The Role of CD28 cosignaling molecules on anti-viral immune responses in Chronic Kidney Disease

CD28 共信号分子在慢性肾脏病抗病毒免疫反应中的作用

基本信息

  • 批准号:
    9759637
  • 负责人:
  • 金额:
    $ 6.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-08-05 至 2020-08-04
  • 项目状态:
    已结题

项目摘要

Abstract Limiting immune-mediated damage following transplantation while maintaining protective immunity requires precise regulation of the immune system. A major challenge is the activation of alloreactive T lymphocytes, which is carefully controlled by the balance of costimulatory and coinhibitory signals T cells receive. The CD28/CTLA-4 pathway is the prototypic co-signaling pathway in T cells, with CTLA-4 co-inhibition acting as the counter-signal to CD28 costimulation as they bind the same receptors, CD80 and CD86. Immunomodulation via blockade of this pathway is a promising approach to prevent inappropriate T cell activation in the setting of transplantation. Belatacept, which binds to CD80/86, is the first costimulation blocker to be FDA approved for use in clinical transplantation and offers significantly improved long-term graft function and fewer toxicities compared to calcineurin inhibitors (CNIs). Use of Belatacept was associated with increased rates of EBV-associated post-transplant lymphoproliferative disorder (PTLD), which is normally kept under strict control by the immune surveillance activities of virus-specific CD8+ T cells. The idea that CD28-mediated signals are required for sufficient EBV-specific CD8+ T cell responses and control of viral recrudescence has recently come into question. Two recent studies have suggested that blocking CD28 is fundamentally different than blocking CD80/CD86 with regard to EBV-specific adaptive immune responses and viral control. Recently, a reagent that selectively targets CD28, while leaving CTLA-4-mediated inhibition intact, has been developed. These anti-CD28 domain antibodies have been shown to be roughly five times more potent than Belatacept against CD86- driven T cell proliferation and to be a more potent inhibitor of graft rejection when compared to CTLA-4 Ig treatment. Given the potent immunosuppressive effects of the anti-CD28 dAb, understanding the impact of selective CD28 blockade on protective immunity is an important clinical question. Additionally, this comparison has never been made in the setting of pre-transplant chronic kidney disease (CKD) in which patients have a well-documented immune dysregulation leading to increased susceptibility to infections, immune-activation-associated inflammation, and poor responses to vaccines. To this end, we plan to directly compare the effects of selective CD28 blockade vs. CTLA-4 Ig on protective immune responses to both murine cytomegalovirus (CMV) as well as MHV-68, a murine homolog of EBV, in both healthy WT mice and mice affected by CKD. Determining the precise effects of CD28 vs. CD80/86 blockade on the generation, maintenance, and functionality of CMV- and MHV-specific CD8+ T cell responses in these settings will provide mechanistic insight and inform the development of novel selective CD28 blockers for use in clinical transplantation.
摘要 限制移植后免疫介导的损伤,同时保持保护性免疫 需要精确调节免疫系统一个主要的挑战是同种异体反应性T细胞的激活, 淋巴细胞,这是仔细控制的平衡,共刺激和共抑制信号T 细胞接收。CD 28/CTLA-4途径是T细胞中的原型共信号传导途径,其中CTLA-4 共抑制作为CD 28共刺激的反信号,因为它们结合相同的受体CD 80 CD86通过阻断这一途径进行免疫调节是一种很有前途的预防方法。 在移植环境中不适当的T细胞活化。Belatacept与CD 80/86结合, 第一个共刺激阻滞剂被FDA批准用于临床移植, 与钙调磷酸酶抑制剂(CNI)相比,改善了长期移植功能,毒性更低。使用 贝拉西普与EB病毒相关的移植后淋巴增生性淋巴结转移的发生率增加有关。 疾病(PTLD),这是通常保持在严格的控制下的免疫监视活动, 病毒特异性CD 8 + T细胞。CD 28介导的信号是足够的EBV特异性免疫所必需的, CD 8 + T细胞应答和病毒复发的控制最近受到质疑。最近的两 研究表明,阻断CD 28与阻断CD 80/CD 86是根本不同的, 关于EBV特异性适应性免疫应答和病毒控制。最近,一种选择性地 靶向CD 28,同时保持CTLA-4介导的抑制完整。这些抗CD 28 结构域抗体已经显示出比贝拉西普针对CD 86- 与CTLA-4相比,它可以驱动T细胞增殖,并成为更有效的移植物排斥抑制剂 IG治疗。考虑到抗CD 28 dAb的强效免疫抑制作用, 选择性CD 28阻断对保护性免疫影响是一个重要的临床问题。此外,本发明还 这种比较从未在移植前慢性肾病(CKD)的情况下进行过, 哪些患者有充分记录的免疫失调,导致对 感染、免疫激活相关炎症和对疫苗的不良反应。为此我们 计划直接比较选择性CD 28阻断与CTLA-4 IG对保护性免疫的影响 小鼠巨细胞病毒(CMV)和MHV-68(EBV的小鼠同源物)的应答, 健康WT小鼠和受CKD影响的小鼠。确定CD 28与CD 80/86的精确效应 阻断CMV和MHV特异性CD 8 + T细胞的产生、维持和功能 在这些环境中的反应将提供机制的见解,并告知新的选择性的发展。 用于临床移植的CD 28阻断剂。

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 }}

Rebecca L Crepeau其他文献

Rebecca L Crepeau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

The earliest exploration of land by animals: from trace fossils to numerical analyses
动物对陆地的最早探索:从痕迹化石到数值分析
  • 批准号:
    EP/Z000920/1
  • 财政年份:
    2025
  • 资助金额:
    $ 6.16万
  • 项目类别:
    Fellowship
Animals and geopolitics in South Asian borderlands
南亚边境地区的动物和地缘政治
  • 批准号:
    FT230100276
  • 财政年份:
    2024
  • 资助金额:
    $ 6.16万
  • 项目类别:
    ARC Future Fellowships
The function of the RNA methylome in animals
RNA甲基化组在动物中的功能
  • 批准号:
    MR/X024261/1
  • 财政年份:
    2024
  • 资助金额:
    $ 6.16万
  • 项目类别:
    Fellowship
Ecological and phylogenomic insights into infectious diseases in animals
对动物传染病的生态学和系统发育学见解
  • 批准号:
    DE240100388
  • 财政年份:
    2024
  • 资助金额:
    $ 6.16万
  • 项目类别:
    Discovery Early Career Researcher Award
Zootropolis: Multi-species archaeological, ecological and historical approaches to animals in Medieval urban Scotland
Zootropolis:苏格兰中世纪城市动物的多物种考古、生态和历史方法
  • 批准号:
    2889694
  • 财政年份:
    2023
  • 资助金额:
    $ 6.16万
  • 项目类别:
    Studentship
Using novel modelling approaches to investigate the evolution of symmetry in early animals.
使用新颖的建模方法来研究早期动物的对称性进化。
  • 批准号:
    2842926
  • 财政年份:
    2023
  • 资助金额:
    $ 6.16万
  • 项目类别:
    Studentship
Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research
研究人类晚期胎儿肺组织和 3D 体外类器官在肺发育研究中替代和减少动物
  • 批准号:
    NC/X001644/1
  • 财政年份:
    2023
  • 资助金额:
    $ 6.16万
  • 项目类别:
    Training Grant
RUI: Unilateral Lasing in Underwater Animals
RUI:水下动物的单侧激光攻击
  • 批准号:
    2337595
  • 财政年份:
    2023
  • 资助金额:
    $ 6.16万
  • 项目类别:
    Continuing Grant
RUI:OSIB:The effects of high disease risk on uninfected animals
RUI:OSIB:高疾病风险对未感染动物的影响
  • 批准号:
    2232190
  • 财政年份:
    2023
  • 资助金额:
    $ 6.16万
  • 项目类别:
    Continuing Grant
A method for identifying taxonomy of plants and animals in metagenomic samples
一种识别宏基因组样本中植物和动物分类的方法
  • 批准号:
    23K17514
  • 财政年份:
    2023
  • 资助金额:
    $ 6.16万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了