含对硝基苯丙氨酸的B淋巴细胞刺激因子疫苗对狼疮肾炎模型小鼠的保护作用

戴辉腾; 田浤; 黄捷; 陈超; 蔡棣; 高向东; 姚文兵

doi:10.11665/j.issn.1000-5048.20170414

含对硝基苯丙氨酸的B淋巴细胞刺激因子疫苗对狼疮肾炎模型小鼠的保护作用

中国药科大学江苏省生物药物成药性研究重点实验室，生命科学与技术学院

基金项目: 国家自然科学基金资助项目(No.81273426,No.81673343)

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- 刊出日期: 2017-08-24

Protective effects of p-nitrophenylalanine-containing BAFF vaccine on lupus nephritis model mice

摘要

摘要: 考察含对硝基苯丙氨酸的B淋巴细胞刺激因子(BAFF)治疗BAFF过表达的自身免疫性疾病的效果。利用本研究前期构建的工程菌，表达纯化了B淋巴细胞刺激因子的可溶型突变体(smBAFF)以及在其65位定点引入了对硝基苯丙氨酸的改构体(pNO₂Phe⁶⁵smBAFF)。通过考察pNO₂Phe⁶⁵smBAFF体外促小鼠淋巴细胞增殖活性、免疫原性以及所诱导的抗血清对天然BAFF活性的抑制作用，评价了其用于治疗BAFF过表达的自身免疫性疾病的可行性；同时采用了cGVHD(graft-versus-host disease)诱导的狼疮肾炎小鼠模型评价了pNO₂Phe⁶⁵smBAFF的药理活性。结果表明:定点引入了对硝基苯丙氨酸的pNO₂Phe⁶⁵smBAFF不具有促进小鼠淋巴细胞增殖的能力；由于对硝基苯丙氨酸的引入显著增强了蛋白的免疫原性，诱导机体产生了可以抑制天然BAFF活性的交叉抗体；在cGVHD诱导的狼疮肾炎小鼠模型中，pNO₂Phe⁶⁵smBAFF可显著减轻疾病症状。定点引入了对硝基苯丙氨酸的pNO₂Phe⁶⁵smBAFF可以作为治疗BAFF过表达的自身免疫性疾病的候选分子。
- B淋巴细胞刺激因子 /
- 对硝基苯丙氨酸 /
- 免疫原性 /
- cGVHD
Abstract: In order to verify whether p-nitrophenylalanine-containing BAFF vaccine can be used as a candidate molecule for the treatment of autoimmune diseases with BAFF over-expression, a soluble mutant of B cell activating factor belonging to the TNF Family(smBAFF)and its pNO₂Phe mutant(pNO₂Phe⁶⁵smBAFF), which site specific incorporated pNO₂Phe at position 65 of smBAFF, were expressed and purified. In order to evaluate the feasibility of using pNO₂Phe⁶⁵smBAFF to treat BAFF-over-expressed autoimmune diseases, we investigate its Lymphocyte-stimulating capacity, immunogenicity and inhibitory effect of serum on biological activity of natural BAFF. The pharmacological activity of pNO₂Phe⁶⁵smBAFF was evaluated using a cGVHD(graft-versus-host disease)induced SLE mouse model. Results indicated that pNO₂Phe⁶⁵smBAFF, could bind to mouse lymphocytes but could not promote the proliferation of mouse lymphocytes. Moreover, the incorporation of pNO₂Phe significantly increased the immunogenicity and induced cross-antibody, which can inhibit the biological activity of natural BAFF. In cGVHD induced SLE mouse model, pNO₂Phe⁶⁵smBAFF can significantly reduce the symptoms of the disease and play a therapeutic role. Therefore, pNO₂Phe⁶⁵smBAFF can be used as a candidate molecule for the treatment of autoimmune diseases with BAFF over-expression.
- B cell activating factor belonging to the TNF family(BAFF) /
- p-nitrophenylalanine /
- immunogenicity /
- cGVHD

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参考文献(21)

[1]	Mackay F,Schneider P.Cracking the BAFF code[J].Nat Rev Immunol,2009,9(7):491-502.
[2]	Pieper K,Grimbacher B,Eibel H.B-cell biology and development[J].J Allergy Clin Immunol,2013,131(4):959-971.
[3]	Campi I,Tosi D,Rossi S,et al.B Cell activating factor(BAFF)and BAFF receptor expression in autoimmune and nonautoimmune thyroid diseases[J].Thyroid,2015,25(9):1043-1049.
[4]	Wei F,Chang Y,Wei W.The role of BAFF in the progression of rheumatoid arthritis[J].Cytokine,2015,76(2):537-544.
[5]	Boneparth A, Woods M, Huang W, et al. The effect of BAFF inhibition on autoreactive B cell selection in murine SLE[J].Mol Med,2016,22:173-182.
[6]	Mackay F,Woodcock SA,Lawton P,et al.Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations[J].J Exp Med,1999,190(11):1697-1710.
[7]	Stohl W.Inhibition of B cell activating factor(BAFF)in the management of systemic lupus erythematosus(SLE)[J].Exp Rev Clin Immunol,2017,13(6):623-633.
[8]	Zouali M,Uy EA.Belimumab therapy in systemic lupus erythematosus[J].Biol Drugs,2013,27(3):225-235.
[9]	Scheinberg MA,Hislop CM,Martin RS.Blisibimod for treatment of systemic lupus erythematosus:with trials you become wiser[J].Exp Opin Biol Ther,2016,16(5):723-733.
[10]	Richez C,Truchetet M-E,Schaeverbeke T,et al.Atacicept as an investigated therapy for rheumatoid arthritis[J].Exp Opin Investig Drugs,2014,23(9):1285-1294.
[11]	Deng DN,Tian H,Yao WB.Advances in therapeutic B-cell vaccines against chronic diseases[J].J China Pharm Univ(中国药科大学学报),2013,44(5):470-475.
[12]	Zhao Z,Sun HQ,Wei SS,et al.Multiple B-cell epitope vaccine induces a Staphylococcus enterotoxin B-specific IgG1 protective response against MRSA infection[J].Sci Rep,2015,5:12371.
[13]	Kobiyama K,Aoshi T,Narita H,et al.Nonagonistic Dectin-1 ligand transforms CpG into a multitask nanoparticulate TLR9 agonist[J].Proc Natl Acad Sci U S A,2014,111(8):3086-3091.
[14]	Bohnen C, Wangorsch A, Schulke S, et al. Vaccination with recombinant modified vaccinia virus Ankara prevents the onset of intestinal allergy in mice[J].Allergy,2013,68(8):1021-1028.
[15]	Martins KA,Steffens JT,van Tongeren SA,et al.Toll-like receptor agonist augments virus-like particle-mediated protection from Ebola virus with transient immune activation[J].PLoS ONE,2014,9(2):e89735.
[16]	Xie J,Schultz PG.An expanding genetic code[J].Methods,2005,36(3):227-238.
[17]	Grunewald J,Tsao ML,Perera R,et al.Immunochemical termination of self-tolerance[J].Proc Natl Acad Sci U S A,2008,105(32):11276-11280.
[18]	Grunewald J,Hunt GS,Dong L,et al.Mechanistic studies of the immunochemical termination of self-tolerance with unnatural amino acids[J].Proc Natl Acad Sci U S A,2009,106(11):4337-4342.
[19]	Gauba V, Grunewald J, Gorney V, et al. Loss of CD4 T-cell-dependent tolerance to proteins with modified amino acids[J].Proc Natl Acad Sci U S A,2011,108(31):12821-12826.
[20]	Kessel C,Nandakumar KS,Peters FB,et al.A single functional group substitution in C5a breaks B cell and T cell tolerance and protects against experimental arthritis[J].Arthritis Rheumatol,2014,66(3):610-621.
[21]	Liu Y, Xu L, Opalka N, et al. Crystal structure of sTALL-1 reveals a virus-like assembly of TNF family ligands[J].Cell,2002,108(3):383-394.

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含对硝基苯丙氨酸的B淋巴细胞刺激因子疫苗对狼疮肾炎模型小鼠的保护作用

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出版历程

Protective effects of p-nitrophenylalanine-containing BAFF vaccine on lupus nephritis model mice

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