Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/66394
標題: 表現豬介白素-2、介白素-18與丙型干擾素並評估其做為豬瘟活減毒疫苗佐劑之效力
Expression and Evaluation of Porcine Interleukin-2, Interleukin-18 and Interferon-gamma as Adjuvants for a Live-attenuated Vaccine against Classical Swine Fever Virus
作者: 范怡馨
Fan, Yi-Hsin
關鍵字: IL-2;介白素-2;IL-18;IFN-γ;adjuvant;CSFV;cytokine;介白素-18;丙型干擾素;佐劑;典型豬瘟病毒;細胞素
出版社: 獸醫微生物學研究所
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摘要: 
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。

The 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.
URI: http://hdl.handle.net/11455/66394
其他識別: U0005-0402200809561900
Appears in Collections:微生物暨公共衛生學研究所

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