吲哚胺-2,3-双加氧酶抑制剂联合铝佐剂对甲型肝炎减毒活疫苗诱导小鼠体液免疫应答的效应分析
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摘要
目的探讨吲哚胺-2,3-双加氧酶(IDO)抑制剂INCB024360类似物与铝佐剂联合对甲型肝炎减毒活疫苗(HepA-1)诱导小鼠体液免疫应答的影响,以评价其复合佐剂效应。方法分别将三种不同剂量的INCB024360类似物(150μg,100μg,50μg)与Al(OH)_3(300μg)复合后与HepA-1共同免疫ICR小鼠分别作为复合佐剂1组,2组,3组,同时设空白对照组、单纯疫苗组、铝佐剂对照组和单一INCB024360类似物(100μg)组,共免疫一次,于免疫后4周、8周、12周、16周进行尾静脉采血,采用间接酶联免疫吸附法(ELISA)检测小鼠血清抗甲型肝炎病毒(HAV)IgG抗体水平。结果除空白对照组外,各组小鼠免疫后4周、8周、12周、16周,均产生抗HAV IgG抗体,抗体水平随免疫时间的延长逐渐升高,于12周达到峰值。复合佐剂2组[HepA-118 EU+Al(OH)_3 300μg+INCB024360类似物100μg]产生的抗体水平最高且持续时间较长,在8周和12周时,其对HepA-1的免疫增强效应显著高于单一佐剂组以及铝佐剂对照组(P<0.05,t值分别为3.169、2.439)。4周、8周、12周、16周,单一佐剂组与单纯疫苗组差异均不具有统计学意义(P>0.05)。结论 IDO抑制剂INCB024360类似物与铝佐剂复合后具有较强的复合佐剂效应,免疫增强效应优于铝佐剂对照组;但是单一的INCB024360类似物不具有显著佐剂效应。
Objective To investigate the compound effect of indoleamine-2,3-dioxygenase(DDO)inhibitor INCB024360 analogue combined with aluminum adjuvant on humoral immune response induced by hepatitis A virus(HAV) attenuated live vaccine(HepA-1) in mice.Methods The ICR mice were injected respectively with HepA-1(18EU) and Al(OH)_3(300μg) and three different doses(150 μg,100μg,50 μg) of INCB024360 analogue as experimental group,200 μL for each and one immunization.At the same time,set up the blank group,pure vaccine group,aluminum adjuvant control group and single INCB024360 analogue(100 μg) group.The sera from tail vein blood of mice were collected at the end of 4,8,12 and 16 weeks after immunization and the specific IgG antibody against HAV were detected by indirect ELISA method.Results In addition to the blank group,mice in various group generated anti-HAV IgG at 4,8,12,16 weeks after the immunization.The antibody levels increased as time went on and reached peak at 12 weeks,then decreased gradually.The antibody level of compound adjuvant 2 group is the highest.At 8,12 weeks,the antibody level was significantly higher than pure vaccine group,aluminum adjuvant control group and single INCB024360 analogue group(P<0.05).At 4,8,12,16 weeks,the difference between the single adjuvant group and the simple vaccine group was not statistically significant.Conclusions The compound adjuvant of IDO inhibitor INCB024360 analogue combined with aluminum adjuvant can obviously enhance the HepA-1 induced humoral immune response in mice,and the immunity enhancement effect is better than aluminum adjuvant control group.But the single INCB024360 analogue does not have significant adjuvant effect.
Objective To investigate the compound effect of indoleamine-2,3-dioxygenase(DDO)inhibitor INCB024360 analogue combined with aluminum adjuvant on humoral immune response induced by hepatitis A virus(HAV) attenuated live vaccine(HepA-1) in mice.Methods The ICR mice were injected respectively with HepA-1(18EU) and Al(OH)_3(300μg) and three different doses(150 μg,100μg,50 μg) of INCB024360 analogue as experimental group,200 μL for each and one immunization.At the same time,set up the blank group,pure vaccine group,aluminum adjuvant control group and single INCB024360 analogue(100 μg) group.The sera from tail vein blood of mice were collected at the end of 4,8,12 and 16 weeks after immunization and the specific IgG antibody against HAV were detected by indirect ELISA method.Results In addition to the blank group,mice in various group generated anti-HAV IgG at 4,8,12,16 weeks after the immunization.The antibody levels increased as time went on and reached peak at 12 weeks,then decreased gradually.The antibody level of compound adjuvant 2 group is the highest.At 8,12 weeks,the antibody level was significantly higher than pure vaccine group,aluminum adjuvant control group and single INCB024360 analogue group(P<0.05).At 4,8,12,16 weeks,the difference between the single adjuvant group and the simple vaccine group was not statistically significant.Conclusions The compound adjuvant of IDO inhibitor INCB024360 analogue combined with aluminum adjuvant can obviously enhance the HepA-1 induced humoral immune response in mice,and the immunity enhancement effect is better than aluminum adjuvant control group.But the single INCB024360 analogue does not have significant adjuvant effect.
引文
[1]张防正,胡丽华.吲哚胺-2,3-双加氧酶的免疫调节功能研究新进展[J].中国免疫学杂志,2011,27(1):93-95.
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[3]Pertovaara M,Hasan T,Raitala A,et al.Indoleamine-2,3-dioxygenase activity is increased in patients with systemic lupus erythematosus and predicts disease activation in the sunny season[J].Clin Exp Immunol,2007,150(2):274-278.
[4]Kahler DJ,Mellor AL.T cell regulatory plasmacytoid dendritic cells expressing indoleamine-2,3-dioxygenase[J].Handb Exp Pharmacol,2009,188(188):167-196.
[5]Muller AJ,Duhadaway JB,Donover PS,et al.Inhibition of indoleamine-2,3-dioxygenase,an immunoregulatory target of the cancer suppression gene Bin1,potentiates cancer chemotherapy[J].Nat Med,2005,11(3):312-319.
[6]Peterson AC,La loggia AJ,Hamaker LK,et al.Evaluation of substitutedβ-carbolines as noncompetitive indoleamine-2,3-dioxygenase inhibitors[J].Med Chem Res.1993,25(35):473-482.
[7]许思娟,张连生,吴重阳,等.抑制吲哚胺-2,3-双加氧酶活性促进慢性粒细胞白血病源树突状细胞的功能[J].中国肿瘤治疗杂志,2009,16(2):170-174.
[8]Munn DH.Expression of indoleamine-2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes[J].J Clin Invest,2004,114(2):280-290.
[9]Okamoto A,Nikaido T,Ochiai K,et al.Indoleamine-2,3-dioxygenase serves as a maker of poor prognosis in gene expression profiles of serous ovarian cancer cells[J].Clin Cancer Res,2005,11(16):6030-6039.
[10]Shi JG,Chen X,Punwani NG,et al.Potential under-prediction of Warfarin drug interaction from conventional interaction studies&risk mitigation:a case study with Epacadostat,an IDO1 Inhibitor[J].J Clin Pharmacol,2016,56(11):1-11.
[11]Koblish HK,Hansbury MJ,Bowman KJ,et al.Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDOexpressing tumors[J].Mol Cancer Ther,2010,9(2):489-498.
[12]Liu X,Shin N,Koblish HK,et al.Selective inhibition of IDOl effectively regulates mediators of antitumor immunity[J].Blood,2010,115(17):3520-3530.
[13]徐跃洋,吴俊军.吲哚胺-2,3-双加氧酶IDO1抑制剂研究进展[J].中国新药杂志,2016,25(4):425-432.
[14]Hwu P,Du MX,Lapointe R,et al.Indoleamine-2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation[J].J Immunol,2000,164(7):3596-3599.
[15]李赛凯,徐静,骆莹滨,等.吲哚胺-2,3-双加氧酶与肿瘤免疫逃逸关系的研究进展[J].癌症进展,2016,14(2):134-137.
[16]Schijns VE,Lavelle EC.Trends in vaccine adjuvants[J].Expert Review Vaccines,2011,10(4):539-550.
[17]吴超,邹全明.新型疫苗佐剂的研究进展[J].中国生物工程杂志,2005,25(8):10-15.
[18]Aguilar JC,Rodriguez EG.Vaccine adjuvants revisited[J].Vaccine,2007,25(19):3752-3762.
[19]王丽萍,王越,王海漩,等.酵母多糖-角鲨烯复合佐剂对甲型肝炎和乙型肝炎抗原诱导小鼠体液免疫应答的增强作用[J].中国生物制品学杂志,2013,26(4):473-476.
[20]王琳,王海漩,李建芳,等.烟酰胺腺嘌呤二核苷酸与氢氧化铝联合佐剂对HBsAg诱导小鼠体液免疫应答的影响[J].中国生物制品学杂志,2012,25(9):1143-1146.
[21]Muller AJ,Duhadaway JB,Chang MY,et al.Non-hematopoietic expression of IDO is integrally required for inflammatory tumor promotion[J].Cancer Immunol Immunother,2010,59(11):1655-1663.
[22]楚松林,李莉娟,张连生,等.吲哚胺-2,3-双加氧酶:恶性肿瘤多维治疗模式下的新靶点[J].肿瘤,2016,36(6):711-717.
[2]Mellor A.Indoleamine-2,3-dioxygenase and regulation of T cell immunity[J].Biochem Biophys Res Commun,2005,338(l):20-24.
[3]Pertovaara M,Hasan T,Raitala A,et al.Indoleamine-2,3-dioxygenase activity is increased in patients with systemic lupus erythematosus and predicts disease activation in the sunny season[J].Clin Exp Immunol,2007,150(2):274-278.
[4]Kahler DJ,Mellor AL.T cell regulatory plasmacytoid dendritic cells expressing indoleamine-2,3-dioxygenase[J].Handb Exp Pharmacol,2009,188(188):167-196.
[5]Muller AJ,Duhadaway JB,Donover PS,et al.Inhibition of indoleamine-2,3-dioxygenase,an immunoregulatory target of the cancer suppression gene Bin1,potentiates cancer chemotherapy[J].Nat Med,2005,11(3):312-319.
[6]Peterson AC,La loggia AJ,Hamaker LK,et al.Evaluation of substitutedβ-carbolines as noncompetitive indoleamine-2,3-dioxygenase inhibitors[J].Med Chem Res.1993,25(35):473-482.
[7]许思娟,张连生,吴重阳,等.抑制吲哚胺-2,3-双加氧酶活性促进慢性粒细胞白血病源树突状细胞的功能[J].中国肿瘤治疗杂志,2009,16(2):170-174.
[8]Munn DH.Expression of indoleamine-2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes[J].J Clin Invest,2004,114(2):280-290.
[9]Okamoto A,Nikaido T,Ochiai K,et al.Indoleamine-2,3-dioxygenase serves as a maker of poor prognosis in gene expression profiles of serous ovarian cancer cells[J].Clin Cancer Res,2005,11(16):6030-6039.
[10]Shi JG,Chen X,Punwani NG,et al.Potential under-prediction of Warfarin drug interaction from conventional interaction studies&risk mitigation:a case study with Epacadostat,an IDO1 Inhibitor[J].J Clin Pharmacol,2016,56(11):1-11.
[11]Koblish HK,Hansbury MJ,Bowman KJ,et al.Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDOexpressing tumors[J].Mol Cancer Ther,2010,9(2):489-498.
[12]Liu X,Shin N,Koblish HK,et al.Selective inhibition of IDOl effectively regulates mediators of antitumor immunity[J].Blood,2010,115(17):3520-3530.
[13]徐跃洋,吴俊军.吲哚胺-2,3-双加氧酶IDO1抑制剂研究进展[J].中国新药杂志,2016,25(4):425-432.
[14]Hwu P,Du MX,Lapointe R,et al.Indoleamine-2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation[J].J Immunol,2000,164(7):3596-3599.
[15]李赛凯,徐静,骆莹滨,等.吲哚胺-2,3-双加氧酶与肿瘤免疫逃逸关系的研究进展[J].癌症进展,2016,14(2):134-137.
[16]Schijns VE,Lavelle EC.Trends in vaccine adjuvants[J].Expert Review Vaccines,2011,10(4):539-550.
[17]吴超,邹全明.新型疫苗佐剂的研究进展[J].中国生物工程杂志,2005,25(8):10-15.
[18]Aguilar JC,Rodriguez EG.Vaccine adjuvants revisited[J].Vaccine,2007,25(19):3752-3762.
[19]王丽萍,王越,王海漩,等.酵母多糖-角鲨烯复合佐剂对甲型肝炎和乙型肝炎抗原诱导小鼠体液免疫应答的增强作用[J].中国生物制品学杂志,2013,26(4):473-476.
[20]王琳,王海漩,李建芳,等.烟酰胺腺嘌呤二核苷酸与氢氧化铝联合佐剂对HBsAg诱导小鼠体液免疫应答的影响[J].中国生物制品学杂志,2012,25(9):1143-1146.
[21]Muller AJ,Duhadaway JB,Chang MY,et al.Non-hematopoietic expression of IDO is integrally required for inflammatory tumor promotion[J].Cancer Immunol Immunother,2010,59(11):1655-1663.
[22]楚松林,李莉娟,张连生,等.吲哚胺-2,3-双加氧酶:恶性肿瘤多维治疗模式下的新靶点[J].肿瘤,2016,36(6):711-717.
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