TIM-1, TIM-3 and TIM-4: A gene family that regulates tolerance and immunity

TIM-1、TIM-3 和 TIM-4:调节耐受性和免疫性的基因家族

基本信息

  • 批准号:
    8380754
  • 负责人:
  • 金额:
    $ 31.71万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-09-30 至
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY (See instructions): The TIM gene family was identified using a congenic mouse model in which polymorphisms in TIM-1 and TIM-3 wre associated with Th1-Th2 differentiation and allergen-induced ainway hyperreactivity (AHR) between BALB/c and congenic HBA mice. The long-term goals of Project 3 are to understand how the Tim genes regulate peripheral tolerance, adaptive immune responses, and allergy. In the previous grant period we showed that TIM-1 is an important costimulatory molecule for T cells, that TIM-1 and TIM-4 modulate T cell responses and the development of tolerance, and that TIM-1 and TIM-4 are receptors for phosphatidylserine (PtdSer), a key molecule for recognition and uptake of apoptotic cells. We have found that TIM-3, expressed on Th1 cells and APC, is also a receptor for PtdSer and that the allelic variants of TIM-3 associated with asthma differ in their recognition of PtdSer. These results together suggest a new paradigm for TIM proteins as PtdSer receptors that by regulating the recognition and clearance of apoptotic cells, can regulate tissue homeostasis, T cell responses and the induction of peripheral tolerance. In Specific Aim 1 we will determine the mechanisms by which TIM-4 expressed on APC, and TIM-1, expressed on activated T cells and Th2 cells, regulate oral tolerance and prevent food allergy. We will examine mechanisms by which TIM-4 blockade inhibits oral tolerance induction. In Specific Aim 2, we will characterize the cell types and APC subset(s) in the lamina propria and mesenteric lymph node that express TIM-4, the conditions that modulate expression of TIM-3 and TIM-4 following exposure to danger signals such as bacterial products that initiate food allergy. We will examine the consequences of T cell interaction with TIM-expressing APC on T cell subset differentiation. In Specific Aim 3 we will investigate the role of TIM-3 polymorphic variants, which we have recently shown differ in recognition of apoptotic cells, in modulation of immune responses in BALB/c and HBA mice, and determine the roles of TIM-1 and TIM-3 in modulating the development of airway hyperreactivity in these strains. We have developed unique reagents that will enable us to accomplish these goals. We have generated panels of anti-TIM-1 and TIM-4 mAbs, we have generated TIM-4 and TIM-1 transgenic mice, and TlM-1 deficient mice are now breeding in our colony. Our laboratory has extensive experience in the study of tolerance as a mechanism that protects against Th2-driven immune responses and in the study of dendritic cells (DCs) and antigen-specific CD4+ Tpeg cells. These studies will greatly improve our understanding of immune regulation and lead to new therapies for inflammatory diseases.
项目总结(见说明): 使用同源小鼠模型鉴定TIM基因家族,其中TIM-1中的多态性 TIM-3与BALB/c和HBA小鼠Th 1-Th 2分化和变应原诱导的气道高反应性(AHR)有关。项目3的长期目标是了解Tim基因如何调节外周耐受、适应性免疫反应和过敏。在上一个资助期,我们表明TIM-1是T细胞的一种重要共刺激分子,TIM-1和TIM-4调节T细胞反应和耐受性的发展,TIM-1和TIM-4是磷脂酰丝氨酸(PtdSer)的受体,磷脂酰丝氨酸是识别和摄取凋亡细胞的关键分子。我们已经发现,TIM-3,表达在Th 1细胞和APC,也是PtdSer的受体,并与哮喘相关的TIM-3的等位基因变异体在他们的PtdSer的识别不同。这些结果共同表明了TIM蛋白作为PtdSer受体的新范例,其通过调节凋亡细胞的识别和清除,可以调节组织稳态、T细胞应答和外周耐受的诱导。 在具体目标1中,我们将确定TIM-4在APC上表达的机制,以及TIM-1, 在活化的T细胞和Th 2细胞上表达,调节口服耐受和预防食物过敏。我们将 研究TIM-4阻断抑制口服耐受诱导的机制。在特定目标2中,我们将表征固有层和肠系膜淋巴结中表达TIM-4的细胞类型和APC亚群,这是暴露于危险信号(如引发食物过敏的细菌产物)后调节TIM-3和TIM-4表达的条件。我们将研究T细胞与表达TIM的APC相互作用对T细胞亚群分化的影响。在特定目标3中,我们将研究TIM-3多态性变体的作用,我们最近发现TIM-3多态性变体在识别凋亡细胞、调节BALB/c和HBA小鼠的免疫应答方面存在差异,并确定TIM-1和TIM-3在调节这些菌株中气道高反应性发展方面的作用。 我们开发了独特的试剂,使我们能够实现这些目标。我们有 在制备了抗TIM-1和TIM-4 mAb的组之后,我们已经制备了TIM-4和TIM-1转基因小鼠,并且T1 M-1缺陷型小鼠现在正在我们的群体中繁殖。我们的实验室在耐受性研究方面拥有丰富的经验,耐受性是一种保护免受Th 2驱动的免疫应答的机制,并且在树突状细胞(DC)和抗原特异性CD 4 + Tpeg细胞的研究中具有丰富的经验。这些研究将大大提高我们对免疫调节的理解,并为炎症性疾病带来新的治疗方法。

项目成果

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Rosemarie H DeKruyff其他文献

Rosemarie H DeKruyff的其他文献

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{{ truncateString('Rosemarie H DeKruyff', 18)}}的其他基金

TIM recognition of PtdSer on apoptotic cells and the regulation of immunity
TIM对凋亡细胞PtdSer的识别及免疫调节
  • 批准号:
    8495892
  • 财政年份:
    2010
  • 资助金额:
    $ 31.71万
  • 项目类别:
TIM recognition of PtdSer on apoptotic cells and the regulation of immunity
TIM对凋亡细胞PtdSer的识别及免疫调节
  • 批准号:
    8704253
  • 财政年份:
    2010
  • 资助金额:
    $ 31.71万
  • 项目类别:
TIM recognition of PtdSer on apoptotic cells and the regulation of immunity
TIM对凋亡细胞PtdSer的识别及免疫调节
  • 批准号:
    8082683
  • 财政年份:
    2010
  • 资助金额:
    $ 31.71万
  • 项目类别:
TIM recognition of PtdSer on apoptotic cells and the regulation of immunity
TIM对凋亡细胞PtdSer的识别及免疫调节
  • 批准号:
    7949426
  • 财政年份:
    2010
  • 资助金额:
    $ 31.71万
  • 项目类别:
TIM recognition of PtdSer on apoptotic cells and the regulation of immunity
TIM对凋亡细胞PtdSer的识别及免疫调节
  • 批准号:
    8288920
  • 财政年份:
    2010
  • 资助金额:
    $ 31.71万
  • 项目类别:
TIM-1, TIM-3 and TIM-4: A gene family that regulates tolerance and immunity
TIM-1、TIM-3 和 TIM-4:调节耐受性和免疫性的基因家族
  • 批准号:
    8306826
  • 财政年份:
    2003
  • 资助金额:
    $ 31.71万
  • 项目类别:
TIM-1, TIM-3 and TIM-4: A gene family that regulates tolerance and immunity
TIM-1、TIM-3 和 TIM-4:调节耐受性和免疫性的基因家族
  • 批准号:
    7995554
  • 财政年份:
    2003
  • 资助金额:
    $ 31.71万
  • 项目类别:
TIM-1, TIM-3 and TIM-4: A gene family that regulates tolerance and immunity
TIM-1、TIM-3 和 TIM-4:调节耐受性和免疫性的基因家族
  • 批准号:
    8831793
  • 财政年份:
    2003
  • 资助金额:
    $ 31.71万
  • 项目类别:
TIM-1, TIM-3 and TIM-4: A gene family that regulates tolerance and immunity
TIM-1、TIM-3 和 TIM-4:调节耐受性和免疫性的基因家族
  • 批准号:
    8507123
  • 财政年份:
    2003
  • 资助金额:
    $ 31.71万
  • 项目类别:
Differential Activation Requirements of CD4+ T Cells
CD4 T 细胞的差异激活要求
  • 批准号:
    6382727
  • 财政年份:
    2001
  • 资助金额:
    $ 31.71万
  • 项目类别:

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