应用树鼩对硫酸乙酰肝素佐剂的安全性初步评价
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摘要
目的通过检测佐剂硫酸乙酰肝素(HS)对树鼩皮肤的刺激性反应以及佐剂与甲型肝炎减毒活疫苗(Hep A-1)联合免疫树鼩后主要组织器官的病理分析,探讨以树鼩作为动物模型进行安全性评价的可行性。方法根据给药次数和皮肤是否完整将树鼩随机分组,采用树鼩同体自身左右对比的方法进行皮肤刺激性实验。根据疫苗及佐剂种类将树鼩随机分组,采用皮下免疫方式,免疫后20周取主要组织器官制备病理切片,HE染色,观察主要组织器官病理学特征。结果佐剂HS单次及多次给药对树鼩完整皮肤组和破损皮肤组的受试部位均不产生红斑、水肿等刺激性变化。与对照组相比,HepA-1免疫组以及HepA-1联合HS免疫组的心、肝、脾、肺、肾及大脑组织病理观察,均未见明显异常。结论证实了以树鼩作为动物模型进行疫苗安全性评价的可行性,为以后疫苗及药物评估平台建设提供了基础数据。
Objective To explore the feasibility of tree shrew as an animal model for safety evaluation,through the detection of adjuvant heparan sulfate(HS) of the tree shrew skin irritation and adjuvant with Hepatitis A virus attenuated live vaccine(HepA-1) combined with immune pathological analysis of main organs on tree shrews. Methods According to the dose frequency and skin integrity, the tree shrews were randomly divided into two groups, the skin irritation test performed by tree shrew own left and right contrast. According to the vaccine and adjuvant type the tree shrews randomly divided, subcutaneous immunization. Twenty weeks after immunization, major organs are harvested to make pathological slice and perform HE staining analysis. Results The skin irritation test of adjuvant HS on tree shrews were no erythema, edema and other irritating changes of single and multiple dosing group on integrity skin or damaged skin. There is no significant pathological change between HepA-1 and HepA-1 combined with HS group on heart, liver, spleen, lung and kidney and the brain biopsy. Conclusion The experiment proved that the tree shrew as an animal model for vaccine safety evaluation is feasible, provide the basical data for future vaccine and drug evaluation platform.
Objective To explore the feasibility of tree shrew as an animal model for safety evaluation,through the detection of adjuvant heparan sulfate(HS) of the tree shrew skin irritation and adjuvant with Hepatitis A virus attenuated live vaccine(HepA-1) combined with immune pathological analysis of main organs on tree shrews. Methods According to the dose frequency and skin integrity, the tree shrews were randomly divided into two groups, the skin irritation test performed by tree shrew own left and right contrast. According to the vaccine and adjuvant type the tree shrews randomly divided, subcutaneous immunization. Twenty weeks after immunization, major organs are harvested to make pathological slice and perform HE staining analysis. Results The skin irritation test of adjuvant HS on tree shrews were no erythema, edema and other irritating changes of single and multiple dosing group on integrity skin or damaged skin. There is no significant pathological change between HepA-1 and HepA-1 combined with HS group on heart, liver, spleen, lung and kidney and the brain biopsy. Conclusion The experiment proved that the tree shrew as an animal model for vaccine safety evaluation is feasible, provide the basical data for future vaccine and drug evaluation platform.
引文
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[22]杨净思,陈洪波,杨晓蕾,等.H2株甲肝减毒活疫苗安全性及免疫效果观察[J].中国公共卫生,2005,21(10):1186-1187.
[23]辛忠,李淑焱,廉小黎,等.甲型肝炎减毒活疫苗(L-A-1)猴体安全性及免疫原性研究[J].预防医学论坛,2004,10(5):549-550.
[2]Fan Y,Yu D,Yao YG.Tree shrew database(Tree shrew DB):agenomic knowledge base for the Chinese tree shrew[J].Sci Rep,2014,4:7145.
[3]Yang C,Ruan P,Ou C,et al.Chronic hepatitis B virus infection and occurrence of hepatocellular carcinoma in tree shrews(Tupaia belangeri chinensis)[J].Virol J,2015,12:26.
[4]黄晓燕,徐娟,孙晓梅,等.树鼩在人类疾病动物模型中应用研究进展[J].实验动物科学,2013,30(2):59-64.
[5]Tsubura A,Lai YC,Miki H,et al.Animal models of N-MethylN-nitrosourea-induced mammary cancer and retinal degeneration with special emphasis on therapeutic trials[J].In Vivo,2011,25(1):11-22.
[6]Xie ZC,Riezu-Boj JI,Lasarte JJ,et al.Transmission of hepatitis C virus infection to tree shrew[J].Virology,1998,244(2):513-520.
[7]严瑞琪,苏建家,陈志英,等.人乙型肝炎病毒实验感染成年树鼩的初步研究[J].广西医学院学报,1984,1(1):10-15.
[8]Wang BJ,Tian YJ,Meng ZJ,et al.Establishing a new animalmodel for hepadnaviral infection:susceptibility of Chinese Marmota species to woodchuck hepatitis virus infection[J].Gen Virol,2011,92(3):681-691.
[9]He W,Ren B,Mao F,et al.Hepatitis D virus infection of mice expressing human sodium taurocholate co-transporting polypeptide[J].PLoS Pathog,2015,11(4):e1004840.
[10]Reddy JK,Svoboda DJ,Rao MS.Induction of liver tumors by aflatoxin B1 in the tree shrew(Tupaia glis),a nonhuman primate[J].Cancer Res,1976,36(1):151-160.
[11]中华人民共和国卫生部药政局.新药临床前研究指导原则汇编(药学、药理学、毒理学)[S].1994:205-209.
[12]国家药典委员会.临床用药须知[M].北京:人民卫生出版社,2005:82-83.
[13]陈新谦,金有豫,汤光.新编药物学[M].16版.北京:人民卫生出版社,2007:836-837.
[14]兰芸,王海漩,乌美妮,等.内源性危险信号低分子量硫酸乙酰肝素的免疫佐剂作用[J].中国生物制品学杂志,2011,24(1):5-9.
[15]匡德宣,孙晓梅,陆彩霞,等.实验树鼩主要内分泌器官的组织学观察[J].中国比较医学杂志,2014,24(6):35-39.
[16]Li SA,LEE WH,Zhang Y.Two bacterial infection models in tree shrew for evaluating the efficacy of antimicrobial agents[J].Zool Res,2012,33(1):1-6.
[17]Tian ZF,Shen H,Fu XH,et al.Interaction of hepatitis C virus envelope glycoprotein E2 with the large extracellular loop of tupaia CD81[J].World J Gastroenterol,2009,15(2):240-244.
[18]Xia HJ,Wang CY,Zhang HL,et al.Characterization of spontaneous breast tumor in tree shrews[J].Zool Res,2012,33(1):55-59.
[19]施建东,胡凝珠,赵蕊蕊,等.氢氧化锌与低分子量透明质酸复合佐剂对甲肝乙肝联合抗原的体液免疫增强作用[J].中国生物制品学杂志,2012,25(1):34-36.
[20]Powell JD,Horton MR.Threat matrix:low-molecular-weight hyaluronan(HA)as a danger signal[J].Immunol Res,2005,31(3):207-218.
[21]王东宝,胡云章,胡凝珠,等.树鼩经甲型肝炎减毒活疫苗、乙型肝炎疫苗及联合硫酸乙酰肝素佐剂免疫后的免疫效果评价[J].实验动物与比较医学,2017,37(2):113-117.
[22]杨净思,陈洪波,杨晓蕾,等.H2株甲肝减毒活疫苗安全性及免疫效果观察[J].中国公共卫生,2005,21(10):1186-1187.
[23]辛忠,李淑焱,廉小黎,等.甲型肝炎减毒活疫苗(L-A-1)猴体安全性及免疫原性研究[J].预防医学论坛,2004,10(5):549-550.
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