臺灣博碩士論文加值系統

克沙奇病毒B3型屬於Picornaviridae的human enterovirus B (HEV-B) 類別，感染克沙奇病毒B3型的新生兒嚴重臨床疾病有很多，其中包含心肌炎、肝炎、腦炎和胰臟炎等。抗體依賴性增強現象已知在很多病毒感染都會發生並加重疾病的嚴重程度。為了探討克沙奇病毒B3型和抗體依賴性增強現象之間的關係，我們首先建立了in vitro的模式，利用靜脈注射免疫球蛋白 (IVIG IgG) 和克沙奇病毒B3抗體之免疫球蛋白G (anti-CVB3 IgG) 與克沙奇病毒B3型反應，之後再分別與嗜中性球細胞株 (HL-60)、小鼠巨噬細胞株 (J774.1) 和小鼠肝細胞株 (AML12) 反應。由結果得知在HL-60細胞模式下靜脈注射免疫球蛋白濃度位於52.66到3.29 μg/ml時病毒量大幅上升，J774.1細胞模式下克沙奇病毒B3抗體之免疫球蛋白G濃度1.88到0.118 μg/ml會有增強病毒量的現象，AML12細胞模式下克沙奇病毒B3抗體之免疫球蛋白G濃度0.94到0.12 μg/ml有增強病毒量的現象。此外克沙奇B3型病毒的抗體依賴性增強現象在HL-60細胞所建立的抗體依賴性增強感染模式下是依賴FcγRIII (CD16) 和FcγRII (CD32) 所媒介的抗體依賴性增強現象為主，J774.1細胞所建立的抗體依賴性增強感染模式下是依賴FcγRIII/RII (CD16/32) 和FcγRI (CD64)。我們也觀察了J774.1細胞模式下細胞激素分泌情形，發現介白素-10、介白素-12p70、腫瘤壞死因子和干擾素-γ的分泌情況在抗體存在下有大幅上升的趨勢。另一方面，在J774.1細胞模式下，發現克沙奇B1型病毒的抗體存在之下會增強克沙奇B3型病毒的病毒量。更進一步探討in vivo的情況，以三天大的ICR仔鼠為模式，在第二天大時即注射克沙奇病毒B3抗體之免疫球蛋白G，二十四小時後再給予LD50劑量的克沙奇病毒B3。結果發現當克沙奇病毒B3抗體之免疫球蛋白G濃度為0.94 μg/ml時仔鼠有最高的死亡率。此外，我們還觀察肝功能指數天冬氨酸轉氨? (Aspartate aminotransferase，AST)，丙氨酸轉氨? (Alanine aminotransferase，ALT) 和乳酸脫氫? (Lactic dehydrogenase，LDH) 發現在抗體存在下，感染後第二天和第六天大幅上升。組織病理切片方面，當抗體存在時其肝細胞有較嚴重的空泡化，大量的肝醣沉積和免疫細胞的聚集。在細胞激素分泌方面，介白素-6、介白素-10、腫瘤壞死因子、干擾素-γ和介白素-12p70也觀察到在抗體存在下會大量被分泌。器官病毒的分佈方面，發現肝臟有較高的病毒沉積量，且在抗體存在下病毒量較高。此外，我們建立懷孕小鼠動物模式，ICR懷孕母鼠在周產期時注射不同濃度克沙奇病毒B3抗體之免疫球蛋白G，待仔鼠出生後三天再注射克沙奇B3型病毒，結果發現當懷孕母鼠注射抗體濃度7.52 μg/ml時，仔鼠的存活率最低 (30%)。因此我們藉由建立細胞 (in vitro) 和小鼠動物 (in vivo) 模式證明克沙奇病毒B3型確實有抗體依賴性增強現象，且在抗體存在下會增強病毒感染率和加強發炎細胞激素的分泌而更進一步造成克沙奇病毒B3型致病能力。

Coxsackievirus B3 (CVB3) belongs to the human enterovirus B of Picornaviridae. CVB3 is associated with severe neonatal diseases, including myocarditis, hepatitis, encephalitis, and pancreatitis. Antibody-dependent enhancement (ADE) infection has been reported in several viruses and has been shown to contribute to disease severity. To understand the relationships between CVB3 and ADE, the in vitro model of CVB3 infection through ADE mechanism were established using the human neutrophil cell line HL-60, the mouse macrophage cell line J774.1 and the mouse hepatocyte cell line AML12. The viral titer was significantly enhanced in HL-60 cells at the concentration 3.29-52.66 μg/ml of commercial human immunoglobulin IgG, and in J774.1 cells at the concentration of 0.118-1.88 μg/ml and in AML12 cells at the concentration of 0.12-0.94 μg/ml of mouse anti-CVB3 IgG. Besides, using FcγR blocking antibody FcγRI (CD64), FcγRII (CD32), FcγRIII (CD16), we found anti-FcγRII and anti-FcγRIII could inhibit viral titer in HL-60 cells, anti-FcγRII/III and anti-FcγRI could inhibit viral titer in J774.1 cells. Furthermore, CVB3 infection via ADE can enhance some inflammatory cytokines expression, including interleukin 10 (IL-10), IL-12p70, tumour necrosis factor (TNF), Interferon γ (IFN-γ). The ADE phenomenon also found in J774.1 cells at the concentration of 0.002-0.037 μg/ml of anti-CVB1 IgG with CVB3. To further investigate CVB3 ADE mechanism in vivo, 3-day-old ICR mice were pretreated with various concentrations of anti-CVB3 mouse antiserum IgG 24 hours before infection subcutaneously. The highest death rate of mice was found at concentration of 0.94 μg/ml of anti-CVB3 IgG on the six days post-infection. Moreover, elevation level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) by ADE was observed 2 to 6 days post-infection. Histopathologically, mice infected by ADE also revealed enhanced hepatocyte damage and neutrophil infiltration than control. Furthermore, TNF and IFN-γ peaked on day 2 but IL-6 and IL-10 surged later on day 10 in ADE mice. The viral titer revealed markedly enhanced in liver and heart on day 2 of ADE mice than control. Moreover, pregnant ICR mice were pretreated with various concentrations of anti-CVB3 mouse antiserum IgG. Then, 3-day-old suckling mice were injected with CVB3. The highest mortality rate of suckling mice was found at the concentration of 7.52 μg/ml of anti-CVB3 IgG. In conclusion, our studies demonstrated that the ADE mechanism play an important role in pathogenesis of CVB3 infection by attenuating cytokines expression.

中文摘要 I
英文摘要 III
誌謝 V
目錄 VI
圖目錄 X
縮寫檢索表 XI
壹、緒論 1
一、克沙奇病毒介紹 1
A、克沙奇病毒分型 1
B、克沙奇病毒B型與疾病 2
C、克沙奇病毒B型的流行病學 3
C-1、克沙奇病毒B型的流行年份與感染年齡 3
C-2、在台灣感染克沙奇病毒B型的表徵 4
D、克沙奇病毒B型的結構 4
E、克沙奇病毒B型的傳染途徑與複製週期 5
F、克沙奇病毒B型與發炎性細胞激素的關係 7
二、抗體依賴性增強 (Antibody-dependent enhancement，ADE) 與宿主免疫機制之相關性 11
A、抗體依賴性增強現象其抗體濃度的選擇 11
B、抗體依賴性增強機制 11
C、抗體依賴性增強與宿主細胞激素的關聯性 12
D、相關的克沙奇病毒B型和其他病毒其抗體依賴性增強試驗之研究 13
貳、研究動機與目的 15
參、材料和方法 17
一、材料 17
A、實驗動物 17
B、病毒株 17
C、細胞株 17
D、抗體 18
E、試劑 18
二、方法 20
A、細胞培養 20
1. 細胞繼代培養 20
2. 細胞冷凍保存與解凍使用 21
B、病毒培養與感染 21
1. 病毒大量複製 21
2. 病毒溶斑法 21
3. 中和試驗 22
4. 抗體依賴性增強試驗與阻斷試驗 22
5. 細胞表面Fc的表現 23
6. 細胞激素的表現 (in vitro and in vivo) 23
C、動物實驗 24
1. 免疫血清的製備 24
2. 仔鼠的抗體依賴性增強試驗 24
3. 肝功能檢測和組織切片 25
4. 器官病毒量檢測 25
D、統計方法 25
肆、結果 26
克沙奇病毒B3感染的抗體依賴性增強in vitro模式 26
一、利用人類嗜中性白血球細胞株 (HL-60) 在不同靜脈注射免疫球蛋白的抗體濃度下所建立的in vitro模式 26
A、以病毒溶斑法定量在不同抗體濃度情況下克沙奇病毒B3的病毒量 26
B、Fc接受器與克沙奇病毒B3感染HL-60細胞之抗體依賴性增強的相關性 27
二、利用鼠類巨噬細胞株 (J774.1) 在不同克沙奇B3總和免疫球蛋白的抗體濃度下所建立的in vitro模式 28
A、以病毒溶斑法定量在不同抗體濃度情況下克沙奇病毒B3的病毒量 28
B、Fc接受器與克沙奇病毒B3感染J774.1細胞之抗體依賴性增強的相關性 29
C、在抗體依賴性增強模式下J774.1細胞的細胞激素表現 29
三、利用鼠類肝細胞株 (AML12) 在不同克沙奇B3總和免疫球蛋白的抗體濃度下所建立的in vitro模式 31
A、以病毒溶斑法定量在不同抗體濃度情況下克沙奇病毒B3的病毒量 31
B、在抗體依賴性增強模式下AML12細胞的細胞激素表現 31
C、F c接受器與克沙奇病毒B3感染AML12細胞之抗體依賴性增強的相關性 32
四、克沙奇病毒B3與其他血清型之腸病毒的抗體其抗體依賴性增強現象 32
克沙奇病毒B3感染的抗體依賴性增強in vivo模式 33
一、在不同的克沙奇B3總和免疫球蛋白的抗體濃度下所觀察的小鼠存活率 33
二、在抗體依賴性增強模式下其小鼠的不同器官病毒量分布 34
三、在抗體依賴性增強模式下其小鼠肝功能檢測 34
四、在抗體依賴性增強模式下其小鼠的病理切片 35
五、在抗體依賴性增強模式下其小鼠的細胞激素變化 36
六、建立懷孕小鼠動物模式–懷孕母鼠在不同克沙奇B3總和免疫球蛋白的抗體濃度下所產下仔鼠的存活率 37
伍、討論 39
一、克沙奇病毒B3型感染之抗體依賴性增強模式的建立 39
二、克沙奇病毒B3型感染之抗體依賴性增強模式的病理變化 41
三、克沙奇病毒B3型感染之抗體依賴性增強模式的細胞激素變化 42
四、克沙奇病毒B3型感染之抗體依賴性增強模式與其他腸病毒的抗體依賴性增強現象比較 44
五、克沙奇病毒B3型感染之抗體依賴性增強模式的流行病學意義 45
陸、結論 46
柒、參考文獻 47
圖 58
附錄 72
作者簡歷 76

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