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系統識別號 U0026-0812200912052550
論文名稱(中文) 免疫表面分子之調控與抗慢性C型肝炎病毒療效的相關性
論文名稱(英文) Modulation of immune surface molecules associated with the efficacy of antiviral therapy for chronic hepatitis C virus infection
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 94
學期 2
出版年 95
研究生(中文) 魏雅鈴
研究生(英文) Ya-Ling Wei
電子信箱 t3693101@mail.ncku.edu.tw
學號 t3693101
學位類別 碩士
語文別 中文
論文頁數 121頁
口試委員 指導教授-楊孔嘉
口試委員-張定宗
口試委員-劉校生
口試委員-王憲威
中文關鍵字 干擾素  持續性病毒學反應  C型肝炎病毒  HLA 
英文關鍵字 interferon  HLA  sustained virological response  HCV 
學科別分類
中文摘要 C型肝炎病毒(hepatitis C virus, HCV)感染是一個威脅全球健康的疾病,以干擾素(interferon, IFN)與Ribavirin的合併治療,為目前唯一核准上市的治療方式,治癒率大約在46-78 %之間。合併治療的療效受感染病毒量、病毒基因型,或一些目前還不是十分清楚的病毒或宿主因子影響;而在未知的宿主影響因子中,由於兩藥劑都被認為有免疫調控作用,因此免疫反應的調控亦可能參與其中。受病毒感染,必須要有適當的抗原呈現反應,去引起足夠的適應性細胞性免疫反應將病毒清除。本實驗目的為探討在治療過程中,免疫相關表面蛋白是否受到調控,以及與療效的相關性。在本實驗中收集35位慢性C型肝炎患者,接受合併治療24周,停藥後追蹤24周,並在不同之時間點收集其血液檢體,以流式細胞儀偵測周邊血液單核球細胞(peripheral blood mononuclear cells, PBMCs)上CD81和三種主要和抗原呈現有關的表面分子HLA-ABC、CD86和CD28,看其表現情況在用藥過程中是否受到調控。在流式細胞儀的結果得到持續性病毒學反應(sustained virological response, SVR)的病人(N=26),接受合併治療的過程中,B細胞表面上的HLA-ABC和CD86 有被調升的情況,但對沒有持續性病毒學反應(Non-SVR)的病人(N=9)則沒有這樣的情況。但B細胞表面之HLA-ABC表現量提升並非源自於RNA之增加。在SVR和Non-SVR的病人都可以看到CD28不論在CD4或CD8 T細胞上,表現量都是被調升的。偵測治療前和治療第四周B細胞中HLA mRNA的含量,結果隨著治療HLA mRNA的含量會減少,但核細胞表面的HLA-ABC表現無關聯性。HLA-ABC基因型和療效的相關性,並沒有顯著的意義。我們的結果指出合併治療可以提升B細胞上HLA-ABC和CD86的表現量,並與治療效果相關。


英文摘要 Hepatitis C virus (HCV) diseases threaten global human health. The current treatment for chronic HCV infection with combination regimen of pegylated interferon (IFN)-alpha and ribavirin can exert overall response rate of approximately 46-78%, which is influenced by viral genotype, initial circulating viral load and host factors. Host factors such as immunological regulators seem to affect the outcome of antiviral treatment of pegylated IFN-alpha and ribavirin since both agents are known immumodulators. Proper antigen presentation function is required to elicit sufficient adapted cellular immunity against viral infection, which has been impaired in patients chronically infected with HCV. This study aims to investigate whether the modulation of immuno-surface proteins by pegylated interferon (IFN)-alpha and ribavirin is related to therapeutic responses. We enrolled 35 patients with chronic hepatitis C, who have undergone combination therapy. We longitudinally assessed the effect of anti-HCV agents on the expression levels of CD81, HLA-ABC, CD86 and CD28, the three major components in trigger of antigen-dependent and antigen-independent co-stimulatory signals, in peripheral blood mononuclear cells (PBMCs) from patients receiving combination therapy for 24 weeks and afterward follow-up for 24 weeks. FACS analysis showed that HLA-ABC and CD86 upregulation on B cells during combine therapy in patients with sustained virological response (SVR) (n=26), but not in patients without SVR (n=9). Elevation of surface HLA-ABC expression was not secondary to increased RNA levels in B cells. The treatment induced upregulation of surface CD28 in CD4+ and CD8+ T cells in both of the patient groups. The analysis of polymorphic HLA-ABC alleles showed no significant difference in both patient groups. In conclusion, the expression levels of HLA-ABC and CD86 were up-regulated on B cells during combination therapy only in patients with SVR but not non-SVR.


論文目次 摘要--------------------------------------------------------------------------I
Abstract---------------------------------------------------------------------II
誌謝----------------------------------------------------------------------- III
目錄------------------------------------------------------------------------ IV
圖/表/附錄---------------------------------------------------------------- VIII
第ㄧ章、緒論 (Introduction)---------------------------------------------------1
1. C型肝炎病毒---------------------------------------------------------------3
1-1 C型肝炎病毒的複製機轉----------------------------------------------------3
1-2 C型肝炎病毒基因型--------------------------------------------------------6
1-3 C型肝炎病毒感染的臨床表現------------------------------------------------6
2. C型肝炎抗病毒藥物治療-----------------------------------------------------8
2-1 抗病毒藥物治療之病毒反應------------------------------------------------10
2-2 干擾素的抗病毒作用------------------------------------------------------10
2-3 Ribavirin的抗病毒作用---------------------------------------------------13
2-4 影響抗病毒藥物療效的因素------------------------------------------------14
3. C型肝炎病毒相關之免疫反應------------------------------------------------15
3-1 C型肝炎病毒感染引起宿主免疫反應-----------------------------------------16
3-2 急性C型肝炎的免疫反應---------------------------------------------------17
3-3 慢性C型肝炎的免疫反應---------------------------------------------------18
3-4 C型肝炎病毒躲避宿主免疫攻擊---------------------------------------------19
4.免疫相關表面分子----------------------------------------------------------21
4-1 CD81的分子特性----------------------------------------------------------22
4-2 HLA的分子特性---------------------------------------------------------- 23
4-3 CD86的分子特性----------------------------------------------------------24
4-4 CD28的分子特性----------------------------------------------------------25
5.研究目標------------------------------------------------------------------26
第二章、材料和方法 (Materials and Methods)-----------------------------------28
I.材料----------------------------------------------------------------------31
儀器、試劑、抗體------------------------------------------------------------31
II.方法---------------------------------------------------------------------33
1.臨床病人的收集------------------------------------------------------------33
1-1慢性C型肝炎病人收集------------------------------------------------------33
1-2血液樣本的處理和保存-----------------------------------------------------34
2.檢測HCV RNA 和 HCV 基因型-------------------------------------------------34
2-1 HCV RNA 萃取------------------------------------------------------------34
2-2 HCV反轉錄作用-----------------------------------------------------------35
2-3 HCV Nested 聚合酶鏈鎖反應-----------------------------------------------36
2-4 DNA瓊膠電泳-------------------------------------------------------------37
2-5 HCV RNA即時定量PCR------------------------------------------------------38
2-6 HCV基因型即時定量PCR----------------------------------------------------40
3.免疫相關表面分子之分析----------------------------------------------------41
3-1 周邊血液單核球細胞之分離------------------------------------------------41
3-2 流式細胞儀分析----------------------------------------------------------42
4.人類白血球抗原轉殖--------------------------------------------------------44
4-1細胞Total RNA的萃取------------------------------------------------------44
4-2 HLA反轉錄作用-----------------------------------------------------------44
4-3 HLA聚合酶鏈鎖反應-------------------------------------------------------45
4-4 HLA聚合酶鏈鎖反應產物純化-----------------------------------------------46
4-5接合作用-----------------------------------------------------------------47
4-6轉型至勝任細胞-----------------------------------------------------------48
4-7小量質體萃取-------------------------------------------------------------48
5.人類白血球抗原mRNA測定----------------------------------------------------49
5-1分選細胞-----------------------------------------------------------------49
5-2 HLA mRNA即時定量PCR-----------------------------------------------------50
5-3 G6PDH反轉錄作用---------------------------------------------------------52
5-4 G6PDH即時定量PCR--------------------------------------------------------52
6.HLA基因型-----------------------------------------------------------------53
6-1 PBMC DNA 萃取-----------------------------------------------------------53
7.數據分析------------------------------------------------------------------54
7-1 以SPSS套裝程式進行數據分析----------------------------------------------54
第三章、結果 (Results)-------------------------------------------------------55
1. 慢性C型肝炎患者基本資料分析----------------------------------------------57
2.慢性C型肝炎患者接受合併治療期間CD81表現之變化-----------------------------59
2-1 B細胞CD81表現-----------------------------------------------------------59
2-2單核球細胞CD81表現-------------------------------------------------------59
2-3 CD4 T細胞CD81表現-------------------------------------------------------59
2-4 CD8 T細胞CD81表現-------------------------------------------------------60
2-5 NK細胞CD81表現----------------------------------------------------------60
2-6 NK T細胞CD81表現--------------------------------------------------------60
3.慢性C型肝炎患者接受合併治療期間HLA-ABC表現之變化--------------------------61
3-1 B細胞HLA-ABC的表現------------------------------------------------------61
3-2 單核球細胞HLA-ABC的表現-------------------------------------------------62
4.慢性C型肝炎患者接受合併治療期間CD86表現之變化-----------------------------62
4-1 B細胞CD86的表現---------------------------------------------------------63
4-2單核球細胞CD86的表現-----------------------------------------------------63
5.慢性C型肝炎患者接受合併治療期間CD28表現之變化-----------------------------64
5.1 CD4 T細胞CD28的表現-----------------------------------------------------65
5-2 CD8 T細胞CD28的表現-----------------------------------------------------65
6. HLA基因型----------------------------------------------------------------67
7.細胞分選及HCV RNA和HLA mRNA的測量-----------------------------------------68
7-1 B細胞HCV RNA 之測定-----------------------------------------------------68
7-1構築HLA標準質體----------------------------------------------------------69
7-2 HLA標準曲線的建立-------------------------------------------------------69
7-3 B細胞HLA mRNA的表現-----------------------------------------------------69
第四章、討論 (Discussion)----------------------------------------------------71
1.免疫相關表面蛋白和HCV療效的相關性-----------------------------------------72
1-1 CD81與HCV抗病毒療效的相關性---------------------------------------------72
1-2 HLA、CD86、CD28與HCV抗病毒療效的相關性----------------------------------73
2. HLA基因型和HCV療效的相關性-----------------------------------------------75
3. HLA mRNA表現量與HLA 表面蛋白表現量的相關性-------------------------------75
4.結語--------------------------------------------------------------------- 77
表/圖 (Tables and Figures)---------------------------------------------------78
參考文獻 (References)-------------------------------------------------------108
附錄 (Appendixes)-----------------------------------------------------------118
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