Analysis of Pathogenic T Cell Response in MS

MS 中致病性 T 细胞反应的分析

• 批准号: 7035573
• 负责人: David A. Hafler
• 金额: $ 36万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035573
• 关键词: cytokine; tissues; transcription factor

Description (provided by applicant): Mice that lack T-bet, a Th1 transcription factor that controls Th1 lineage commitment, are almost completely protected from developing EAE, a mouse model of multiple sclerosis. However, the degree of protection afforded by loss of T-bet cannot be attributed solely to the loss of the hallmark Th1 cytokine, IFN-y, since mice lacking IFN-y, IFN-yR or Stall actually develop more severe EAE than controls. This discrepancy may be partly attributed to the simultaneous function of T-bet in profoundly inhibiting the production of the protective cytokines IL-4, IL-10 and TGF|3 as well as a function for T-bet in controlling migration and adhesion of effector Th1 cells. It may also relate to a role for T bet in the terminal maturation of NK cells. Thus mice that lack T-bet have a marked increase in Th2 cells, and in levels of two immunosuppressive cytokines, TGFp and IL-10. In contrast, T-bet-/- mice have reduced numbers of mature NK cells and lack NK T cells altogether. T-bet-/- Th1 cells also have altered patterns of expression of certain chemokines and chemokine receptors. Of special interest to us therefore is a further exploration of the factors that account for the striking difference in susceptibility to EAE between T-bet and Statl deficient mice. This will require identification of the cell types, cytokines, chemokines and adhesion molecules involved in mediating protection vs. susceptibility to EAE in these transcription factor mutant strains, and also includes exploring the mechanism by which T-bet inhibits the production of TGFp and IL-10. Whatever the mechanisms, however, the very profound effects of loss of T-bet on EAE warrant a search to establish whether polymorphisms in T-bet are associated with human MS. In contrast to IFN-y and IL-4, little is known about the transcription factors that control the tissue specific expression of the IL-10 gene. This is an important deficiency as a role for this highly immunosuppressive cytokine in autoimmune diseases and in EAE in particular has been well documented and exceeds that of IL-4. We propose to study the regulation of the IL-10 gene in T cells and to identify the transcription factors that directly control its tissue-specific expression. We have three Specific Aims: 1- Explore the basis for the different EAE susceptibility of T-bet- versus Statl deficient mice; 2- Investigate the function of T-bet in Th2 and T regulatory cells; 3- Establish the basis for tissue specific regulation of the IL-10.

描述（申请人提供）： 缺乏T-bet（一种控制Th 1谱系定型的Th 1转录因子）的小鼠几乎 EAE是一种多发性硬化症的小鼠模型。然而，由T-bet的损失提供的保护程度不能仅仅归因于标志性Th 1细胞因子IFN-γ的损失，因为缺乏IFN-γ、IFN-γ R或Stall的小鼠实际上比对照组发展更严重的EAE。这种差异可能部分归因于T-bet同时具有显著抑制保护性细胞因子IL-4、IL-10和TGF-β产生的功能。|3以及T-bet在控制效应Th 1细胞的迁移和粘附中的功能。这也可能与T bet在NK细胞终末成熟中的作用有关。因此，缺乏T-bet的小鼠的Th 2细胞和两种免疫抑制细胞因子TGF β和IL-10的水平显著增加。相比之下，T-bet-/-小鼠的成熟NK细胞数量减少，完全缺乏NK T细胞。T-bet-/-Th 1细胞也具有某些趋化因子和趋化因子受体的表达模式改变。因此，我们特别感兴趣的是进一步探索解释T-bet和Statl缺陷小鼠之间对EAE的易感性的显著差异的因素。这将需要鉴定参与介导这些转录因子突变株中对EAE的保护与易感性的细胞类型、细胞因子、趋化因子和粘附分子，并且还包括探索T-bet抑制TGF β和IL-10产生的机制。然而，无论机制如何，T-bet的损失对EAE的非常深远的影响保证搜索，以建立T-bet的多态性是否与人类MS。与IFN-γ和IL-4相反，很少有人知道的转录因子，控制IL-10基因的组织特异性表达。这是一个重要的缺陷，因为这种高度免疫抑制性细胞因子在自身免疫性疾病中的作用，特别是在EAE中的作用已经被充分证明，并且超过了IL-4。我们建议研究IL-10基因在T细胞中的调节，并确定直接控制其组织特异性表达的转录因子。我们有三个具体目标：1-探索T-bet-与Statl缺陷小鼠的不同EAE易感性的基础; 2-研究T-bet在Th 2和T调节细胞中的功能; 3-建立IL-10的组织特异性调节的基础。