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研究生:彭榮桂
研究生(外文):Jung-Kuei Peng
論文名稱:介白素IL-4以及IL-10之結合效應抑制組織胞漿菌感染中第一型輔助性T細胞之產生而不改變其極性
論文名稱(外文):The Combined Effect of IL-4 and IL-10 Suppresses the Generation of, But Does Not Change, the Polarity of Type-1 T Cells in Histoplasma Infection
指導教授:伍安怡
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:免疫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:93
語文別:英文
論文頁數:101
中文關鍵詞:組織胞漿菌炎第一型第二型免疫反應干擾素
外文關鍵詞:HistoplasmosisType-1 and type-2 immune responseinterferon
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在小鼠的全身性組織胞漿菌炎感染模式中會誘發強烈之第一型細胞激素產生,我們利用此模式來探討在組織胞漿菌感染之免疫反應中,若在第一型T細胞priming階段存在第二型拮抗型細胞激素介白素(IL-4,IL-10)下會否改變第一型T細胞之極性。小鼠在感染組織胞漿菌之前先注射二劑山羊抗鼠IgD免疫球蛋白血清(G�埒��)後,會誘發強烈之第二型細胞激素表現。於感染後第七及第十四天,我們發現G�埒�堀B理過之小鼠之干擾素-�蚺狨雪|被抑制,並且在脾臟及肺臟部位之病菌負荷量將會顯著增加。干擾素-�蛌穛{細胞之數目以及每顆細胞產生干擾素-�蚺孝{度均被大量降低。此現象不只存在於CD4 T細胞,同時CD8 T細胞亦被影響。干擾素-�蛌穛{細胞之數目降低之現象並非由於G�埒�� 所引起在脾臟中的T細胞增殖缺失、細胞死亡或是細胞對刺激不作反應。而在G�埒�� 處理過之細胞激素介白素IL-4單一基因缺陷小鼠以及IL-10單一基因缺陷小鼠中,此因組織胞漿菌感染而誘發之干擾素-�蛌穛{細胞數目會部分回復。有趣的是,在G�埒�� 處理過之細胞激素介白素IL-4以及IL-10雙重基因缺陷小鼠中表現干擾素-�蚺妓茩M數目則是完全的回復。因此,第二型拮抗型細胞激素介白素IL-4與IL-10共同抑制表現干擾素-�袉茩M之產生。此外,由一長期研究的結果顯示當IL-4與IL-10逐漸降低時,組織胞漿菌誘發表現干擾素-�蚺妓茩M則會快速的升高並且清除病菌的能力會改善,這些結果顯示在感染初期T細胞被活化時IL-4與IL-10的存在並不會改變T細胞的極性。
Dominant type-1 cytokine production is induced in a murine model of systemic histoplasmosis. We used this model to investigate whether the presence of antagonistic cytokines during T cell priming changes the polarity of T cells in response to Histoplasma infection. Before infection with Histoplasma capsulatum, mice were injected twice with goat anti-mouse IgD antiserum (GaMd), which induced expression of dominant type-2 cytokines. At days 7 and 14 after infection, the GaMd-treated mice had suppressed IFN-g response and a significantly greater fungal burden in their spleens and lungs. The number of IFN-g-producing cells as well as the level of IFN-g produced per cell was greatly reduced. Not only CD4+ T cells but also CD8+ T cells were affected. Reduction of IFN-g-producing T cells is not a result in T cell expansion, T cell death, or intrinsic defect in TCR signaling. There was no difference in the numbers of CD4 and CD8 T cells in infected mice with or without GaMd treatment. The number of Histoplasma-induced IFN-g-producing cells was partially restored in GaMd-treated IL-4-/- and IL-10-/- mice and completely restored in IL-4-/-IL-10-/- mice. Thus, the combined effect of IL-4 and IL-10 suppressed the generation of IFN-g-producing cells. A longitudinal study demonstrated that as IL-4 and IL-10 decreased, the number of Histoplasma-induced IFN-g-producing cells rapidly increased, and fungal clearance improved, demonstrating that the presence of IL-4 and IL-10 did not permanently change the polarity of T cells.
Abstract (Chinese)……………………………………………………………………... 2
Abstract…………………………………………………………………………………. 3

Chapter I. Introduction………………………………………………………………. 8
1.1 Background………………………………………………………………………… 9
1.1.1 Type-1 and type-2 T cells differentiation………………………………….. 9
1.1.1.1 T cells subsets…………………………………………………………. 9
1.1.1.2 Th1 cells differentiation……………………………………………….. 9
1.1.1.3 Th2 cells differentiation……………………………………………….. 11
1.1.2 Goat anti-mouse IgD antiserum (GaMd) induces immunoglobulin production and cytokines expression in mice………………………………..
14
1.1.3 Histoplasma capsulatum infection and host defense……………………. 15
1.1.4 Regulation of type-1 and type-2 cytokines in experimental model…….. 16
1.2 Objectives.…………………………………………………………….…………… 18

Chapter II. Materials and Methods………………………………………………… 19
2.1 Experimental Methods…………………………………………………………….. 20
2.1.1 Mice…………………………………………………………………………… 20
2.1.2 Experimental design………………………………………………………… 20
2.1.3 Fungus infection………………………………………………………..…… 21
2.1.4 Preparation of mouse splenic leukocytes………………………………… 21
2.1.5 Fungus counts………………………………………………………………. 21
2.1.6 Genotyping of IL-4-/-IL-10-/- mice from tail DNA………………………..… 22
2.1.7 Total RNA isolation and reverse transcription (RT)…………………….… 23
2.1.8 Competitive RT-PCR……………………………………………………...… 24
2.1.9 7-amino-actinomycin D staining………………………………………….… 25
2.1.10 Cell surface marker and intracytoplasmic cytokines staining…………. 25
2.1.11 IgE ELISA assay……………………………………………………….…… 26
2.1.12 IFN-g ELISA assay…………………………………………………….…… 27
2.1.13 IL-2 ELISA assay……………………………………………………...…… 27
2.1.14 Statistical analysis…………………………………………………….…… 28
2.2 Experimental Materials………………………………………………………….… 29
2.2.1 Hank’s balanced salt solution (HBSS)………………………………….…. 29
2.2.2 Complete RPMI-1640 medium…………………………………………..… 29
2.2.3 RBC lysis buffer……………………………………………………………… 30
2.2.4 Enriched BHI agar slant………………………………………………..…… 30
2.2.5 Sabourand’s agar plate………………………………………………...…… 30
2.2.6 10 × PBS buffer……………………………………………………………… 30
2.2.7 Intracellular cytokines staining buffer……………………………………… 31
2.2.8 Intracellular cytokines staining fixation buffer…………………………..… 31
2.2.9 Intracellular cytokines staining permeabilization buffer……………..…… 31
2.2.10 ELISA coating buffer…………………………………………………..…… 32
2.2.11 ELISA blocking buffer……………………………………………………… 32
2.2.12 ELISA washing buffer……………………………………………………… 32
2.2.13 IgE ELISA substrate buffer…………………………………………...…… 32
2.2.14 ELISA stop solution………………………………………………...……… 32
2.2.15 DEPC H2O…………………………………………………………..……… 33
2.2.16 5 × TBE buffer…………………………………………….…………...…… 33
2.2.17 Reagents………………………………………………………………….… 33
2.2.18 Antibodies…………………………………………………………………... 34
2.2.19 Sequences of primers………………………………………………….….. 35
2.2.20 Instruments……………………………………………………………….… 36

Chapter III. Results…………………………………………………………………… 38
3.1 Establishment of type-1 Histoplasma infectious response and type-2 GaMd-induced cytokines response in vivo…………………………………….
39
3.1.1 Histoplasma infection induces a dominant type-1 response…………… 39
3.1.2 GaMd treatment induces a dominant type-2 cytokine response………. 39
3.2 The effect of GaMd-induced type-2 cytokines response on the regulation of Histoplasma infectious type-1 response…………………………….…………
40
3.2.1 GaMd treatment profoundly suppresses Histoplasma-induced IFN-g response………………………………………………………………………
40
3.2.2 GaMd treatment retards fungal clearance……………………………..…. 41
3.2.3 IL-4 is partially responsible for GaMd–induced suppression……………. 42
3.2.4 IL-4 and IL-10 together mediate GaMd–induced suppression of IFN-�� response………………………………………………………………………
43
3.2.5 Reduction of IFN-g-producing T cells is not a result in T cell expansion, T cell death, or intrinsic defect in TCR signaling………………………….
44
3.3 The suppressive effect of GaMd�non the generation of IFN-g-producing cells is transient………………………………………………………………………....
45
3.3.1 The presence of IL-4 and IL-10 at early infectious phase does not change the ultimate polarity of type-1 T cells……………………………..
45

Chapter IV. Discussion……………………………………………………………… 47
4.1 The effects of IL-4 and IL-10 on the regulation of type-1 immune response in different infectious models…………………………………………………..……
48
4.2 GaMd-induced IL-4 and IL-10 regulate the generation of IFN-g-producing cells in response to Histoplasma infection……………………………………..
49
4.3 The effect of IL-4 overexpression on IFN-g production in pulmonary histoplasmosis...............................................................................................
50
4.4 GaMd-induced IL-4 and IL-10 expression on T cell IFN-g production in systemic histoplasmosis………………………………………………………….
50
4.5 The possibility of affecting IL-12 production by IL-4 and IL-10……………….. 51
4.6 The nature and dosage of pathogens may affect the polarity of T cells……… 52
4.7 The T-box gene family transcription factors regulate IFN-g production in CD4+ and CD8+ T cells……………………………………………………………
53
4.8 A negative role of endogenous IL-4 and IL-10 in regulating the generation of IFN-g-producing cells……………………………………………………………..
53
4.9 Conclusion…………………………………………………………………………. 54
References…………………………………………………………………………… 55
Tables and Figures…………………………………………………………………… 74
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