatment,respectively; posttreatment TASS were significantly lower than that at baseline(P=0.01; P=0.001). The TASS of the drug group were(2.25±0.76),(1.75±0.52) and(1.10±0.64) at baseline, half a year after treatment and one year after treatment, respectively; posttreatment TASS were significantly lower than that at baseline(P=0.03;P < 0.001). After treatment, the TASS in the SLIT group were significantly lower than those in the drug group(t=1.79, P=0.08; t=2.32, P=0.03). In the SLIT group, TMS were(2.10±0.72),(1.50±0.51) and(0.70±0.57) at baseline, half a year of treatment and one year after treatment, respectively; posttreatment TMS were significantly lower than that at baseline(P=0.003; P < 0.001). TMS of the drug group at baseline, treatment for half a year and one year after treatment were(2.20±0.83),(1.55±0.61) and(1.20±0.62) score, respectively; posttreatment TMS were significantly lower than that at baseline(P=0.004; P=0.12). After one year of treatment, TMS in the SLIT group was significantly lower than that in the drug group(t=2.66, P=0.01). The expression of ILC2 in the SLIT group was(2.96±0.30)%,(2.47±0.20)% and(2.05±0.19)% at baseline, half a year after treatment and one year later, respectively; posttreatment expression of ILC2 was significantly lower than that at baseline(P< 0.001). The expression of ILC2 in the drug group was(2.94±0.26)%,(2.87±0.27)% and(2.28±0.21)% at baseline, half a year after treatment and one year later, respectively; ILC2 expression at one year of treatment was significantly lower than that at baseline(P < 0.001). After treatment, the expression of ILC2 in the SLIT group was significantly lower than that in the drug group(t=5.36, P < 0.001; t=3.73, P < 0.001). IL-13 levels in the SLIT group were(21.67±1.13)%,(20.34±1.03)% and(18.17±1.33) % at baseline, half a year after treatment and one year later, respectively; posttreatment IL-13 levels were significantly lower than that at baseline(P < 0.001).The levels of IL-13 in the drug group were(21.99±0.83)%,(21.83±0.81)% and(19.08±0.63)% at baseline, half a year after treatment and one year later, respectively; IL-13 level at one year of treatment was significantly lower than that at baseline(P < 0.001). After treatment, IL-13 levels in the SLIT group were significantly lower than those in the drug group(t=5.05, P < 0.01; Z=2.76, P=0.01). Conclusion Drug therapy combined with SLIT can significantly reduce drug use. SLIT can significantly reduce the percentage of ILC2 in peripheral blood of children with asthma, and down-regulate the level of cytokine IL-13.
引文
1 Durham SR,Nelson H.Allergen immunotherapy:a centenary celebration[J].World Allergy Organ J,2011,4(6):104-106.
2中华医学会儿科学分会呼吸学组,《中华儿科杂志》编辑委员会.儿童支气管哮喘诊断与防治指南[J].中华儿科杂志,2016,54(3):167-181.
3中华医学会儿科学分会呼吸学组,《中华儿科杂志》编辑委员会.儿童支气管哮喘诊断与防治指南[J].中华儿科杂志,2008,46(10):745-753.
4 Canonica GW,Baena Cagnani CE,Bousquet J,et al.Recommendations for standardization of clinical trials with Allergen Specific Immunotherapy for respiratory allergy.A statement of a World Allergy Organization(WAO)taskforce[J].Allergy,2007,62(3):317-324.
5张翔,鲍一笑.2型固有淋巴样细胞与哮喘[J].国际免疫学杂志,2014,37(6):507-514.
6全国儿科哮喘协作组,中国疾病预防控制中心环境与健康相关产品安全所.第三次全国城市儿童哮喘流行病学调查[J].中华儿科杂志,2013,51(10):729-735.
7 Eifan AO,Calderon MA,Durham SR.Allergen immunotherapy for house dust mite:clinical efficacy and immunological mechanisms in allergic rhinitis and asthma[J].Expert Opin Biol Ther,2013,13(11):1543-1556.
8李丰,曹松华.IgE介导的儿童过敏性疾病的诊断及治疗[J].临床儿科杂志,2013,31(1):97-98.
9 Shaw JL,Fakhri S,Citardi MJ,et a1.IL-33-responsive innatelymphoid cells ale all important source of IL-13 in chronic rhinosinusitis with nasal polyps[J].Am J Respir Crit Care Med,2013,188(4):432-439.
10 Roediger B,Kyle R,Yip KH,et a1.Cutaneous immunosurveillance and regulation of inflammation hy group 2 innate lymphoid cells[J].Nat Immunol,2013,14(6):564-573.
11 Mjosberg JM,Trifari S,Crellin NK,et a1.CRTH2 and CDl61 define a human IL-25 and IL-33-responsive type 2 innate lymphoid celltype[J].NatImmunol,2011,12(11):1055-1062.
12 Allakhverdi Z,Comeau MR,Smith DE,et a1.CD34+hemopoietic progenitor cells are potent effectors of allergic inflammation[J].J Allergy Clin Immunol,2009,123(2):472-478.
13 Jia Y,Fang X,Zhu X,et al.IL-13+Type 2 Innate Lymphoid Cells Correlate with Asthma Control Status and Treatment Response[J].AM J Resp cell mol,2016,55(5):675-683.
14 Licona-Lim6n P,Kim LK,Palm NW,et al.TH2,allergy and group 2innate lymphoid cells[J].Nat immunol,2013,14(6):536-542.
15 Klein Woherink RG,Kleinjan A,van Nimwegen M,et al.Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma[J].Eur J Immunol,2012,42(5):1106-1116.
16 Lao-Araya M,Steveling E,Scadding GW,et al.Seasonal increases in peripheral innate lymphoid type 2 cells are inhibited by subcutaneous grass pollen immunotherapy[J].J Allergy Clin Immunol,2014,134(5):1193-1195.
2中华医学会儿科学分会呼吸学组,《中华儿科杂志》编辑委员会.儿童支气管哮喘诊断与防治指南[J].中华儿科杂志,2016,54(3):167-181.
3中华医学会儿科学分会呼吸学组,《中华儿科杂志》编辑委员会.儿童支气管哮喘诊断与防治指南[J].中华儿科杂志,2008,46(10):745-753.
4 Canonica GW,Baena Cagnani CE,Bousquet J,et al.Recommendations for standardization of clinical trials with Allergen Specific Immunotherapy for respiratory allergy.A statement of a World Allergy Organization(WAO)taskforce[J].Allergy,2007,62(3):317-324.
5张翔,鲍一笑.2型固有淋巴样细胞与哮喘[J].国际免疫学杂志,2014,37(6):507-514.
6全国儿科哮喘协作组,中国疾病预防控制中心环境与健康相关产品安全所.第三次全国城市儿童哮喘流行病学调查[J].中华儿科杂志,2013,51(10):729-735.
7 Eifan AO,Calderon MA,Durham SR.Allergen immunotherapy for house dust mite:clinical efficacy and immunological mechanisms in allergic rhinitis and asthma[J].Expert Opin Biol Ther,2013,13(11):1543-1556.
8李丰,曹松华.IgE介导的儿童过敏性疾病的诊断及治疗[J].临床儿科杂志,2013,31(1):97-98.
9 Shaw JL,Fakhri S,Citardi MJ,et a1.IL-33-responsive innatelymphoid cells ale all important source of IL-13 in chronic rhinosinusitis with nasal polyps[J].Am J Respir Crit Care Med,2013,188(4):432-439.
10 Roediger B,Kyle R,Yip KH,et a1.Cutaneous immunosurveillance and regulation of inflammation hy group 2 innate lymphoid cells[J].Nat Immunol,2013,14(6):564-573.
11 Mjosberg JM,Trifari S,Crellin NK,et a1.CRTH2 and CDl61 define a human IL-25 and IL-33-responsive type 2 innate lymphoid celltype[J].NatImmunol,2011,12(11):1055-1062.
12 Allakhverdi Z,Comeau MR,Smith DE,et a1.CD34+hemopoietic progenitor cells are potent effectors of allergic inflammation[J].J Allergy Clin Immunol,2009,123(2):472-478.
13 Jia Y,Fang X,Zhu X,et al.IL-13+Type 2 Innate Lymphoid Cells Correlate with Asthma Control Status and Treatment Response[J].AM J Resp cell mol,2016,55(5):675-683.
14 Licona-Lim6n P,Kim LK,Palm NW,et al.TH2,allergy and group 2innate lymphoid cells[J].Nat immunol,2013,14(6):536-542.
15 Klein Woherink RG,Kleinjan A,van Nimwegen M,et al.Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma[J].Eur J Immunol,2012,42(5):1106-1116.
16 Lao-Araya M,Steveling E,Scadding GW,et al.Seasonal increases in peripheral innate lymphoid type 2 cells are inhibited by subcutaneous grass pollen immunotherapy[J].J Allergy Clin Immunol,2014,134(5):1193-1195.