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系統識別號 U0026-1808201415570100
論文名稱(中文) 以體外及小鼠模式探討抗登革病毒非結構性蛋白1 多株及單株抗體的治療效果
論文名稱(英文) Studies on the therapeutic effects of anti-dengue virus nonstructural protein 1 polyclonal and monoclonal antibodies both in vitro and in vivo
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 102
學期 2
出版年 103
研究生(中文) 陳珮瑋
研究生(英文) Pei-Wei Chen
電子信箱 lern934@hotmail.com
學號 s46011011
學位類別 碩士
語文別 英文
論文頁數 74頁
口試委員 指導教授-林以行
口試委員-葉才明
口試委員-羅伯安德森
口試委員-林秋烽
中文關鍵字 登革病毒  非結構性蛋白1  治療性單株抗體 
英文關鍵字 dengue virus  nonstructural protein 1  therapeutic monoclonal antibodies 
學科別分類
中文摘要 登革病毒 (dengue virus; DENV) 是一種具有四種血清型並會透過病媒蚊傳播至人類的病毒,主要盛行在熱帶和亞熱帶地區。登革病毒感染會造成的疾病有從較輕微的登革熱 (DF) 到嚴重的登革出血熱 (DHF) 和登革休克症 (DSS)。迄今仍無獲許可的疫苗或抗病毒治療。實驗室先前研究顯示,會和宿主抗原交叉反應的抗原決定位在登革病毒非結構性蛋白1 (NS1) 的C 端部分序列,造成抗NS1抗體所介導的內皮細胞凋亡及血小板失能。所以我們將登革病毒NS1的C端序列去除或置換為日本腦炎病毒 (JEV) NS1的C端,分別產生了ΔC NS1及DJ NS1蛋白質。過去實驗室研究顯示,被動給予抗ΔC NS1及抗DJ NS1抗體兩次,可以提供登革病毒感染的小鼠治療效果。我們進一步在治療小鼠模式中測試給予單劑量抗修飾後的NS1抗體對抗DENV感染的效果,實驗結果顯示給予單劑量抗DJ NS1抗體可以顯著地降低DENV感染引起的出血時間延長。除了多株抗體,我們也探討抗NS1單株抗體的治療效果。單株抗體2E8可以辨認四種血清型的NS1蛋白,但並不會辨認NS1的交叉反應抗原。進一步分析顯示2E8的抗原決定位在NS1上可被辨認到的區域。我們發現單株抗體2E8也可以活化補體,將被感染的細胞裂解掉。嵌合性單株抗體2E8以及另一株治療性單株抗體候選者31B2也可以活化補體,裂解被感染的細胞。在小鼠的研究模式中,給予單株抗體2E8也可以減少DENV感染所造成的小鼠尾部出血時間延長、病毒蛋白表現量、以及巨噬細胞在局部感染區域的浸潤程度。我們進一步在感染後第五天發現,不論在感染後的第一天、第三天或第四天給予抗DJ NS1抗體或單株抗體2E8皆可以降低DENV造成的出血時間延長及出血情形。總括以上結果,給予單劑量的抗DJ NS1抗體或單株抗體2E8可以保護小鼠對抗登革病毒感染,因此抗修飾後的NS1抗體可能做為治療登革疾病的一個選擇。
英文摘要 Dengue virus (DENV) is a mosquito-transmitted flavivirus with four serotypes and is endemic in tropical and subtropical regions of the world. Infection with DENV causes diseases ranging from mild dengue fever to severe dengue hemorrhagic fever and dengue shock syndrome. Currently, there is no approved vaccine to prevent dengue infection. Our previous studies showed that the cross-reactive epitopes reside in the C-terminal region of DENV nonstructural protein 1 (NS1), and cause anti-DENV NS1 antibodies (Abs)-mediated endothelial cell apoptosis and platelet dysfunction. Therefore, we deleted the C-terminal region of DENV NS1 protein or replaced the C-terminal region with JEV NS1 protein, to generate ΔC NS1 and DJ NS1, respectively. Our previous studies also suggested that passive immunization with anti-ΔC or anti-DJ NS1 Abs twice can provide some therapeutic effects in DENV-infected mice. In this study, we attempted to determine the effective single dose of anti-modified NS1 Abs against DENV infection in a therapeutic mouse model. Results showed that the DENV-induced prolonged bleeding time was significantly reduced by treatment with anti-DJ NS1 Abs with a single dosage. Besides polyclonal Abs, we also investigated the therapeutic effects of anti-NS1 monoclonal Abs (mAbs). The mAb 2E8 can recognize NS1 of all four DENV serotypes, but does not recognize epitopes of DENV NS1 which cross-react with host proteins. Further analysis showed that the epitope recognized by mAb 2E8 is on the solvent accessible area of NS1. We found that mAb 2E8 causes complement-mediated cytolysis in vitro after DENV infection. Chimeric mAb 2E8 and another therapeutic candidate mAb 31B2 also induce complement-mediated cytolysis of DENV-infected cells. In the mouse model studies, treatment with mAb 2E8 reduced mouse tail prolonged bleeding time, viral antigen expression, and macrophage infiltration to local infection sites. We further found that administering anti-DJ NS1 or mAb 2E8 at day 1, 3, or 4 post-inoculation reduced prolonged bleeding time and hemorrhage even at day 5 post-infection. In summary, administration of a single dose of anti-DJ NS1 Abs or mAb 2E8 protected mice against DENV infection, suggesting that anti-modified DENV NS1 Abs may be a therapeutic option against dengue disease.
論文目次 中文摘要 I
Abstract II
Acknowledgement IV
Contents V
Table and Figure List IX
Abbreviations XI
Introduction 1
Characteristics of dengue virus 1
Epidemiology of dengue virus infection 3
Clinical symptoms of dengue disease 4
The pathogenesis of dengue virus infection 4
Animal models of dengue virus infection 7
Therapeutic antibodies development for dengue virus 9
Objective and Specific Aims 11
1. To determine the effective single dose of Abs in a therapeutic mouse model. 11
2. To identify the protective effects provided by anti-DENV NS1 mAbs in vitro. 11
3. To evaluate the therapeutic effects of anti-DENV NS1 mAb 2E8 in DENV-infected mouse models. 12
Materials and Methods 13
A. Materials 13
A-1 Mice 13
A-2 Cell lines 13
A-3 Virus 13
A-4 Preparation of recombinant proteins and Abs 14
A-5 Drugs and reagents 14
A-6 Antibodies 17
A-7 Kits 18
A-8 Consumables 18
A-9 Instruments 20
B. Methods 21
B-1 Cell cultures 21
B-2 Virus culture 21
B-3 Plaque assay 21
B-4 ELISA 22
B-5 Infection of endothelial cells with DENV 22
B-6 Flow cytometry 23
B-7 Ab-dependent complement-mediated cytolytic assay 23
B-8 Therapeutic model 23
B-9 Mouse tail bleeding time determination 24
B-10 Immunohistochemistry staining 24
B-11 Statistics 25
Results 26
1. To determine the effective single dose of Abs in a therapeutic mouse model. 26
1.1 Preparation of Abs against DENV NS1, JEV NS1, ΔC NS1, and DJ NS1 proteins. 26
1.2 Determination of the effective single dose of anti-DJ NS1 Abs in a DENV-infected therapeutic mouse model. 26
1.3 Anti-DJ NS1 Abs reduce viral antigen NS3 expression in local skin tissues. 27
1.4 Anti-DJ NS1 Abs reduce DENV-induced macrophage infiltration at local infection sites. 27
2. To identify the protective effects provided by anti-DENV NS1 mAbs in vitro. 28
2.1 Preliminary screening of mAbs against DENV NS1. 28
2.2 The epitope recognized by mAb 2E8 is accessible and conserved on DENV NS1. 28
2.3 The mAb 2E8 specifically binds to DENV-infected cells and induces complement-mediated cytolysis. 29
2.4 The mAb 31B2 and chimeric mouse-human mAb 2E8 bind to DENV-infected cells and cause complement-mediated cytolysis. 29
3. To evaluate the therapeutic effects of anti-DENV NS1 mAb 2E8 in DENV-infected mouse models. 30
3.1 The mAb 2E8 effectively reduces DENV-induced prolonged bleeding time in STAT1-/- mice. 30
3.2 The mAb 2E8 decreases DENV antigen NS3 expression at local infection sites in STAT1-/- mice. 31
3.3 The mAb 2E8 reduces DENV-induced macrophage infiltration to local infection sites in STAT1-/- mice. 31
3.4 The mAb 2E8 effectively reduces DENV-induced prolonged bleeding time in wild-type mice. 31
3.5 The mAb 2E8 decreases DENV antigen NS3 expression at local infection sites in wild-type mice. 32
3.6 The mAb 2E8 reduces DENV-induced macrophage infiltration to local infection sites in wild-type mice. 32
3.7 Different time points for administering therapeutic Abs in DENV-induced hemorrhage mouse model. 33
Discussion 35
References 42
Table and Figures 51
Appendix 73
Curriculum Vitae 74
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