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研究生:許晉詮
研究生(外文):Jimm Jinn-Chyuan Sheu
論文名稱:誘發主動性自體免疫反應以調控B細胞的治療方策
論文名稱(外文):A therapeutic approach for controlling B cells based on inducing active specific autoimmunity
指導教授:張子文張子文引用關係
指導教授(外文):Tse Wen Chang
學位類別:博士
校院名稱:國立清華大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:英文
論文頁數:114
中文關鍵詞:B細胞自體免疫反應治療方策蛋白質疫苗
外文關鍵詞:B cellsautoimmunitytherapeutic approachprotein vaccine
相關次數:
  • 被引用被引用:1
  • 點閱點閱:102
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  • 收藏至我的研究室書目清單書目收藏:1
某些血漿蛋白、細胞激素、以及細胞表面抗原的過量表現將引致疾病。因此,如何調控這些蛋白分子的含量是治療這些疾病的一種方略。許多單株抗體已被發展成有效的藥物來治療這些相關疾病,但抗體藥物在病人體內可能引起免疫反應,降低藥物的療效。利用特殊的蛋白質疫苗來誘發專一性的主動自體免疫反應,以對抗與疾病相關的自體抗原,是值得研發的另類治療方策。如此的蛋白質藥物,可與之前的抗體藥物或傳統的化學藥物同步施打;而誘發出的自體免疫抗體,將可提升臨床治癒率並防止疾病的復發。
在此論文,二種不同的方式被證明可以產生具專一性的自體免疫反應︰一、將自體抗原與異種免疫球蛋白的Fc片段結合,以提供T型淋巴細胞輔助用的抗原結構;二、利用同源性蛋白間的模擬作用(mimicry)。我們已證實數種被認為具B型淋巴細胞專一性的抗原,如︰Ig (CD79a)、Ig (CD79b)或CD20等分子,能在BALB/c小鼠體內引起自體免疫反應。實驗顯示,從受測小鼠產生的自體免疫抗體,可以認別自體抗原的基因重組蛋白,也可結合認別小鼠的B型淋巴細胞。在受測小鼠的血液中,B型淋巴細胞的相對含量比對照組低;當這些小鼠被施打第二抗原時,其抗體免疫反應會降低,顯示其B型淋巴細胞的功能受到抑制。在本論文中,我們也討論如何利用此蛋白質疫苗的觀念,研發治療B型淋巴癌或某些自體免疫疾病的臨床藥物。
Abnormally elevated expression of certain plasma proteins, cytokines, and cell surface molecules is found related to the development of certain diseases. Controlling the expression of these autologous molecules may be exploited as a means to control the progression of such diseases. The approach of using monoclonal antibodies specific for those autologous molecules as a new class of biopharmaceuticals for treating the affected diseases has been actively pursued and numerous successes have been achieved. However, the potential immunogenicity of the therapeutic antibodies may elicit antibody responses in the recipients and hence compromise the efficacy of such therapies. As an alternative, inducing active autoimmunity with specificity against disease-related autologous antigens in immunogenic forms has been evaluated as a feasible approach. Such therapeutic vaccines may be administrated in combination with antibodies or conventional chemotherapeutic agents. The induced autoantibodies may potentially improve therapeutic efficacy and prevent from elapses of these diseases.
In this thesis, two different approaches have been demonstrated to induce auto-reactive/cross-reactive immunity with designed specificity: one, fusing peptides of autologous antigens with T cell epitopes based on foreign Fc, and two, homologous protein mimicry. Several B cell specific antigens, such as Ig (CD79a), Ig (CD79b) and CD20, have been explored to trigger T cell-dependent antibody responses in BALB/c mice. The induced auto-reactive/cross-reactive antibodies can recognize the targeted self antigens both in vitro and in vivo, and bind to cells of a mouse B cell line. The proportions of B cells in the peripheral blood of treated mice decreased, as compared to those of control mice immunized with irrelevant antigens. Furthermore, the treated mice also made reduced antibody response against a 2nd antigen, indicating the reduction of B cell biofunctions. The implications of employing the present concepts to develop a therapeutic approach for treating patients with B cell neoplastic diseases or with certain antibody-mediated autoimmune diseases are discussed.
Chapter I Background and Significance………………………………001
Inducing active specific auto-reactivity against disease-related self antigens
Chapter II Ig[beta] (CD79b) Antigen……………………………012
Inducing specific reactivity against B cells in mice by immunizing with an Fc fusion protein containing self-Ig[beta]
Abstract……………………………………………………….. 013
Introduction…………………………………………………… 014
Materials and Methods……………………………………….. 016
Results…………………………………………………………. 021
Discussion…………………………………………………….. 032
Chapter III CD20 Antigen...…………………………………036
Down regulation of B cells by immunization with a fusion protein of a self CD20 peptide and a foreign IgG.Fc fragment
Abstract……………………………………………………….. 037
Introduction…………………………………………………… 038
Materials and Methods……………………………………….. 040
Results…………………………………………………………. 046
Discussion…………………………………………………….. 058
Chapter IV Ig[alpha] (CD79a) Antigen...………………………062
Inducing antigenic cross-reactivity against B cells in mice by immunizing with human Ig[alpha] to mice
Abstract……………………………………………………….. 063
Introduction…………………………………………………… 064
Materials and Methods……………………………………….. 066
Results…………………………………………………………. 071
Discussion…………………………………………………….. 085
Chapter V Discussion and Clinical Applications…….088
Preparation of Fc fusion proteins for clinical use as therapeutic agents
Reference ………………………………………………………………….099
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