重组人干扰素α1b含片对大鼠免疫功能的调节作用
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摘要
目的探讨重组人干扰素α1b(recombinant human interferonα1b,rhIFNα1b)含片对大鼠免疫功能的调节作用。方法将大鼠按体重随机分为模型组(空白基质片干粉)、阳性对照组(匹多莫德)及rhIFNα1b含片低(1 000 IU/片)、中(10 000 IU/片)、高(50 000 IU/片)剂量组,每组14只,给予相应药物,每日1次,连续给药3周,于首次给药第7、9天经腹腔注射环磷酰胺,60 mg/kg,同时设正常对照组(10只),末次给药8 h后开始禁食,24 h后称量大鼠体重,计算胸腺及脾脏系数,检测血清及脾脏细胞中白细胞介素-2(interleukin-2,IL-2)、IL-4、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、IFNα水平,同时检测血清、唾液中IgG及IgA水平。结果与正常对照组比较,模型组大鼠体重及胸腺系数均明显降低(P <0. 05),血清中IL-2、IL-4、TNF-α、IFNα、IgG及IgA水平均明显下降(P <0. 01),脾脏中IL-4、TNF-α及IFNα水平均明显下降(P <0. 01),唾液中IgG及IgA水平均明显下降(P <0.01)。与模型组比较,各剂量rhIFNα1b含片组大鼠的体重、胸腺及脾脏系数差异均无统计学意义(P> 0. 05);血清及脾脏中IL-2、IL-4、TNF-α及IFNα水平有不同程度的升高;血液及唾液中IgA水平明显升高(P <0. 05)。结论中、高剂量的rhIFNα1b含片对大鼠免疫功能具有明显的改善作用。
Objective To investigate the regulatory effect of recombinant human interferon α1b(rhIFNα1b)lozenges on immune function of rats. Methods Rats were divided into five groups by weight,14 for each. The rats in model,positive control and three test groups were treated with empty matrix powder,pidotimod and rIFNα1b at dosages of 1 000,10 000 and 50 000 IU/lozenge respectively,once a day for 3 weeks,and injected i.p. with cyclophosphamide at a dosage of 60 mg/kg on days 7 and 9,using ten normal rats as control. The rats were fasted 8 h and weighed 24 h after the last administration,of which the thymus and spleen coefficients were calculated,and the IL-2,IL-4,tumor necrosis factor-α(TNF-α) and IFNα levels in sera and spenocytes as well as IgG and IgA levels in sera and saliva were determined.Results As compared with those of normal control,the bodyweight and thymus coefficient(P < 0. 05),the IL-2,IL-4,TNF-α,IFNα,IgG and IgA levels in sera(each P < 0. 01),as well as IL-4,TNF-α and IFNα levels in spleen(P < 0. 01)and IgG and IgA levels in saliva(P < 0. 01)of rats in model group decreased significantly. However,as compared with those in model group,the bodyweight and thymus and spleen coefficients of rats treated with rhIFNα1b lozenges at various dosages showed no significant difference(P > 0. 05),while the IL-2,IL-4,TNF-α and IFNα levels in sera and spleen increased at different degrees,and the IgA levels in sera and saliva increased significantly(P < 0. 05). Conclusion The IFNα1b lozenges at moderate and high dosages improved the immune function of rats significantly.
Objective To investigate the regulatory effect of recombinant human interferon α1b(rhIFNα1b)lozenges on immune function of rats. Methods Rats were divided into five groups by weight,14 for each. The rats in model,positive control and three test groups were treated with empty matrix powder,pidotimod and rIFNα1b at dosages of 1 000,10 000 and 50 000 IU/lozenge respectively,once a day for 3 weeks,and injected i.p. with cyclophosphamide at a dosage of 60 mg/kg on days 7 and 9,using ten normal rats as control. The rats were fasted 8 h and weighed 24 h after the last administration,of which the thymus and spleen coefficients were calculated,and the IL-2,IL-4,tumor necrosis factor-α(TNF-α) and IFNα levels in sera and spenocytes as well as IgG and IgA levels in sera and saliva were determined.Results As compared with those of normal control,the bodyweight and thymus coefficient(P < 0. 05),the IL-2,IL-4,TNF-α,IFNα,IgG and IgA levels in sera(each P < 0. 01),as well as IL-4,TNF-α and IFNα levels in spleen(P < 0. 01)and IgG and IgA levels in saliva(P < 0. 01)of rats in model group decreased significantly. However,as compared with those in model group,the bodyweight and thymus and spleen coefficients of rats treated with rhIFNα1b lozenges at various dosages showed no significant difference(P > 0. 05),while the IL-2,IL-4,TNF-α and IFNα levels in sera and spleen increased at different degrees,and the IgA levels in sera and saliva increased significantly(P < 0. 05). Conclusion The IFNα1b lozenges at moderate and high dosages improved the immune function of rats significantly.
引文
[1]ZHANG H.The mechanism of USP15 regulation in typeⅠinterferon and global analysis of ubiquitome in PRRSV-infected cells[D].Wuhan:Huazhong Agricultural University,2016.(in Chinese)张欢.泛素特异性蛋白酶USP15调控Ⅰ型干扰素的机制研究以及PRRSV感染细胞的泛素化蛋白质组学[D].湖北武汉:华中农业大学,2016.
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[5]XU X X,LI S R,WU H Y,et al.Clinical study of combination of application of recombinant human interferonα2b suppositories and nifuratel yystatin soft capsules in treatment of recurrent vulvovaginal candidiasis[J].Chin Modern Med 2017,24(10):96-98.(in Chinese)徐晓贤,李世荣,吴会银.重组人干扰素α2b栓联合硝夫太尔制霉菌素软胶囊医治复发性外阴阴道假丝酵母菌病的临床研讨[J].中国当代医药,2017,24(10):96-98.
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[7]KINOSHITA K,IWASA T,ASAMTE-APPIAH E,et al.Preclinical and clinical properties of elbasvir(ERELSA誖Tablets 50 mg)and Grazoprevir(GRAZYNA誖Tablets 50 mg),novel therapeutic agents for hepatitis C[J].Nihon Yakurigaku Zasshi,2017,150(1):41-53.
[8]LI F,ZHAO X Q,JIANG Z H,et al.Toxicity test of recombinant interferinα-2a buccal tablets in guinea pigs[J].Clin J Med Offic,2007,35(6):837-838.(in Chinese)李芳,赵晓青,姜志恒,等.重组人干扰素α-2a口含片剂的豚鼠毒性试验[J].临床军医杂志,2007,35(6):837-838.
[9]GONG F L.Medical Immunology[M].(4th ed)Beijing:Science Press,2014:51.(in Chinese)龚非力.医学免疫学[M].第4版北京:科学出版社,2014:51.
[10]WANG Y,JIANG W M.Immunoregulatory effect of oral low dose interferonα[J].Chin J Biologicals,2012,25(9):1234-1236.(in Chinese)王妍,蒋为民.口含低剂量干扰素α的免疫调节作用[J].中国生物制品学杂志,2012,25(9):1234-1236.
[11]MA T S,GE Y C,REN H J,et al.Effect of contain of recombinant human interferonα2b(rhIFNα-2b)on immune function of mouse[J].J Dalian Med Univ,2005,27(4):256-259.(in Chinese)马天舒,葛迎春,任慧君,等.重组人干扰素α-2b含片对小鼠免疫功能的影响[J].大连医科大学学报,2005,27(4):256-259.
[12]ZHANG C C,YOU J L.The clinical research of WD-5 with biological response modifiers with IFN-α2b&IL-2 in the quality of life of renal cell carcinoma patients of stageⅢ,Ⅳ[J].Chin Arch Trad Chin Med,2016,34(2):447-450.(in Chinese)张辰岑,尤建良.微调五号方或联合生物反应调节剂对Ⅲ、Ⅳ期肾癌患者生存质量影响的临床研究[J].中华中医药学刊,2016,34(2):447-450.
[13]THEOFILOPOULOS A N,BACCALA R,BEUTLER B,et al.Type I interferons(α/β)in immunity and autoimmunity[J].Annu Rev Immunol,2005,23:307-336.
[14]ESPINOSA E,SORIANO V,MALVEHY J,et al.Treatment patterns of adjuvant interferon-α2b for high-risk melanoma:a retrospective study of the Grupo Espa觡ol Multidisciplinar de Melanoma-Prima study[J].Melanoma Res,2016,26(3):278-283.
[15]WANG L N,FAN X D,SUN E L,et al.Study on antitumor effect of recombinant hIFN-α-2b-BCG in vitro[J].J Tianjin Med Univ,2016,22(5):377-380.(in Chinese)王丽宁,范晓东,孙二琳,等.重组hIFN-α-2b-BCG抗肿瘤效应的体外研究[J].天津医科大学学报,2016,22(5):377-380.
[16]王雪,陈泽莲.干扰素口含片及其它非注射用干扰素制剂的研究进展及临床应用[J].药学实践杂志,1999,17(5):274-275.
[17]COMMINS J M,BEILHARZ M W,KRAKOWKA S.Oral use of interferon[J].J Interferon Cytokine Res,1999,19(8):853-857.
[18]LASFAR A,DE LA TORRE A,ABUSHAHBA W,et al.Concerted action of IFN-αand IFN-λinduces local NK cell immunity and halts cancer growth[J].Oncotarget,2016,7(31):49259-49267.
[19]DE JONG T D,VOSSLAMBER S,MANTEL E,et al.Physiological evidence for diversification of IFNα-and IFNβ-mediated response programs in different autoimmune diseases[J].Arthritis Res Ther,2016,18(1):49.doi:10.1186/s13075-016-0946-9.
[20]BERGAUER A,SOPEL N,KROB B,et al.IFN-α/IFN-λresponses to respiratory viruses in paediatric asthma[J].Eur Respir J,2016,49(2):pii:1700006.doi:10.1183/13993003.00006-2017.
[2]CHEN J.MicroRNA-373 facilitated the replication of porcine reproductive and respiratory syndrome virus(PRRSV)by its negative regulation of typeⅠinterferon induction[D].Changchun:Jilin University,2016.(in Chinese)陈静.MicroRNA-373通过负向调控Ⅰ型干扰素促进猪繁殖与呼吸综合征病毒(PRRSV)复制的机制研究[D].吉林长春:吉林大学,2016.
[3]JI F,WEI B,YEO Y H,et al.Systematic review with metaanalysis:effectiveness and tolerability of interferon-free directacting antiviral regimens for chronic hepatitis C genotype 1 in routine clinical practice in Asia[J].Aliment Pharmacol Ther,2018,47(5):550-562.
[4]LUTHERER L O,NUGENT K M,SCHOETTLE B W,et al.Low-dose oral interferonαpossibly retards the progression of idiopathic pulmonary fibrosis and alleviates associated cough in some patients[J].Thorax,2011,66(5):446-447.
[5]XU X X,LI S R,WU H Y,et al.Clinical study of combination of application of recombinant human interferonα2b suppositories and nifuratel yystatin soft capsules in treatment of recurrent vulvovaginal candidiasis[J].Chin Modern Med 2017,24(10):96-98.(in Chinese)徐晓贤,李世荣,吴会银.重组人干扰素α2b栓联合硝夫太尔制霉菌素软胶囊医治复发性外阴阴道假丝酵母菌病的临床研讨[J].中国当代医药,2017,24(10):96-98.
[6]QIAN J,ZHONG L J.Influence of cydiodine buccal tablets combined with Kangfuxin liquid on cytokines in plasma of patients with recurrent oral ulcer[J].Chin J Clin Pharmacol,2016,32(17):1539-1542.(in Chinese)钱进,钟良君.西地碘含片联合康复新液对复发性口腔溃疡患者血浆中细胞因子的影响[J].中国临床药理学杂志,2016,32(17):1539-1542.
[7]KINOSHITA K,IWASA T,ASAMTE-APPIAH E,et al.Preclinical and clinical properties of elbasvir(ERELSA誖Tablets 50 mg)and Grazoprevir(GRAZYNA誖Tablets 50 mg),novel therapeutic agents for hepatitis C[J].Nihon Yakurigaku Zasshi,2017,150(1):41-53.
[8]LI F,ZHAO X Q,JIANG Z H,et al.Toxicity test of recombinant interferinα-2a buccal tablets in guinea pigs[J].Clin J Med Offic,2007,35(6):837-838.(in Chinese)李芳,赵晓青,姜志恒,等.重组人干扰素α-2a口含片剂的豚鼠毒性试验[J].临床军医杂志,2007,35(6):837-838.
[9]GONG F L.Medical Immunology[M].(4th ed)Beijing:Science Press,2014:51.(in Chinese)龚非力.医学免疫学[M].第4版北京:科学出版社,2014:51.
[10]WANG Y,JIANG W M.Immunoregulatory effect of oral low dose interferonα[J].Chin J Biologicals,2012,25(9):1234-1236.(in Chinese)王妍,蒋为民.口含低剂量干扰素α的免疫调节作用[J].中国生物制品学杂志,2012,25(9):1234-1236.
[11]MA T S,GE Y C,REN H J,et al.Effect of contain of recombinant human interferonα2b(rhIFNα-2b)on immune function of mouse[J].J Dalian Med Univ,2005,27(4):256-259.(in Chinese)马天舒,葛迎春,任慧君,等.重组人干扰素α-2b含片对小鼠免疫功能的影响[J].大连医科大学学报,2005,27(4):256-259.
[12]ZHANG C C,YOU J L.The clinical research of WD-5 with biological response modifiers with IFN-α2b&IL-2 in the quality of life of renal cell carcinoma patients of stageⅢ,Ⅳ[J].Chin Arch Trad Chin Med,2016,34(2):447-450.(in Chinese)张辰岑,尤建良.微调五号方或联合生物反应调节剂对Ⅲ、Ⅳ期肾癌患者生存质量影响的临床研究[J].中华中医药学刊,2016,34(2):447-450.
[13]THEOFILOPOULOS A N,BACCALA R,BEUTLER B,et al.Type I interferons(α/β)in immunity and autoimmunity[J].Annu Rev Immunol,2005,23:307-336.
[14]ESPINOSA E,SORIANO V,MALVEHY J,et al.Treatment patterns of adjuvant interferon-α2b for high-risk melanoma:a retrospective study of the Grupo Espa觡ol Multidisciplinar de Melanoma-Prima study[J].Melanoma Res,2016,26(3):278-283.
[15]WANG L N,FAN X D,SUN E L,et al.Study on antitumor effect of recombinant hIFN-α-2b-BCG in vitro[J].J Tianjin Med Univ,2016,22(5):377-380.(in Chinese)王丽宁,范晓东,孙二琳,等.重组hIFN-α-2b-BCG抗肿瘤效应的体外研究[J].天津医科大学学报,2016,22(5):377-380.
[16]王雪,陈泽莲.干扰素口含片及其它非注射用干扰素制剂的研究进展及临床应用[J].药学实践杂志,1999,17(5):274-275.
[17]COMMINS J M,BEILHARZ M W,KRAKOWKA S.Oral use of interferon[J].J Interferon Cytokine Res,1999,19(8):853-857.
[18]LASFAR A,DE LA TORRE A,ABUSHAHBA W,et al.Concerted action of IFN-αand IFN-λinduces local NK cell immunity and halts cancer growth[J].Oncotarget,2016,7(31):49259-49267.
[19]DE JONG T D,VOSSLAMBER S,MANTEL E,et al.Physiological evidence for diversification of IFNα-and IFNβ-mediated response programs in different autoimmune diseases[J].Arthritis Res Ther,2016,18(1):49.doi:10.1186/s13075-016-0946-9.
[20]BERGAUER A,SOPEL N,KROB B,et al.IFN-α/IFN-λresponses to respiratory viruses in paediatric asthma[J].Eur Respir J,2016,49(2):pii:1700006.doi:10.1183/13993003.00006-2017.