Studies of Antigen Stimulation

抗原刺激的研究

基本信息

  • 批准号:
    7846477
  • 负责人:
  • 金额:
    $ 3.74万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-06-19 至 2010-09-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The purpose of our research is to explain antigen presentation by class II MHC molecules having a strong biochemical, quantitative and mechanistic foundation in order to avoid the many empiricisms that dominate this complex area. We investigated how the model protein antigen hen egg-white lysozyme (HEL) was processed by antigen presenting cells (APC); and established the chemical basis for the processing, selection by, and binding of, its various peptides to I-Ak molecules. This now places us in a situation where these parameters can be strictly related to the biology of the T cell response, i.e. to the specificities and frequencies of HEL clones. The first aim of this renewal is to examine post translational modification of the HEL peptides induced when APC are activated by cytokines. Evidence is presented that activated APC can modify HEL to generate specific T cells to the modified peptides. The initial focus of examination is on HEL peptides in which their tyrosines and tryptophans are nitrated (or oxidized). The plans are to characterize the specificities of the T cells, the biology of the APC that induces the changes, and the biochemical nature of the changes using mass spectrometry approaches. The biology of the T cells to modified peptides will be examined in mice bearing a T cell receptor as a transgene; we intend to identify the possible role of the T cells in inflammation and tissue pathology focusing on beta cells expressing HEL. In the second aim, an explanation is sought for why the response to the various HEL epitopes does not relate to the number of peptide-MHC complex presented by APC. We can quantitate the density of the various peptide-MHC complexes from HEL: those represented at a high level induce about the same number of T cells as those presented at about one- or two-hundred fold less. We consider a possible number of explanations such as molecular competition, competition or cooperativity of the complexes on APC surface, the time of persistence of the complexes, and finally the modulating presence of the murine lysozyme, a strong cross-reactive protein expressed normally on APC. By knowing these important variables, we should be able to have a much fuller understanding of the CD4 T cell responses. The experiments are based on; i) using HEL molecules with relevant biochemical changes that alter either epitope expressions or the persistence of an epitope in APC, ii) tracing the cellular response with TCR receptor transgenic mice to more than one epitope, iii) using APC in transfer systems; and, iv) genetically ablating the murine lysozyme gene.
描述(由申请人提供):我们研究的目的是解释具有强大生化、定量和机制基础的 II 类 MHC 分子的抗原呈递,以避免主导这一复杂领域的许多经验主义。我们研究了抗原呈递细胞(APC)如何加工模型蛋白抗原母鸡蛋白溶菌酶(HEL);并建立了其各种肽与 I-Ak 分子的加工、选择和结合的化学基础。现在,我们处于这样一种情况:这些参数可以与 T 细胞反应的生物学(即 HEL 克隆的特异性和频率)严格相关。 此次更新的首要目的是检查当 APC 被细胞因子激活时诱导的 HEL 肽的翻译后修饰。有证据表明,活化的 APC 可以修饰 HEL,从而产生针对修饰肽的特异性 T 细胞。检查的最初重点是 HEL 肽,其中酪氨酸和色氨酸被硝化(或氧化)。该计划旨在利用质谱方法来表征 T 细胞的特异性、诱导变化的 APC 生物学特性以及变化的生化性质。将在携带 T 细胞受体作为转基因的小鼠中检查 T 细胞对修饰肽的生物学作用;我们打算确定 T 细胞在炎症和组织病理学中的可能作用,重点关注表达 HEL 的 β 细胞。 第二个目标是寻求解释为什么对各种 HEL 表位的反应与 APC 呈递的肽-MHC 复合物的数量无关。我们可以定量 HEL 中各种肽-MHC 复合物的密度:高水平的肽-MHC 复合物诱导的 T 细胞数量与低水平的肽-MHC 复合物的数量大致相同。我们考虑了多种可能的解释,例如 APC 表面复合物的分子竞争、竞争或协同性、复合物的持续时间,以及最后的鼠溶菌酶(一种在 APC 上正常表达的强交叉反应蛋白)的调节存在。通过了解这些重要变量,我们应该能够更全面地了解 CD4 T 细胞反应。 实验基于; i) 使用具有相关生化变化的 HEL 分子来改变表位表达或 APC 中表位的持久性,ii) 追踪 TCR 受体转基因小鼠对多个表位的细胞反应,iii) 在转移系统中使用 APC; iv) 从基因上消除鼠溶菌酶基因。

项目成果

期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Functional redundancy between thymic CD8α+ and Sirpα+ conventional dendritic cells in presentation of blood-derived lysozyme by MHC class II proteins.
Costimulatory requirements of murine Th1 clones. The role of accessory cell-derived signals in responses to anti-CD3 antibody.
小鼠 Th1 克隆的共刺激要求。
Neutrophils influence the level of antigen presentation during the immune response to protein antigens in adjuvants.
Regulation of interleukin 1 gene expression by adherence and lipopolysaccharide.
通过粘附和脂多糖调节白细胞介素 1 基因表达。
Antigen processing and intracellular Ia. Possible roles of endocytosis and protein synthesis in Ia function.
抗原加工和细胞内 Ia。
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EMIL Raphael UNANUE其他文献

EMIL Raphael UNANUE的其他文献

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{{ truncateString('EMIL Raphael UNANUE', 18)}}的其他基金

Identification of relevant peptides involved in the initiation and progression of autoimmune diabetes
鉴定参与自身免疫性糖尿病发生和进展的相关肽
  • 批准号:
    10246429
  • 财政年份:
    2018
  • 资助金额:
    $ 3.74万
  • 项目类别:
Identification of relevant peptides involved in the initiation and progression of autoimmune diabetes
鉴定参与自身免疫性糖尿病发生和进展的相关肽
  • 批准号:
    9689765
  • 财政年份:
    2018
  • 资助金额:
    $ 3.74万
  • 项目类别:
AUTOIMMUNE DIABETES: EARLY EVENTS IN ISLETS OF LANGERHANS
自身免疫性糖尿病:朗格汉斯岛的早期事件
  • 批准号:
    9197630
  • 财政年份:
    2015
  • 资助金额:
    $ 3.74万
  • 项目类别:
CHARACTERIZATION OF ANTIGENIC PEPTIDES PRESENTED BY I-AG7
I-AG7 呈现的​​抗原肽的表征
  • 批准号:
    8361393
  • 财政年份:
    2011
  • 资助金额:
    $ 3.74万
  • 项目类别:
IDENTIFICATION OF MODIFIED AND NATURAL HEL PEPTIDE FRAGMENTS PRESENTED BY MHC
MHC 呈现的修饰和天然 HEL 肽片段的鉴定
  • 批准号:
    8361330
  • 财政年份:
    2011
  • 资助金额:
    $ 3.74万
  • 项目类别:
ANTIGEN PROCESSING IN NITCIITA
NITCIITA 中的抗原处理
  • 批准号:
    8361361
  • 财政年份:
    2011
  • 资助金额:
    $ 3.74万
  • 项目类别:
IDENTIFICATION OF MODIFIED AND NATURAL HEL PEPTIDE FRAGMENTS PRESENTED BY MHC
MHC 呈现的修饰和天然 HEL 肽片段的鉴定
  • 批准号:
    8168678
  • 财政年份:
    2010
  • 资助金额:
    $ 3.74万
  • 项目类别:
PEPTIDES IDENTIFIED FROM THE TYPE I DIABETES ASSOCIATED MHC CLASS I-H2-KD
从 I 型糖尿病相关 MHC I-H2-KD 类中鉴定出的肽
  • 批准号:
    8168690
  • 财政年份:
    2010
  • 资助金额:
    $ 3.74万
  • 项目类别:
ANTIGEN PROCESSING IN NITCIITA
NITCIITA 中的抗原处理
  • 批准号:
    8168713
  • 财政年份:
    2010
  • 资助金额:
    $ 3.74万
  • 项目类别:
CHARACTERIZATION OF ANTIGENIC PEPTIDES PRESENTED BY I-AG7
I-AG7 呈现的​​抗原肽的表征
  • 批准号:
    8168793
  • 财政年份:
    2010
  • 资助金额:
    $ 3.74万
  • 项目类别:

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