Memory CD4 T cell driven antibody responses to renal allografts

记忆 CD4 T 细胞驱动的抗体对肾同种异体移植物的反应

基本信息

  • 批准号:
    7891954
  • 负责人:
  • 金额:
    $ 34.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-06-08 至 2015-05-31
  • 项目状态:
    已结题

项目摘要

Despite improved immunosuppression and roufine PRA screening, alloreacfive anfibodies (alloAb) mediate a significant proportion of acute allograft rejection episodes and contribute to the development of chronic rejection. Production of pathogenic alloAb isotypes requires interactions between B cells and helper CD4 T cells specific for donor anfigens. Typically, this help occurs in germinal centers within secondary lymphoid organs and is dependent on CD40/CD154 cosfimulatory pathway. However, the T cell repertoire of many humans contains alloreacfive memory T cells that are resistant to immunosuppression or cosfimulatory blockade. Our preliminary data show that donor-reactive memory CD4 T cells induce higher titers of alloAb compared to naive CD4 T cells even in the absence of conventional germinal center formafion and CD40/CD154 interacfion. However, the mechanisms underiying the observed high alloAb titers as well as anatomical sites and molecular requirements of help by memory CD4 T cells are sfill unknown and need to be tested. The goal of this study is to identify functional phenotype of memory CD4 T cells providing help for alloreacfive B cells and to investigate the characteristic features and requirements for this help. We have developed a mouse model of kidney transplantation to study donor-specific alloAb responses induced by memory CD4 T cells. We hypothesize that compared to naive cells, memory CD4 T cells inifiate enhanced development of GCs and greater proliferation of B cells, promote production of alloAb with higher affinifies for donor antigens and induce enhanced development of long-lived Ab secrefing plasma cells and memory B cells. We further propose that while follicular helper memory T cells are superior in inducing alloAb responses compared to other lineages, help by memory CD4 T cells can occur outside of typical germinal centers and can bypass the requirement for CD40/CD154 interacfion via alternative molecular pathways such as TLR and BAFF/APRIL signaling. We will test this hypothesis in three Specific Aims: Aim 1. To investigate the mechanisms of superior alloantibody production induced by donor-specific memory CD4 T cells in response to renal allografts. Aim 2. To identify functional phenotype of memory CD4 T cells capable of providing help for alloantibody production after renal allograft placement. Aim 3. To determine the location and molecular requirements of help provided by memory CD4 T cells for alloantibody production.
尽管免疫抑制得到改善并进行常规 PRA 筛查,同种异体反应性抗体 (alloAb) 仍然介导 急性同种异体移植排斥反应的比例很大,并有助于慢性排斥反应的发展 拒绝。致病性同种抗体同种型的产生需要 B 细胞和辅助 CD4 T 之间的相互作用 对供体抗原具有特异性的细胞。通常,这种帮助发生在次级淋巴内的生发中心 器官,并且依赖于 CD40/CD154 共刺激途径。然而,许多 T 细胞库 人类含有同种反应性记忆 T 细胞,可抵抗免疫抑制或共刺激 封锁。我们的初步数据表明,供体反应性记忆 CD4 T 细胞诱导更高滴度的同种抗体 与初始 CD4 T 细胞相比,即使在没有常规生发中心形成的情况下, CD40/CD154 相互作用。然而,观察到的高同种抗体滴度的机制以及 记忆 CD4 T 细胞的解剖部位和分子需求尚不清楚,需要 被测试。本研究的目的是确定记忆 CD4 T 细胞的功能表型,为 同种反应性 B 细胞并研究其特征和要求对此有帮助。我们有 开发了一种肾移植小鼠模型来研究供体特异性同种抗体反应 记忆 CD4 T 细胞。我们假设与初始细胞相比,记忆 CD4 T 细胞启动增强 GC 的发育和 B 细胞的更大增殖,促进具有更高亲和力的同种抗体的产生 供体抗原并诱导长寿命抗体分泌浆细胞和记忆 B 的增强发育 细胞。我们进一步提出,虽然滤泡辅助记忆 T 细胞在诱导 alloAb 方面更胜一筹 与其他谱系相比,在记忆 CD4 T 细胞的帮助下,反应可以发生在典型的生发细胞之外 中心并可以通过替代分子途径绕过 CD40/CD154 相互作用的要求 例如 TLR 和 BAFF/APRIL 信令。我们将在三个具体目标中检验这一假设: 目的 1. 研究供体特异性记忆诱导产生优质同种抗体的机制 CD4 T 细胞对肾同种异体移植物的反应。目标 2. 鉴定记忆 CD4 T 细胞的功能表型 能够为同种异体肾移植术后产生同种抗体提供帮助。目标 3. 确定 记忆 CD4 T 细胞为同种抗体产生提供帮助的位置和分子要求。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Anna Valujskikh其他文献

Anna Valujskikh的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Anna Valujskikh', 18)}}的其他基金

Mechanisms of alloantibody production following renal transplantation
肾移植后同种抗体产生的机制
  • 批准号:
    10357956
  • 财政年份:
    2021
  • 资助金额:
    $ 34.4万
  • 项目类别:
Mechanisms of alloantibody production following renal transplantation
肾移植后同种抗体产生的机制
  • 批准号:
    10228265
  • 财政年份:
    2021
  • 资助金额:
    $ 34.4万
  • 项目类别:
Mechanisms of alloantibody production following renal transplantation
肾移植后同种抗体产生的机制
  • 批准号:
    10551197
  • 财政年份:
    2021
  • 资助金额:
    $ 34.4万
  • 项目类别:
Designing induction therapies to target memory T cells in high risk recipients
设计针对高危受者记忆 T 细胞的诱导疗法
  • 批准号:
    9027079
  • 财政年份:
    2015
  • 资助金额:
    $ 34.4万
  • 项目类别:
Designing induction therapies to target memory T cells in high risk recipients
设计针对高危受者记忆 T 细胞的诱导疗法
  • 批准号:
    9193613
  • 财政年份:
    2015
  • 资助金额:
    $ 34.4万
  • 项目类别:
Designing induction therapies to target memory T cells in high risk recipients
设计针对高危受者记忆 T 细胞的诱导疗法
  • 批准号:
    10682434
  • 财政年份:
    2014
  • 资助金额:
    $ 34.4万
  • 项目类别:
Designing induction therapies to target memory T cells in high risk recipients
设计针对高危受者记忆 T 细胞的诱导疗法
  • 批准号:
    8878467
  • 财政年份:
    2014
  • 资助金额:
    $ 34.4万
  • 项目类别:
Designing induction therapies to target memory T cells in high risk recipients
设计针对高危受者记忆 T 细胞的诱导疗法
  • 批准号:
    10362129
  • 财政年份:
    2014
  • 资助金额:
    $ 34.4万
  • 项目类别:
CD4 Memory T Cells and Allograft Rejection
CD4 记忆 T 细胞和同种异体移植排斥
  • 批准号:
    8078592
  • 财政年份:
    2010
  • 资助金额:
    $ 34.4万
  • 项目类别:
Memory CD4 helper T cells and antibody production following renal transplantation
肾移植后记忆 CD4 辅助 T 细胞和抗体产生
  • 批准号:
    9283290
  • 财政年份:
    2010
  • 资助金额:
    $ 34.4万
  • 项目类别:

相似海外基金

Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
  • 批准号:
    23H01982
  • 财政年份:
    2023
  • 资助金额:
    $ 34.4万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
  • 批准号:
    23KJ0116
  • 财政年份:
    2023
  • 资助金额:
    $ 34.4万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
  • 批准号:
    10682794
  • 财政年份:
    2023
  • 资助金额:
    $ 34.4万
  • 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
  • 批准号:
    10598276
  • 财政年份:
    2023
  • 资助金额:
    $ 34.4万
  • 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
  • 批准号:
    2233343
  • 财政年份:
    2023
  • 资助金额:
    $ 34.4万
  • 项目类别:
    Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
  • 批准号:
    2233342
  • 财政年份:
    2023
  • 资助金额:
    $ 34.4万
  • 项目类别:
    Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
  • 批准号:
    479363
  • 财政年份:
    2023
  • 资助金额:
    $ 34.4万
  • 项目类别:
    Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
  • 批准号:
    10681989
  • 财政年份:
    2023
  • 资助金额:
    $ 34.4万
  • 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
  • 批准号:
    2237240
  • 财政年份:
    2023
  • 资助金额:
    $ 34.4万
  • 项目类别:
    Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
  • 批准号:
    2305592
  • 财政年份:
    2023
  • 资助金额:
    $ 34.4万
  • 项目类别:
    Continuing Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了