The role of TIGIT in Treg-mediated suppression of C8+ T cells in Transplantation

TIGIT 在移植中 Treg 介导的 C8 T 细胞抑制中的作用

基本信息

  • 批准号:
    10668239
  • 负责人:
  • 金额:
    $ 2.28万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-04-01 至 2023-05-31
  • 项目状态:
    已结题

项目摘要

Summary/Abstract Transplantation is a curative strategy for end stage organ failure. In order to avoid immune-mediated rejection of the grafted tissue, recipients receive life-long immunosuppression. Calcineurin and mTOR inhibitors for immunosuppression are successful in preventing graft rejection but are associated with significant adverse off- target toxicities. In order to better preserve the health of both the graft and the transplant recipient, alternative immunosuppressive therapies have been sought. Belatacept, a CTLA-4Ig fusion protein, suppresses the immune system by binding to CD80 and CD86 on antigen presenting cells (APCs) to block CD28 (costimulatory) and CTLA-4 (coinhibitory) signaling on T cells. By blocking interactions that are specific for immune cells, the use of CTLA-4Ig mitigates off-target toxicities associated with calcineurin inhibitors and increases the longevity of the graft and health of the patient. However, CTLA-4Ig is associated with increased risk of acute rejection episodes compared to calcineurin inhibitors, which has prohibited its widespread clinical adoption despite the improved long-term outcomes. Regulatory T cells are essential to maintaining immune homeostasis and promoting tolerance in transplant, but the blockade of signaling through CD28 and CTLA-4 is detrimental to their survival and function. Therefore, CTLA-4Ig therapy inhibits Tregs from controlling CD8+ T cells as they execute acute rejection. Identifying costimulatory and coinhibitory pathways that can be targeted to enhance the suppressive capacity of Tregs in the setting of CTLA-4Ig therapy is essential to improving targeted immunosuppressive therapies. TIGIT is a T-cell inhibitory receptor with Ig and ITIM domains expressed on Tregs that can be targeted with antibodies to fine-tune Treg function. Agonistic anti-TIGIT antibodies have been shown to induce apoptosis of costimulation blockade-resistant memory T cells in a Treg- dependent manner. The experiments outlined in this proposal study the mechanisms by which TIGIT signaling on Tregs enhances Treg function in the face of CTLA-4Ig therapy to reduce CD8 + T cell responses to allograft challenge. In Aim 1 we will determine if cell-autonomous TIGIT signaling increases the abundance of Tregs within grafted tissue and increases the secretion of suppressive molecules to enhance Treg function. In Aim 2 we will determine the impact of Treg-specific TIGIT signaling on effector CD8+ T cell responses to allograft. These studies will be performed using novel Treg-specific TIGIT knockout animals (Foxp3-Cre x TIGITfl/fl). Together, these data will illuminate the therapeutic potential of TIGIT agonism in combination with costimulation blockade therapeutics to mitigate acute allograft rejection.
总结/摘要 移植是终末期器官衰竭的治疗策略。为了避免免疫介导的排斥反应 移植组织的受体接受终身免疫抑制。钙调磷酸酶和mTOR抑制剂, 免疫抑制在预防移植物排斥方面是成功, 目标毒性。为了更好地保护移植物和移植受体的健康, 一直在寻求免疫抑制疗法。Belatacept是一种CTLA-4 Ig融合蛋白, 免疫系统通过结合抗原呈递细胞(APC)上的CD 80和CD 86来阻断CD 28 (共刺激)和CTLA-4(共抑制)信号传导。通过阻止特定于 在免疫细胞中,使用CTLA-4 Ig减轻了与钙调磷酸酶抑制剂相关的脱靶毒性, 增加移植物的寿命和患者的健康。然而,CTLA-4 Ig与增加的 与钙调磷酸酶抑制剂相比,急性排斥反应发作的风险,这已经阻止了其广泛的临床应用。 尽管长期结果有所改善,但仍然没有通过。调节性T细胞对维持免疫至关重要 体内平衡和促进移植耐受,但通过CD 28和CTLA-4的信号传导的阻断, 不利于它们的生存和功能。因此,CTLA-4 Ig治疗抑制了Tcl 3对CD 8 + T细胞的控制, 当它们执行急性排斥反应时。识别可以靶向的共刺激和共抑制途径 在CTLA-4 Ig治疗的情况下,增强TGFAP的抑制能力对于改善 靶向免疫抑制疗法。TIGIT是具有IG和ITIM结构域的T细胞抑制性受体 表达在T细胞上,可以用抗体靶向以微调Treg功能。激动性抗TIGIT 已经显示抗体诱导Treg-1中共刺激阻断抗性记忆T细胞的凋亡。 依赖的方式。该提案中概述的实验研究了TIGIT信号转导的机制。 在面对CTLA-4 Ig治疗以减少对同种异体移植物的CD 8 + T细胞应答时,TCR 4增强Treg功能 挑战.在目标1中,我们将确定细胞自主TIGIT信号传导是否增加TIGIT的丰度。 在移植的组织内,并增加抑制性分子的分泌以增强Treg功能。在目标2中 我们将确定Treg特异性TIGIT信号传导对效应CD 8 + T细胞对同种异体移植物应答的影响。 这些研究将使用新型Treg特异性TIGIT敲除动物(Foxp 3-Cre X TIGITfl/fl)进行。 总之,这些数据将阐明TIGIT激动剂与TIGIT激动剂组合的治疗潜力。 共刺激阻断疗法以减轻急性同种异体移植物排斥。

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 }}

Christina Rose Hartigan其他文献

Christina Rose Hartigan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 }}

相似海外基金

WELL-CALF: optimising accuracy for commercial adoption
WELL-CALF:优化商业采用的准确性
  • 批准号:
    10093543
  • 财政年份:
    2024
  • 资助金额:
    $ 2.28万
  • 项目类别:
    Collaborative R&D
Investigating the Adoption, Actual Usage, and Outcomes of Enterprise Collaboration Systems in Remote Work Settings.
调查远程工作环境中企业协作系统的采用、实际使用和结果。
  • 批准号:
    24K16436
  • 财政年份:
    2024
  • 资助金额:
    $ 2.28万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Unraveling the Dynamics of International Accounting: Exploring the Impact of IFRS Adoption on Firms' Financial Reporting and Business Strategies
揭示国际会计的动态:探索采用 IFRS 对公司财务报告和业务战略的影响
  • 批准号:
    24K16488
  • 财政年份:
    2024
  • 资助金额:
    $ 2.28万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 2.28万
  • 项目类别:
    EU-Funded
Assessing the Coordination of Electric Vehicle Adoption on Urban Energy Transition: A Geospatial Machine Learning Framework
评估电动汽车采用对城市能源转型的协调:地理空间机器学习框架
  • 批准号:
    24K20973
  • 财政年份:
    2024
  • 资助金额:
    $ 2.28万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 2.28万
  • 项目类别:
    EU-Funded
Our focus for this project is accelerating the development and adoption of resource efficient solutions like fashion rental through technological advancement, addressing longer in use and reuse
我们该项目的重点是通过技术进步加快时装租赁等资源高效解决方案的开发和采用,解决更长的使用和重复使用问题
  • 批准号:
    10075502
  • 财政年份:
    2023
  • 资助金额:
    $ 2.28万
  • 项目类别:
    Grant for R&D
Engage2innovate – Enhancing security solution design, adoption and impact through effective engagement and social innovation (E2i)
Engage2innovate — 通过有效参与和社会创新增强安全解决方案的设计、采用和影响 (E2i)
  • 批准号:
    10089082
  • 财政年份:
    2023
  • 资助金额:
    $ 2.28万
  • 项目类别:
    EU-Funded
De-Adoption Beta-Blockers in patients with stable ischemic heart disease without REduced LV ejection fraction, ongoing Ischemia, or Arrhythmias: a randomized Trial with blinded Endpoints (ABbreviate)
在没有左心室射血分数降低、持续性缺血或心律失常的稳定型缺血性心脏病患者中停用β受体阻滞剂:一项盲法终点随机试验(ABbreviate)
  • 批准号:
    481560
  • 财政年份:
    2023
  • 资助金额:
    $ 2.28万
  • 项目类别:
    Operating Grants
Collaborative Research: SCIPE: CyberInfrastructure Professionals InnoVating and brOadening the adoption of advanced Technologies (CI PIVOT)
合作研究:SCIPE:网络基础设施专业人员创新和扩大先进技术的采用 (CI PIVOT)
  • 批准号:
    2321091
  • 财政年份:
    2023
  • 资助金额:
    $ 2.28万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了