臺灣博碩士論文加值系統

腸病毒七十一型(EV71)是嗜神經性的病毒，感染幼童會造成致死性腦炎和長期神經性的後遺症。在EV71感染的過程中，宿主的免疫反應所扮演的角色一直都是很具爭議。在我們先前所建立EV71感染小鼠模式中，被感染的小鼠可以產生相似於人類感染時的神經性症狀及死亡情形，因此我們利用小鼠模式來探討免疫細胞在EV71感染所扮演的角色；發現被病毒感染的小鼠需要依賴淋巴球來降低中樞神經和周邊組織內的病毒量。所以我們可以藉由增加淋巴球數量及活性來提高宿主的後天性免疫反應，作為預防致死EV71感染的一種療法。因為樹突狀細胞(dendritic cell; DCs)是最具有潛力的抗原呈現細胞，能將特異性抗原呈現給T淋巴球，對於浸潤至腦部T淋巴球的活化進而引起後天性免疫反應是不可或缺的。我們利用EV71感染小鼠模式發現，在EV71感染小鼠的腦部，能夠偵測到有DCs、T淋巴球和B淋巴球浸潤現象，而且在這些淋巴球浸潤到腦部之前，DCs即會出現在感染小鼠腦部。先前報告以免疫增強劑Flt3 ligand，透過干擾素反應來降低神經性疱疹病毒在小鼠造成的死亡。於是我們也以Flt3 ligand來治療EV71感染小鼠，實驗結果發現於EV71感染前事先給予野生種小鼠Flt3 ligand處理，能增加組織中之傳統DCs (conventional DCs)和淋巴球浸潤，來清除感染組織中的病毒量和降低感染小鼠的死亡率、患病率以及後來所引發的後肢麻痺之後遺症。由於Flt3 ligand也可降低CD4 T或是CD8 T淋巴球缺乏小鼠之死亡，但無法降低SCID或B淋巴球缺乏小鼠的死亡，顯示B淋巴球在EV71感染的過程所扮演的保護角色是必要。同時我們以in vitro的實驗來探討EV71感染人類DCs的情形，發現DC-SIGN能部分調控EV71感染DCs，並且病毒可在細胞內進行複製，製造出具感染性的病毒子代。另外，可在感染的DCs偵測到病毒抗原和病毒基因的表現。進一步分析發現，EV71感染能夠延長DCs存活率、促使DCs活化和釋放IL-6、IL-12以及TNF-α等細胞激素。被病毒感染的DCs在和T淋巴球共同培養後，會刺激T淋巴球進行增生反應。這些研究結果將使我們更加了解EV71的致病機轉，在in vivo和in vitro實驗中，我們發現EV71感染後可以誘導DCs和淋巴球產生保護性免疫反應，並發現Flt3 ligand可以保護小鼠對抗病毒感染，這項研究成果提供Flt3 ligand應用於事前預防致死性EV71感染上的潛力。

Enterovirus 71 (EV71) causes encephalitis and long-term neurological sequelae in hundreds of thousands of young children. However, there are no vaccines currently available to reduce fatal infection in part because the EV71 pathogenesis is incompletely understood. Our previous data showed that T and B lymphocytes and antibody response protected mice from EV71 infection. Dendritic cells (DCs) play a crucial role in antiviral immunity by functioning as professional antigen presenting cells to prime T helper lymphocytes and by secreting cytokines to modulate immune responses. Using a neonatal mouse model, we showed here that following infection, DCs were present before the infiltration of lymphocytes in the brains of infected mice. Moreover, pretreatment with the hematopoietic growth factor fms-like tyrosine-kinase 3 ligand (Flt3 ligand) resulted in an increase in adaptive immunity components, conventional DCs and lymphocytes, and significantly reduced the mortality and paralysis sequela of infected immunocompetent mice by decreasing the viral loads in tissues. Flt3 ligand pretreatment also reduced the mortality of CD4 or CD8 T-lymphocyte-deficient mice, but not SCID mice deficient in lymphocytes or B-lymphocyte-deficient mice infected with EV71. We conclude that Flt3 ligand administration promotes resistance to EV71 infection by enhancing B-lymphocyte response. Moreover, we also showed that EV71 productively infected human immature DCs and expressed viral antigen in DCs. EV71 infection of DCs was partially mediated by DC-SIGN. Further analyses revealed that EV71 increased the viability, activation, release of cytokines, interleukin-6, interleukin-12, and tumor necrosis factor-α, in DCs. Moreover, EV71 enabled DCs to stimulate T-cell proliferation. Collectively, these findings suggest that EV71 infection of human DCs in vivo is very likely to elicit protective immunity. Our findings provide a greater understanding of EV71 pathogenesis and also raise the prospect that Flt3 ligand treatment may protect hosts with increased risk for viral infection.

中文摘要 1
英文摘要 3
誌謝 5
總目錄 7
圖目錄 10
緒論 12
一、腸病毒七十一型病毒學概論 13
二、腸病毒七十一型流行病學 15
三、腸病毒七十一型臨床症狀和致病機轉 16
四、宿主免疫反應在腸病毒七十一型感染的角色 18
五、樹突狀細胞所扮演的免疫學角色 19
六、樹突狀細胞與病毒間交互作用 21
七、DC-SIGN在樹突狀細胞在病毒感染中所扮演角色 24
八、Flt3 ligand的特性和免疫調節功能 .26
研究動機及特定目標 29
材料與方法 31
一、實驗動物 31
二、細胞株 31
三、病毒株 31
四、口服感染ICR小鼠模式 32
五、小鼠組織病毒量測定 32
六、病毒溶菌斑分析 32
七、偵測感染小鼠腦部與脾臟之免疫細胞分佈情況 32
八、Flt3 ligand處理新生小鼠 33
九、中和試驗 34
十、以體外方式將人類單核球細胞分化樹突狀細胞 35
十一、病毒感染人類未成熟樹突狀細胞 37
十二、反轉錄酵素-聚合酵素連鎖反應 38
十三、免疫螢光偵測人類未成熟樹突狀細胞之表面病毒抗原 40
十四、利用DC-SIGN抗體阻止病毒感染人類未成熟樹突狀細胞 40
十五、病毒感染人類未成熟樹突狀細胞之細胞數目存活率測定 41
十六、偵測病毒感染人類樹突狀細胞後細胞活化分子的表現情形 41
十七、酵素結合抗體分析細胞激素 41
十八、病毒感染人類樹突狀細胞之刺激T淋巴球增生能力測定 41
十九、統計 42
結果 43
一、用小鼠模式偵測樹突狀細胞和淋巴球在腸病毒七十一型感染中
的分佈情形 43
1. 病人和小鼠之感染組織的樹突狀細胞和淋巴球浸潤現象 43
2. B、CD4+ T和CD8+ T淋巴球能藉由減少感染組織中的病毒量進
而降低感染小鼠的致死 44
二、探討Flt3 ligand用來保護小鼠免於腸病毒七十一型致命感染的機轉 45
1. Flt3 ligand能減少感染組織中的病毒量因而降低感染小鼠的死亡
率、患病率以及後來所引發的後肢麻痺之後遺症 45
2. Flt3 ligand能增加小鼠脾臟和腦部之樹突狀細胞和T淋巴球的浸
潤與活化 47
3. Flt3 ligand藉由樹突狀細胞引起後天性免疫反應來保護小鼠對抗
病毒感染 48
三、探討腸病毒七十一型與人類樹突狀細胞之間的互動 51
1. 由人類周邊單核球細胞建立人類未成熟和成熟樹突狀細胞 51
2. 腸病毒七十一型能夠感染人類未成熟樹突狀細胞並在細胞內進行
病毒複製 52
3. DC-SIGN能部分調控腸病毒七十一型感染人類未成熟樹突狀細胞 54
4. 病毒感染人類樹突狀細胞會延長細胞的存活率、促使細胞活化和
釋放細胞激素 54
5. 病毒感染人類樹突狀細胞會刺激人類T淋巴球增生 56
討論 57
結論 65
參考文獻 66
圖附錄 78
附圖 107
已出版論文 113
已接受發表之論文 121

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