本文關(guān)鍵詞：胸腺基質(zhì)淋巴細(xì)胞生成素在免疫應(yīng)答反應(yīng)中的新功能　出處：《浙江大學(xué)》2012年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 胸腺基質(zhì)淋巴細(xì)胞生成素 調(diào)節(jié)性T細(xì)胞 樹突狀細(xì)胞 脂多糖 Th2細(xì)胞 Th9細(xì)胞 白細(xì)胞介素9 過敏性呼吸道炎癥

【摘要】：胸腺基質(zhì)淋巴細(xì)胞生成素(thymic stromal lymphopoietin, TSLP)是一種上皮細(xì)胞來源的細(xì)胞因子,通過作用于髓樣和淋巴樣細(xì)胞,協(xié)調(diào)天然免疫和適應(yīng)性免疫,在起始和促進(jìn)Th2細(xì)胞介導(dǎo)的過敏性炎癥中起至關(guān)重要的作用。隨著研究的不斷深入,TSLP作為哮喘和其它過敏性疾病的新型治療靶標(biāo)逐漸成為可能。考慮到促炎因子和炎癥因子在多種組織中引起TSLP生成,TSLP極有可能在除了由Th2細(xì)胞介導(dǎo)的疾病之外的其它炎癥中,有更廣泛的作用。在本論文中,我們進(jìn)一步研究了TSLP在過敏性炎癥致病機(jī)理中的作用,特別是對(duì)調(diào)節(jié)呼吸道免疫耐受和過敏性炎癥之間平衡所起的作用,以及TSLP在LPS介導(dǎo)的Th2型炎癥中的作用,并研究了在過敏性呼吸道炎癥中,TSLP能否促進(jìn)產(chǎn)生IL-9的Th9細(xì)胞的分化和功能。 在外周系統(tǒng)中誘導(dǎo)產(chǎn)生抗原特異性的調(diào)節(jié)性T細(xì)胞(iTreg)是維持針對(duì)無害抗原的黏膜免疫耐受的重要機(jī)制。在本研究中,我們發(fā)現(xiàn)在小鼠外周系統(tǒng)中,TSLP抑制了iTreg的生成,其抑制作用大小呈劑量依賴關(guān)系。與此相應(yīng),在患異位性皮炎(atopic dermatitis)的兒童中,其血清中的TSLP水平顯著增加。因此,TSLP抑制呼吸道免疫耐受并造成過敏原致敏,從而導(dǎo)致過敏性呼吸道炎癥發(fā)生的重要機(jī)理之一是TSLP抑制了iTreg的分化。 針對(duì)無害抗原,TSLP是否以及如何誘生Th2細(xì)胞分化,仍不十分清楚。使用OVA和LPS的小鼠鼻腔致敏模型,我們發(fā)現(xiàn)TSLP信號(hào)僅在低濃度LPS誘導(dǎo)的Th2細(xì)胞偏向的呼吸道炎癥中所必需,而不被高濃度LPS所誘導(dǎo)的Thl型炎癥所需要。我們進(jìn)一步闡明了,低濃度LPS活化成熟的骨髓來源的樹突狀細(xì)胞(BMDC)表達(dá)相對(duì)高水平的Tslp和低水平的Il12a,并以依賴于TSLP的方式誘導(dǎo)初始DO11.10T細(xì)胞分化成Th2細(xì)胞。當(dāng)過繼轉(zhuǎn)移至野生型受體小鼠時(shí),低濃度LPS和OVA激活的DC誘導(dǎo)嗜酸性粒細(xì)胞主導(dǎo)的呼吸道炎癥,當(dāng)Tslp缺失的DC被轉(zhuǎn)移時(shí),在受體小鼠中誘生嗜中性粒細(xì)胞主導(dǎo)的呼吸道炎癥。這些數(shù)據(jù)表明,在低濃度LPS的刺激下,DC產(chǎn)生的TSLP在誘導(dǎo)Th2細(xì)胞的分化中起重要作用,并因此表明,除了抗原/MHCII和共刺激分子之外,TSLP可作為抗原提呈細(xì)胞來源的第三方極化信號(hào),來引導(dǎo)效應(yīng)T細(xì)胞的分化。 我們發(fā)現(xiàn)在體外培養(yǎng)Th9細(xì)胞時(shí),TSLP會(huì)使Th9細(xì)胞增加IL-9的表達(dá),且IL-9的表達(dá)量與TSLP劑量呈正相關(guān)。過繼轉(zhuǎn)移OVA特異性的Th2或Th9細(xì)胞至野生型受體中,用OVA或OVA+TSLP呼吸道激發(fā)后,TSLP增強(qiáng)了注射Th9細(xì)胞的小鼠的IL-9表達(dá)及其過敏性炎癥,卻對(duì)被轉(zhuǎn)移Th2細(xì)胞的小鼠影響甚微�？笽L-9抗體處理被轉(zhuǎn)移Th9細(xì)胞的受體小鼠,則顯著降低其肺部炎癥。TSLP甚至在TSLP受體缺失的受體小鼠中仍能增強(qiáng)Th9細(xì)胞介導(dǎo)的呼吸道炎癥,這表明TSLP在體內(nèi)對(duì)Th9細(xì)胞有直接作用。進(jìn)一步的研究表明,在肺部特異性表達(dá)的轉(zhuǎn)基因TSLP刺激肺部產(chǎn)生IL-9,而用抗IL-9抗體處理則減弱了TSLP引發(fā)的呼吸道炎癥。綜上所述,我們的研究揭示了TSLP促進(jìn)Th9細(xì)胞的分化和功能,并表明了IL-9在TSLP介導(dǎo)的過敏性炎癥中必不可少。
[Abstract]:Thymic stromal lymphopoietin (thymic stromal, lymphopoietin, TSLP) is a cytokine derived from epithelial cells, by acting on myeloid and lymphoid cells that coordinate innate immunity and adaptive immunity, in the initiation and promotion play an important role in Th2 cell mediated allergic inflammation. With the deepening of the study, as TSLP a new target for treatment of asthma and other allergic diseases has become possible. Considering the production of proinflammatory cytokines and inflammatory factors induced by TSLP generated in a variety of tissues, TSLP is very likely in addition to other inflammation mediated by Th2 cells in disease have a broader role. In this thesis, we further study the role of TSLP in pathogenesis of allergic inflammation, especially on the regulation of immune tolerance between respiratory and allergic inflammation and balance the role of TSLP in Th2 mediated by LPS The role of inflammation and the ability of TSLP to promote the differentiation and function of Th9 cells that produce IL-9 in allergic respiratory inflammation.
Induced in the peripheral system for generating antigen-specific regulatory T cells (iTreg) is an important mechanism to maintain the mucosal immune tolerance to innocuous antigens. In this study, we found that in mouse peripheral system, TSLP inhibited the formation of iTreg, its inhibitory effect is dose dependent relationship with this. Accordingly, in patients with atopic dermatitis (atopic dermatitis) in children, the serum level of TSLP was significantly increased. Therefore, TSLP inhibited the immune tolerance and cause respiratory allergen sensitization, which leads to an important mechanism of allergic airway inflammation is one of the TSLP inhibited the differentiation of iTreg.
According to innocuous antigens, whether and how TSLP induced Th2 cell differentiation remains unclear. Mouse nasal hypersensitivity model using OVA and LPS, we found that the required airway inflammation induced by TSLP signaling only in the low concentration of LPS in Th2 cells without being biased, Thl type inflammation induced by high concentration of LPS we need to further clarify. The low concentration of LPS activation and maturation of bone marrow derived dendritic cells (BMDC) express relatively high levels of Tslp and low levels of Il12a, and induce the initial differentiation of DO11.10T cells into Th2 cells in a TSLP dependent manner. When the adoptive transfer to the wild-type receptor in mice, eosinophilic airway inflammation acid granulocyte dominated by low concentrations of LPS and OVA activated DC, when the deletion of the Tslp DC was transferred, in recipient mice induced eosinophilic airway inflammation neutrophil dominant. These data suggest that LPS stimulation at low concentrations The TSLP produced by DC plays an important role in the differentiation of Th2 cells. Therefore, TSLP can be used as the third party polarized signal from antigen presenting cells to guide the differentiation of T cells, except for /MHCII and costimulatory molecules.
We found that Th9 cells cultured in vitro, TSLP can make Th9 cells increase the expression of IL-9, expression of IL-9 and TSLP was dose related. The adoptive transfer of Th2 or Th9 cells to wild-type receptor specific OVA, OVA or OVA+TSLP stimulate the respiratory tract, TSLP enhanced the expression of IL-9 injection of Th9 cells in mice and the allergic inflammation, but little effect on mice were transferred Th2 cells. Anti IL-9 antibody treated by transfer of Th9 cell receptor in mice, significantly reduced the lung inflammation even in the absence of the TSLP receptor.TSLP receptor in mice can enhance airway inflammation mediated by Th9 cells, suggesting that TSLP has a direct effect in vivo. On Th9 cells. Further studies showed that IL-9 TSLP expression in transgenic lung specific stimulation of the lungs, and the use of anti IL-9 antibody treatment attenuates airway inflammation induced by TSLP. In summary, our research The study reveals that TSLP promotes the differentiation and function of Th9 cells, and indicates that IL-9 is essential in the allergic inflammation mediated by TSLP.

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類號(hào)】：R392

【共引文獻(xiàn)】

相關(guān)博士學(xué)位論文 前1條

1 昌薇;TSLP在動(dòng)脈粥樣硬化炎癥反應(yīng)中的作用和機(jī)制[D];華中科技大學(xué);2012年

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本文編號(hào)：1373265