Immune Responses To Ocular Antigens
对眼抗原的免疫反应
基本信息
- 批准号:8149128
- 负责人:
- 金额:$ 143.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Targeted at learning about pathogenic processes of inflammatory eye diseases, this project focused in FY 2010 on populations of T-cells involved in these processes. We investigated two populations of recently identified T-helper cells, specifically producing IL-17 ("Th17" cells), or IL-9 ("Th9" cells). In addition, we analyzed the role of the SLAT/Def6 gene in immune-mediated ocular inflammation.
1) Th17 Cells. We extended our studies aimed at further analysis of the immunobiological features of the two subpopulations of Th17 cells. In previous studies, detailed in our FY 2008 and FY 2009 Reports we described new procedures we developed for the generation of the two subpopulations of Th17 cells, one pathogenic the other is not. The experimental system we use consists of two lines of transgenic mice. T-cells of one line, designated 3A9, express T-cell receptor (TCR) specific against hen egg lysozyme (HEL), while mice of the other line, named HEL-Tg, express HEL in their eyes. When acquiring pathogenicity, T-cells of the 3A9 line induce inflammation in eyes of the HEL-Tg recipients. The pathogenic subpopulation of Th17 cells is generated by activation of naive CD4 lymphocytes of 3A9 mice with HEL and antigen-presenting cells (APC), whereas the non-pathogenic subpopulation is generated by activation of the naive CD4 lymphocytes by antibodies against the surface molecules CD3 and CD28. Both subpopulations are polarized by incubation with the cytokines IL-6 and TGF-beta. This study was extended in FY 2010 as described below.
(i) Cells of the pathogenic subpopulation produce large amounts of the cytokine IL-22. To examine the possibility that IL-22 participates in the pathogenic effects of these cells, we treated recipients of the cells with antibody against IL-22. The antibody had no effect on the pathogenic effect of the Th17 cells, thus suggesting that IL-22 plays no significant role in the pathogenic capacity.
(ii) Immunostaining of the pathogenic Th17 cell line revealed a clear separation between cells that produce IL-22 and those that produce IL-17. This observation thus suggests the existence of a subset within the subpopulation of pathogenic "Th17", that selectively produces IL-22. It is of note that T-helper cell lines specifically producing IL-22 were described with human cells, but not with mouse cells and our study thus identifies for the first time IL-22 producing mouse T-cells.
(iii) Published studies indicate that IL-23 is critical for the generation of pathogenic Th17. To investigate the participation of IL-23 in the generation of pathogenic Th17 in our system we added this cytokine to cultures in which non-pathogenic Th17 were generated (by activation with plate-bound antibodies). No pathogenicity was generated in these cultures. In contrast, addition of APC and HEL to these cultures did generate pathogenicity. We further showed that the activity of APC/HEL is apparently mediated by cell-cell activation, rather than release of IL-23, since the induction of pathogenicity was not affected by addition of anti-IL-23 antibody to the culture medium.
(iv) The non-pathogenic subpopulation of Th17 exhibited a moderate level of immunoregulatory activity, shown by their capacity to inhibit the pathogenic effect of the pathogenic Th17 cells.
2. Th9 cells. Our FY 2009 Report summarized our preliminary observations concerning Th9 cells, lymphocytes that specifically produce the cytokine IL-9. Research carried out in 2010 yielded the following new information:
(i) Further analysis of the Th9 pathogenicity revealed that these cells do induce ocular inflammation when adoptively transferred into recipient mice expressing the target antigen (HEL) in their eyes, but only when tested on day 3 in culture, at the peak of the IL-9 production. Importantly, no disease was induced by Th9 cells harvested just one day later (day 4), at the time point when IL-9 production was sharply reduced, as recorded in our FY 2009 Report.
(ii) Analysis of the cells infiltrating the inflamed recipient mouse eyes revealed that, unlike observations with Th1- or Th17- induced ocular inflammation, no IL-9 producing cells were detected in eyes with Th9-induced inflammation. This finding is in line with the observation we made previously (recorded in FY 2009), that IL-9 production is unusually short lived following the cell activation. This assumption is also supported by our finding that Th cells expressing IL-9 were detected in the recipient blood, where no target antigen is present and no activation could take place.
(iii) Th9 cells retain their phenotype, despite the reduction in IL-9 production following activation. This feature was indicated by our finding that re-stimulation of Th9 cells expressing no detectable IL-9 (following extended time in culture) responded by a typical secondary immune response, of IL-9 production at faster pace and higher levels than those of the primary response.
(iv) Incubating Th9 cells in media with polarizing cytokine specific for other Th phenotypes revealed low levels of switching to Th1 or Th17 phenotypes, but considerable switching levels to the Th2 phenotype.
3. Participation of the SLAT/Def6 gene in immune-mediated ocular inflammation. The essential role of the SLAT/Def6 gene in pathogenic immune processes was demonstrated in studies with mice deficient in this gene, that were found to be inferior to wild-type controls in their capacity to develop cell-mediated immune response. We are developing a colony of the SLAT/Def6 deficient mice and preliminary data show that their capacity to develop experimental autoimmune uveitis (EAU) is significantly lower than that of their wild-type controls.
该项目针对学习炎症性眼部疾病的致病过程,集中于2010财年,这些项目涉及这些过程中涉及的T细胞种群。我们研究了两个最近鉴定出的T-辅助细胞的种群,特别是产生IL-17(“ Th17”细胞)或IL-9(“ TH9”细胞)。此外,我们分析了SLAT/DEF6基因在免疫介导的眼部炎症中的作用。
1)Th17细胞。我们扩展了旨在进一步分析Th17细胞两个亚群的免疫生物学特征。在以前的研究中,在我们的2008财年和2009财年的报告中详细介绍了我们为生成Th17细胞两个亚群开发的新程序,一种致病性不是。我们使用的实验系统由两条转基因小鼠组成。一条线的T细胞,指定为3A9,针对母鸡溶菌酶(HEL)的特异性T型T细胞受体(TCR),而另一条名为Hel-TG的小鼠在他们的眼中表达HEL。在获得致病性时,3A9线的T细胞会引起HEL-TG受体眼睛的炎症。 Th17细胞的致病性亚繁殖是通过用HEL和抗原呈现细胞(APC)激活3A9小鼠的幼稚CD4淋巴细胞(APC)而产生的,而非致病亚种群是通过抗抗体CD3和CD3和CD3和CD3和CD3和CD3的抗体激活而产生的。两种亚群都通过与细胞因子IL-6和TGF-β孵育。如下所述,这项研究在2010财年进行了扩展。
(i)致病性亚群的细胞产生大量的细胞因子IL-22。为了检查IL-22参与这些细胞的致病作用的可能性,我们用抗IL-22的抗体治疗了细胞的受体。该抗体对Th17细胞的致病作用没有影响,因此表明IL-22在致病能力中没有重要作用。
(ii)致病性TH17细胞系的免疫染色显示产生IL-22的细胞与产生IL-17的细胞之间存在明显的分离。因此,该观察结果表明在病原“ Th17”的亚群中存在一个子集,该子群有选择地产生IL-22。值得注意的是,用人类细胞描述了特异性产生IL-22的T-辅助细胞系,但没有用小鼠细胞描述,因此我们的研究首次鉴定出产生小鼠T细胞的IL-22。
(iii)发表的研究表明,IL-23对于致病性TH17的产生至关重要。为了研究IL-23在系统中的致病性Th17产生中的参与,我们将这种细胞因子添加到了非致病性Th17的培养物中(通过使用板块结合的抗体激活)。在这些培养物中未产生致病性。相反,在这些培养物中添加APC和HEL确实会产生致病性。我们进一步表明,APC/HEL的活性显然是由细胞细胞激活而不是释放IL-23介导的,因为致病性的诱导不受添加到培养基中的抗IL-23抗体的影响。
(iv)TH17的非致病亚种群表现出中等水平的免疫调节活性,这表明其能力抑制致病性TH17细胞的致病作用。
2。Th9细胞。 我们的2009财年报告总结了有关TH9细胞的初步观察,该观察是特异性产生细胞因子IL-9的淋巴细胞。 2010年进行的研究产生了以下新信息:
(i)对TH9致病性的进一步分析表明,这些细胞确实会诱发眼部炎症,而当他们眼中表达靶抗原(HEL)的受体小鼠时,只有在IL-9产生的峰值的第3天进行培养物测试时,才会诱发眼部炎症。重要的是,正如我们2009财年的报告所记录的那样,在一天后(第4天)收获的TH9细胞(第4天)收获的Th9细胞没有诱发的疾病。
(ii)分析浸润受发炎受体小鼠眼睛的细胞的分析表明,与Th1-或Th17诱导的眼部炎症的观察不同,在具有TH9诱导的炎症的眼中未检测到IL-9产生的细胞。这一发现与我们先前对的观察结果一致(2009财年记录),IL-9的产生在细胞激活后生存异常短。我们的发现也支持了这种假设,即在受体血液中检测到表达IL-9的细胞,那里不存在靶抗原,也不会激活。
(iii)尽管激活后IL-9产生降低,但TH9细胞仍保留其表型。我们的发现表明了这一特征,即对未检测到的IL-9(培养时间延长)的TH9细胞的重新刺激是由典型的次级免疫反应响应,比初级反应的典型次级免疫反应,IL-9产生的速度和更高的水平。
(iv)在培养基中孵育Th9细胞具有针对其他表型的偏振细胞因子的偏振细胞因子,发现切换到TH1或TH17表型的水平较低,但切换水平相当大,可以向TH2表型。
3。SLAT/DEF6基因参与免疫介导的眼部炎症。在缺乏该基因的小鼠的研究中,SLAT/DEF6基因在致病性免疫过程中的基本作用证明了其以野生型对照的较低,以开发细胞介导的免疫反应的能力。我们正在开发一个SLAT/DEF6缺乏小鼠的菌落,初步数据表明,它们开发实验性自身免疫性葡萄膜炎(EAU)的能力明显低于其野生型对照。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Igal Gery其他文献
Igal Gery的其他文献
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{{ truncateString('Igal Gery', 18)}}的其他基金
Immune-related mechanisms in the pathogenic processes of retinal degeneration
视网膜变性发病过程中的免疫相关机制
- 批准号:
8737672 - 财政年份:
- 资助金额:
$ 143.6万 - 项目类别:
Immune-related mechanisms in the pathogenic processes of retinal degeneration
视网膜变性发病过程中的免疫相关机制
- 批准号:
9155604 - 财政年份:
- 资助金额:
$ 143.6万 - 项目类别:
Expression of immune-related molecules in the normal and diseased eye
正常和患病眼睛中免疫相关分子的表达
- 批准号:
7594098 - 财政年份:
- 资助金额:
$ 143.6万 - 项目类别:
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