新颖BAFF拮抗肽体抑制BAFF与其受体TACI相互作用的功能研究

发布时间：2018-03-16 17:34

本文选题：B淋巴细胞活化因子（BAFF）　切入点：钙调和亲环素配基相互作用因子（TACI）　出处：《天津大学》2014年硕士论文　论文类型：学位论文

【摘要】：肿瘤坏死因子超家族配体B淋巴刺激细胞因子（Blymphocytestimulator,BAFF)，，是1999年发现的一种与人体免疫调控密切相关的细胞因子，是肿瘤坏死因子(TNF)家族的第13位成员。BAFF在体内主要以膜结合型和水溶型存在，BAFF作为一种B淋巴细胞的共刺激细胞因子，在免疫原的刺激下能特异的刺激B淋巴细胞的增殖和分化并诱导其分泌免疫球蛋白。然而BAFF作为一种细胞因子，体内对靶细胞发挥生物学活性需要结合特异性的受体，目前为止发现的BAFF特异的受体有三种，分别是钙调和亲环素配基相互作用因子（TACI）、B细胞成熟抗原（BCMA）、BAFF受体（BAFF-R）。 BAFF在体液免疫中发挥着重要作用，而且体内的过量表达会与某些自身免疫疾病有关，用BAFF受体融合蛋白可以封闭BAFF生物学功能，也许会成为治疗人SLE和其他一些自身免性疾病的一种新的治疗方法。BAFF拮抗肽可能成为治疗自身免疫疾病和某些肿瘤的新型药物制剂。B细胞刺激因子受体-Fc除具有可与BAFF特异结合阻断其生物学活性的作用外，还具有免疫球蛋白体内半衰期长、组织穿透力强、Fc片段还具有稳定蛋白等特性。基于这些理论本课题研究通过计算机模拟技术筛选TACI受体与BAFF作用的高亲和结构区域模拟肽，并合成肽基因片段通过连接肽与人lgG1的Fc连接构建重组质粒，最后表达新型肽体，即小肽-Fc融合蛋白（TA/TC-Linker-Fc），依据对肽体的功能研究发现融合蛋白与BAFF有高的结合活性及对B细胞有抑制增殖作用且能缓解类风湿关节模型小鼠的症状，有望成为治疗自身免疫疾病的潜在生物制剂。
[Abstract]:Tumor necrosis factor superfamily ligand B lymphoid stimulating cytokine (Blymphocyt estimator), a cytokine closely related to human immune regulation, was discovered in 1999. BAFF is the 13th member of TNF family. BAFF mainly exists in membrane binding and water soluble type as a B lymphocyte costimulatory cytokine. The immunogen stimulates the proliferation and differentiation of B lymphocytes and induces the secretion of immunoglobulin. However, as a cytokine, BAFF needs to bind to specific receptors for the biological activity of target cells in vivo. Up to now, there are three kinds of BAFF specific receptors, which are calcium and cyclophile ligand interaction factor (TACMAA B cell maturation antigen, BAFF-RN). BAFF plays an important role in humoral immunity, and overexpression in vivo may be related to some autoimmune diseases. BAFF receptor fusion protein can block the biological function of BAFF. It may become a new treatment for human SLE and other autoimmune diseases. BAFF antagonistic peptide may be a new drug preparation for the treatment of autoimmune diseases and certain tumors. In addition to the specific binding with BAFF to block its biological activity, It also has the characteristics of long half-life in vivo of immunoglobulin, strong tissue penetration and stable protein. Based on these theories, we studied the screening of high affinity region mimic peptides of TACI receptor and BAFF by computer simulation. The recombinant plasmid was constructed by ligating the peptide with FC of human lgG1, and a novel peptide was expressed. According to the study on the function of peptide body, the fusion protein has high binding activity with BAFF, inhibits the proliferation of B cells and alleviates the symptoms of rheumatoid joint model mice. It is expected to be a potential biological agent for the treatment of autoimmune diseases.
【学位授予单位】：天津大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R96

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