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dc.description.abstract細胞素應用於疫苗佐劑的研究愈來愈受到關注,本研究之目的在表現具生物活性之豬細胞素,包括介白素-2 (interleukin-2, IL-2)、介白素-18 (interleukin-18, IL-18) 以及丙型干擾素 (interferon-gamma, IFN-γ),並分析其做為豬瘟疫苗佐劑之效力。在本研究中,我們完成了豬隻IL-2、IL-18以及IFN-γ之cDNA基因選殖與定序。自杜洛克品系與藍瑞斯/杜洛克混品系豬隻選殖IFN-γ之cDNA株,分別命名為PoIFN-γ-W與PoIFN-γ-M,其中PoIFN-γ-M存在一個Q67R的胺基酸變異。本研究接著將豬的IL-2、IL-18以及 IFN-γ之 cDNAs選殖至pET32載體,並於大腸桿菌中表現重組蛋白,將純化好之重組蛋白利用質譜儀分析 (matrix-assisted laser desorption ionization time-of-flight mass spectrometry, MALDI-TOF MS) 確認其身份。繼而分析 IL-2與IL-18之生物活性,於培養之豬白血球中,加入重組 IL-2 蛋白 (rPoIL-2) 與重組 IL-18蛋白 (rPoIL-18) 進行刺激,之後利用反轉錄-聚合酶鏈反應 (reverse transcription-polymerase chain reaction, RT-PCR) 分析,結果顯示CD25與IFN-γ基因表現會分別受到誘導。rPoIFN-γ-W與rPoIFN-γ-M 兩種蛋白在抑制PK-15細胞之增殖、與刺激豬之血液單核球中一氧化氮 (nitric oxide, NO) 分泌方面皆呈現相當的活性。然而,於假性狂犬病病毒 (pseudorabies virus, PRV) 之病毒斑抑制活性方面,rPoIFN-γ-W蛋白具備較高之病毒抑制能力 (P < 0.001),本研究首度在IFN-γ基因之編碼區(coding region) 發現了對蛋白活性有影響之功能性單核苷酸多形性 (single nucleotide polymorphism, SNP)。 我們隨即於無特定病原 (specific pathogen free, SPF) 豬隻中進行兔化豬瘟減毒疫苗 (Lapinized China strain, LPC) 之動物試驗,分別添加IFN-γ (50 μg 或20 μg)、IL-2 (20 μg)、IL-18 (20 μg) 或 IL-2合併IL-18 (IL-2+IL-18, 各20 μg) 做為LPC疫苗佐劑。流式細胞儀的分析結果顯示高劑量IFN-γ(IFN-γHi, 50 μg) 與IL-2均能顯著增加 (P < 0.05) 接種疫苗豬隻CD4+ T cells之表現,而分別注射IFN-γ、IL-2與IL-2+IL-18做為LPC疫苗佐劑之豬隻其MHC-II+ 細胞亦有顯著上升 (P < 0.01)。此外,IL-2 、IL-18以及IL-2+IL-18皆能促進LPC疫苗之體液性免疫反應 (humoral anamnestic response)。這些結果證明了細胞素IL-2、IL-18與IFN-γ 能做為豬瘟疫苗之良好佐劑。 在本研究中,我們比較豬隻經LPC疫苗與LPC/IFN-γ免疫後之基因表現差異性,利用RT-PCR 以及抑制性扣減雜合法 (suppression subtractive hybridization, SSH) 進行分析,結果顯示免疫注射LPC/IFN-γ之豬隻脾臟細胞中T-cell factor-4 (Tcf-4) 基因的表現會增加,經原位雜合法 (in situ hybridization, ISH) 分析,我們發現在免疫LPC/IFNγLo (20 μg) 與LPC/IFNγHi的豬隻脾臟之生發中心 (germinal center) 與動脈周圍淋巴鞘 (periarterial lymphatic sheath, PALS) 部位,可偵測到Tcf-4基因高度表現,此部位主要組成細胞分別為B細胞與CD4+ 細胞,由於B細胞為抗原呈現細胞,主要將抗原經MHC-II分子呈現給CD4+ T細胞,此結果與我們在流式細胞儀分析中觀察到LPC/IFNγHi免疫後豬隻之CD4+ T 細胞與MHC-II+ 細胞有上升的情形相符。zh_TW
dc.description.abstractThe usages of cytokines as vaccine adjuvants have received growing interest. The specific aims of this study were to express bioactive recombinant porcine cytokines, in particular, interleukin-2 (IL-2), interleukin-18 (IL-18), and interferon-gamma (IFN-γ), and to evaluate their efficacy as vaccine adjuvants against classical swine fever virus (CSFV). In this study, cDNAs of porcine IFN-γ, IL-2, and IL-18 were cloned and sequenced. Porcine IFN-γcDNA clones from Duroc and Landrance/Duroc hybrid were designated as rPoIFN-γ-W and rPoIFN-γ-M, respectively. A novel point mutation that resulted in Q67R replacement of the mature protein was identified in rPoIFN-γ-M. The cDNAs of porcine IL-2, IL-18, and IFN-γ were subcloned into pET32 vector to express the recombinant proteins in Escherichia coli (E. coli). The purified proteins were identified by Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). By performing reverse transcription-polymearse chain reaction (RT-PCR), our in vitro data showed that recombinant porcine IL-2 (rPoIL-2), and IL-18 (rPoIL-18) were able to induce the gene expression of CD25 and IFN-γ in porcine leukocytes, respectively. Recombinant PoIFN-γ-W (rPoIFN-γ-W) and PoIFN-γ-M (rPoIFN-γ-M) proteins exhibited comparable activities in antiproliferation of PK-15 cells and nitric oxide (NO) induction of porcine peripheral monocytes. However, antiviral activity of rPoIFN-γ-W protein was significantly higher (P < 0.001) than that of rPoIFN-γ-M protein as determined by a pseudorabies virus (PRV)-based plaque inhibition assay. This is the first report that shows the functional single nucleotide polymorphism (SNP) in the coding region of IFN-γ. Subsequently, specific pathogen free (SPF) pigs were vaccinated with a live-attenuated CSFV vaccine (Lapinized China strain, LPC), using recombinant porcine IFN-γ (50 μg or 20 μg), IL-2 (20 μg), IL-18 (20 μg), or IL-2 plus IL-18 (IL-2+IL-18, 20 μg each) as the adjuvant. Results of flow cytometric analysis indicated that co-administration of LPC vaccine with IFN-γHi (50 μg) or IL-2 could significantly increase (P < 0.05) the CD4+ T cells in vaccinated pigs. Likewise, MHC-II+ subpopulation was significantly up-regulated (P < 0.01) in vaccinated pigs co-administered with IFN-γHi, IL-2, or IL-2+IL-18. Furthermore, addition of IL-2, IL-18, or IL-2+IL-18 could improve the LPC vaccine to elicit a stronger humoral anamnestic response. These results show that porcine IL-2, IL-18, and IFN-γ may serve as adjuvants for LPC vaccine. Genes that were differentially expressed between pigs receiving LPC and LPC/IFN-γ were explored. By employing suppression subtractive hybridization (SSH) technique and reverse transcription-polymerase chain reaction (RT-PCR), we found that T-cell factor-4 (Tcf-4) gene was up-regulated in splenocytes of pigs receiving LPC/IFN-γ. By in situ hybridization (ISH), we further localized overexpression of Tcf-4 gene in germinal center and periarterial lymphatic sheath (PALS) of the spleen, which mainly comprised B cells and CD4+ T cells respectively, in both LPC/IFNγLo (20 μg) and LPC/IFNγHi groups. Because B cells may serve as antigen presenting cells to present antigen to CD4+ T cells via the MHC-II molecule, the result of ISH corresponded well with our flow cytometric data that MHC-II+ and CD4+ T cells subpopulations were significantly elevated in LPC/IFNγHi group.en_US
dc.description.tableofcontentsTABLE OF CONTENTS Abstract (Chinese) ------------------------------- I Abstract (English) ------------------------------- III Table of Contents -------------------------------- V List of tables ----------------------------------- IX List of figures ---------------------------------- X List of abbreviations ---------------------------- XII Chapter 1 Introduction & Literature reviews ------- 1 1.1. Introduction ---------------------------- 2 1.2. Background of cytokines ----------------- 3 1.3. IL-2 ------------------------------------ 4 1.3.1. Natural functions and synthesis -- 4 1.3.2. Receptors ------------------------ 5 1.3.3. Applications --------------------- 5 1.4. IL-18 ----------------------------------- 6 1.4.1. Natural functions and synthesis -- 6 1.4.2. Receptors ------------------------ 6 1.4.3. Applications --------------------- 7 1.5. IFN-γ ------------------------------------ 8 1.5.1. Natural functions and synthesis -- 8 1.5.2. Receptors ------------------------ 8 1.5.3. Applications --------------------- 9 Chapter 2 Molecular cloning, expression and functional analysis of porcine IL-2 and IL-18 --------------- 10 2.1. Introduction ---------------------------- 11 2.2. Materials and methods ------------------- 13 2.2.1. Isolation and stimulation of porcine leukocytes ----------------------- 13 2.2.2. cDNA synthesis and PCR amplification of PoIL-2 and PoIL-18 --------------- 13 2.2.3. Construction of plasmid pETpoIL-2 and pETpoIL-18 ----------------------- 13 2.2.4. Expression and purification of rPoIL-2 and rPoIL-18 proteins ----------- 14 2.2.5. SDS-PAGE and Western blot analysis - 15 2.2.6. MALDI-TOF MS analysis ------------ 15 2.2.7. Bioactivity assays for rPoIL-2 and rPoIL-18 ------------------------- 15 2.2.8. RNA isolation and RT-PCR --------- 15 2.3. Results --------------------------------- 17 2.3.1. Cloning and sequencing of porcine IL-2 and IL-18 cDNAs ------------ 17 2.3.2. Expression and purification of rPoIL-2 and rPoIL-18 proteins ---- 17 2.3.3. Identification of rPoIL-2 and rPoIL-18 proteins by MALDI-TOF MS analysis --------------------- 17 2.3.4. Induction of CD25 expression by rPoIL-2 in porcine leukocytes ---- 18 2.3.5. Induction of IFN-γ expression by rPoIL-18 in porcine leukocytes --- 18 2.4. Discussion ------------------------------ 19 Chapter 3 A missense polymorphism in porcine IFN-γ cDNA affects antiviral activity of the protein variant 31 3.1. Introduction ---------------------------- 32 3.2. Materials and methods ------------------- 34 3.2.1. Isolation and stimulation of porcine leukocytes -------------- 34 3.2.2. Cloning of PoIFN-γ cDNA variants and construction of rPoIFN-γ expression plasmids -------------- 34 3.2.3. Sequence accession numbers ------- 34 3.2.4. Sequence alignment --------------- 35 3.2.5. Expression and purification of rPoIFN-γ protein variants--------- 35 3.2.6. SDS-PAGE and Western blot analysis 35 3.2.7. MALDI-TOF MS analysis ------------ 35 3.2.8. Plaque inhibition assay for antiviral activity --------------- 36 3.2.9 Antiproliferation assay ----------- 36 3.2.10. NO secretion assay -------------- 37 3.2.11. Statistical analysis ------------ 37 3.3. Results --------------------------------- 38 3.3.1. Cloning and sequencing of PoIFN-γ cDNA variants -------------------- 38 3.3.2. Expression of rPoIFN-γ-W and rPoIFN-γ-M protein variants in E. coli 38 3.3.3. Antiviral activity of rPoIFN-γ protein variants ----------------- 39 3.3.4. Antiproliferation activity of rPoIFN-γ protein variants -------- 40 3.3.5. NO induced in monocytes by rPoIFN-γ protein variants ------- 40 3.4. Discussion ------------------------------ 41 Chapter 4 Immunomodulatory effects of recombinant porcine IL-2, IL-18, and IFN-γ proteins on a live-attenuated vaccine against classical swine fever virus ------ 52 4.1. Introduction ---------------------------- 53 4.2. Materials and methods ------------------- 55 4.2.1. Pig vaccination and challenge ---- 55 4.2.2. Sample collection ---------------- 55 4.2.3. Flow cytometric analysis --------- 55 4.2.4. Antibody detection --------------- 56 4.2.5. SSH ------------------------------ 56 4.2.6. RT-PCR --------------------------- 56 4.2.7. ISH ------------------------------ 57 4.2.8. Fluorescence immunohistochemistry 57 4.2.9. Statistical analysis ------------- 58 4.3. Results --------------------------------- 59 4.3.1. Vaccination, challenge, and clinical observation ---------------------- 59 4.3.2. Virus detection ------------------ 59 4.3.3. Flow cytometry analysis ---------- 59 4.3.4. Induction of humoral response ---- 60 4.3.5. Differential gene expression in pigs receiving IFN-γ as adjuvant for LPC vaccine ------------------ 60 4.4. Discussion ------------------------------ 62 Chapter 5 Discussion & future directions ---------- 71 References --------------------------------------- 76zh_TW
dc.titleExpression and Evaluation of Porcine Interleukin-2, Interleukin-18 and Interferon-gamma as Adjuvants for a Live-attenuated Vaccine against Classical Swine Fever Virusen_US
dc.typeThesis and Dissertationzh_TW
Appears in Collections:微生物暨公共衛生學研究所


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