TACI分子单抗的制备及其分布的研究
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摘要
肿瘤坏死因子超家族(tumor necrosis factor superfamily，TNFSF)和肿瘤坏死因子受体超家族(TNFRSF)的成员不断增加，它们不仅广泛参与哺乳动物多种生理功能，而且与许多疾病的发病密切相关。跨膜激活剂及钙调亲环素配体相互作用分子(transmembrane activator and calcium modulator and cyclophilin ligand(CAML) interactor，TACI)是近年发现的TNFRSF中的新成员，它可与B细胞刺激物(B lymphocyte stimulator，BlyS，又名BAFF)和增殖诱导配体(a proliferation inducing ligand，APRIL)两种配体结合，介导体液免疫与细胞免疫。B细胞成熟分子(B cell maturation molecule，BCMA)可与TACI竞争结合BlyS及APRIL。最近又发现BAFFR为BAFF的特异性受体。
TACI是Ⅰ型跨膜蛋白，表达于成熟B细胞及活化T细胞表面。在小鼠Ⅱ型胶原诱导的关节炎模型中，应用TACI-Fc融合蛋白可阻断BlyS和APRIL与细胞膜表面的TACI或BCMA结合，从而抑制体液免疫及细胞免疫功能，明显减轻关节炎的病理变化。BlyS转基因鼠表现为B细胞聚集、活化，分泌抗DNA抗体及其他自身抗体(如类风湿因子，RF)，并出现自身免疫性狼疮样肾炎等症状。而TACI-Fc在体外可特异性抑制BlyS介导
第四军医大学硕士学位论文 中文摘要
的B细胞增殖及T细胞活化；在体内可抑制生发中心的形成，减少活化B
细胞数量，阻止肾炎的发展，缓解SLE症状，增加存活率。上述结果表明，
可溶性TACI可能通过干扰自身抗体的分泌而起到治疗作用，显示出良好
的开发前景。制备抗TACI单克隆抗体将为进一步研究TACI分子的结构与
功能及某些自身免疫性疾病提供重要的手段。
E3．5和 E3．7是以人TACI干。融合蛋白免疫BALB八小鼠得至的两株
mAbS。通过研究发现，两株mAbS识别的分子选择性表达于同种异体抗原、
PHA、PMA活化的淋巴细胞表面，包括 CD4禾 CDS＋T细胞亚群。E3．5免疫
组化鉴定，发现其识别的分子表达于38Wb胎儿皮肤真皮层。在扁桃体的
生发中心亦有表达。
The number of tumor necrosis factor superfamily(TNFSF) and tumor necrosis factor receptor superfamily(TNFRSF) has been extremely expanded since large-scale sequencing of "expressed sequence tags(ESTs)" and Bioinformatics have been used.They can not only integrate mammalian biology, but also have correlation with many diseases. Transmembrane activator and calcium modulator and cyclophilin ligand(CAML) interactor(TACI) is a novel member of TNFRSF, which interacts with two ligands,B lymphocyte stimulator (BlyS, also called BAFF) and a proliferation inducing ligand(APRIL),modulating humoral and cellular immunity.B cell maturation molecule(BCMA),another new member of TNFRSF, may compete the binding of TACI with its ligands. Recently,it was found that BAFFR is a specific receptor for BAFF.
TACI belongs to type I transmembrane protein,which expressed on mature B cells and activated T cells. In the mouse model of collagen II -induced rheumatoid arthritis(RA), TACI-Fc could prevent the binding of Blys and APRIL with TACI and/or BCMA, consequently inhibit humoral and cellular immunity,and reduce the pathological changes of rheumatoid arthritis.BlyS transgenic mice cause B cell accumulation and activation, secretion of anti DNA antibody and other autoantibodies (such as RF), and develop the symptom of autoimmune nephritis. TACI-Fc may block B cell proliferation and T cell activation in vitro, decrease the number of B cells, inhibit the generation of germinal center(GC) and alleviate symptoms of nephritis in vivo, and increase the survival rate,suggesting that soluble TACI may have the therapeutic function by interfering the secretion of autoantibodies, and show favorable development prospect. The preparation and characterization of anti TACI monoclonal antibodies will provide important tools in research of the relationship of structure and functions of TACI molecule and the mechanisms of autoimmune diseases.
McAbs E3.5 and E3.7 were raised by B lymphocyte hybridoma technique.We found that the molecule recognized by two mAbs is expressed on both CD4+ and CD8+ T lymphocytes activated by alloantigen, PHA and PMA.Moreover, we found that E3.5 could recognize the molecule expressed on derma of skin of 38wk-fetus and the germinal center of tonsil tissue by immunohistochemical assay.
TACI是Ⅰ型跨膜蛋白，表达于成熟B细胞及活化T细胞表面。在小鼠Ⅱ型胶原诱导的关节炎模型中，应用TACI-Fc融合蛋白可阻断BlyS和APRIL与细胞膜表面的TACI或BCMA结合，从而抑制体液免疫及细胞免疫功能，明显减轻关节炎的病理变化。BlyS转基因鼠表现为B细胞聚集、活化，分泌抗DNA抗体及其他自身抗体(如类风湿因子，RF)，并出现自身免疫性狼疮样肾炎等症状。而TACI-Fc在体外可特异性抑制BlyS介导
第四军医大学硕士学位论文 中文摘要
的B细胞增殖及T细胞活化；在体内可抑制生发中心的形成，减少活化B
细胞数量，阻止肾炎的发展，缓解SLE症状，增加存活率。上述结果表明，
可溶性TACI可能通过干扰自身抗体的分泌而起到治疗作用，显示出良好
的开发前景。制备抗TACI单克隆抗体将为进一步研究TACI分子的结构与
功能及某些自身免疫性疾病提供重要的手段。
E3．5和 E3．7是以人TACI干。融合蛋白免疫BALB八小鼠得至的两株
mAbS。通过研究发现，两株mAbS识别的分子选择性表达于同种异体抗原、
PHA、PMA活化的淋巴细胞表面，包括 CD4禾 CDS＋T细胞亚群。E3．5免疫
组化鉴定，发现其识别的分子表达于38Wb胎儿皮肤真皮层。在扁桃体的
生发中心亦有表达。
The number of tumor necrosis factor superfamily(TNFSF) and tumor necrosis factor receptor superfamily(TNFRSF) has been extremely expanded since large-scale sequencing of "expressed sequence tags(ESTs)" and Bioinformatics have been used.They can not only integrate mammalian biology, but also have correlation with many diseases. Transmembrane activator and calcium modulator and cyclophilin ligand(CAML) interactor(TACI) is a novel member of TNFRSF, which interacts with two ligands,B lymphocyte stimulator (BlyS, also called BAFF) and a proliferation inducing ligand(APRIL),modulating humoral and cellular immunity.B cell maturation molecule(BCMA),another new member of TNFRSF, may compete the binding of TACI with its ligands. Recently,it was found that BAFFR is a specific receptor for BAFF.
TACI belongs to type I transmembrane protein,which expressed on mature B cells and activated T cells. In the mouse model of collagen II -induced rheumatoid arthritis(RA), TACI-Fc could prevent the binding of Blys and APRIL with TACI and/or BCMA, consequently inhibit humoral and cellular immunity,and reduce the pathological changes of rheumatoid arthritis.BlyS transgenic mice cause B cell accumulation and activation, secretion of anti DNA antibody and other autoantibodies (such as RF), and develop the symptom of autoimmune nephritis. TACI-Fc may block B cell proliferation and T cell activation in vitro, decrease the number of B cells, inhibit the generation of germinal center(GC) and alleviate symptoms of nephritis in vivo, and increase the survival rate,suggesting that soluble TACI may have the therapeutic function by interfering the secretion of autoantibodies, and show favorable development prospect. The preparation and characterization of anti TACI monoclonal antibodies will provide important tools in research of the relationship of structure and functions of TACI molecule and the mechanisms of autoimmune diseases.
McAbs E3.5 and E3.7 were raised by B lymphocyte hybridoma technique.We found that the molecule recognized by two mAbs is expressed on both CD4+ and CD8+ T lymphocytes activated by alloantigen, PHA and PMA.Moreover, we found that E3.5 could recognize the molecule expressed on derma of skin of 38wk-fetus and the germinal center of tonsil tissue by immunohistochemical assay.
引文
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[3] Gray, P.W., Aggarwal, B.B., Benton. C.V., Briingman, T.S., Henzel, W.J., Jarrett, J.A., Leung, D.W., Maffatt, B., Ng, P., Svedersky, L.P., et al. Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumor necrosis activity. Nature 1984;312:721-724.
[4] Pennica, D., Nedwin, G.E., Hayflick, J.G., Seeburg, P.H., Deyrynck, R., Palladino, M.A.,Kohr, W.J., Aggarwal, B.B., and Goeddel, D.V. Human tumor necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature 1984;312:724-729.
[5] Idriss, H.T., and Naismith, J.H. TNFα and the TNF receptor superfamily: structure-function relationship(s). Microscopy Res. Tech.. 2000;50:184-195.
[6] Beutler B. and Cerami A. Cachectin and tumor necrosis factor as two sides of the same biological coin. Nature. 1986;320:584-588.
[7] Siegel R.M., Chan F.K.-M., Chun H.J. and Lenardo M.J. The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. Nat. Immunol.,2000; 1:469-474.
[8] Maini R.N. and Taylor P.C. Anti-cytokine therapy for rheumatoid arthritis. Annu. Rev. Med., 2000;51:207-229.
[9] Papadakis K.A. and Targan S.R. Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev. Med., 2000;51:289-298.
[10] Smith C.A., Farrah T. and Goodwin R.G. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell, 1994:76:959-962.
[11] 金伯泉，细胞和分子免疫学，西安，世界图书出版公司，2000
[12] Idriss H.T. and Naismith J.H. TNFα and the TNF receptor superfamily: structure-function relationship(s) Microscopy Res. Tech.,2000; 50:184-195.
[13] Fesik S.W. Insights into programmed cell death through structural biology. Cell, 2000; 103:273-282.
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