Tissue Cytokine Sequestration and Immune Regulation in Autoimmunity

自身免疫中的组织细胞因子隔离和免疫调节

基本信息

  • 批准号:
    10203749
  • 负责人:
  • 金额:
    $ 63.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-07-01 至 2022-06-30
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract In healthy individuals, immune responses are resolved in part by Foxp3+ regulatory T-cells (Treg). In individuals afflicted with type 1 diabetes (T1D) or Multiple Sclerosis (MS), Treg function well ex vivo but fail to prevent disease. This implicates in vivo impairments in Treg function in autoimmunity. A critical factor that governs Treg homeostasis is the cytokine interleukin 2 (IL-2). Unlike some cytokines that circulate freely, IL-2 is mostly bound to the ECM, specifically to heparan sulfate (HS). We have identified a heretofore ignored, fundamental role for HS-mediated IL-2 sequestration in Treg function and stability in vivo. It is well-established that HS-containing proteoglycans (HSPGs) retain and slowly release other cytokines and growth factors over time, thereby contributing to tissue remodeling after injury. We find that inflammation increases the ability of tissues to retain IL-2. We also find that HS-bound IL-2 (HS/IL-2) functions as a superagonist of IL-2R signaling, promoting the expansion and stability of Treg. Finally, we find that heparanase (HPSE) and HS catabolism are required for Treg function in vitro and in vivo, suggesting that Treg may use HPSE to strip IL-2 from HSPG within the extracellular matrix. Conversely, HS/ IL-2 sequestration and acquisition may be impaired in autoimmunity. HS is abundant in healthy pancreatic islets but disappears in the setting of autoimmune insulitis. Similarly, patterns of HSPGs are deranged within white matter lesions in MS. It may be possible to recapitulate HS/IL-2 signals therapeutically. Capitalizing on the tolerogenic properties of HS/IL-2, we have developed synthetic mimetics of HS/IL-2 that expand Treg. Our vision is that these can be conjugated to antigens and used to induce Treg and prevent MS and T1D. In light of these exciting preliminary data, we hypothesize that HS/ IL-2 promotes Treg function and that this pathway is impaired in autoimmunity. We will test this hypothesis in experiments with the following aims: In Aim 1 we will evaluate ECM binding of cytokines in T1D and MS. In Aim 2 we will elucidate how HS/IL-2 acts as a superagonist of IL-2R signaling. In Aim 3 we will develop HS/IL-2 complexes that promote Treg induction and immune tolerance. Together these Aims have the potential to transform our understanding of the mechanisms that promote immune homeostasis in peripheral tissues.
项目总结/摘要 在健康个体中,免疫应答部分由Foxp 3+调节性T细胞(Treg)解决。在 在患有1型糖尿病(T1 D)或多发性硬化症(MS)的个体中,Treg离体功能良好,但不能 预防疾病。这暗示了自身免疫中Treg功能的体内损伤。 控制Treg稳态的关键因素是细胞因子白细胞介素2(IL-2)。不像某些细胞因子, 当IL-2自由循环时,IL-2主要结合于ECM,特别是硫酸乙酰肝素(HS)。 我们已经确定了一个迄今为止被忽视的,在调节性T细胞功能的HS介导的IL-2螯合的基本作用 和体内稳定性。已证实含HS的蛋白聚糖(HSPG)在细胞内保留并缓慢释放 其他细胞因子和生长因子,从而有助于损伤后的组织重塑。我们发现 炎症增加了组织保留IL-2的能力。我们还发现HS结合IL-2(HS/IL-2) 作为IL-2 R信号传导的超激动剂,促进Treg的扩增和稳定性。最后,我们发现 乙酰肝素酶(HPSE)和HS catenin是体外和体内Treg功能所必需的,表明 Treg可以使用HPSE从细胞外基质内的HSPG剥离IL-2。 相反,HS/ IL-2的隔离和获取可能在自身免疫中受损。HS丰富, 健康的胰岛,但在自身免疫性胰岛炎的情况下消失。类似地,HSPG的模式是 在MS的白色病变内紊乱。 有可能在治疗上概括HS/IL-2信号。利用致耐受性特性 在HS/IL-2的合成中,我们已经开发了扩增Treg的HS/IL-2的合成模拟物。我们的愿景是, 与抗原缀合并用于诱导Treg和预防MS和T1 D。 根据这些令人兴奋的初步数据,我们假设HS/ IL-2促进Treg功能, 在自身免疫性中受损。我们将在实验中检验这一假设,目的如下: 在目标1中,我们将评估T1 D和MS中细胞因子的ECM结合。 在目标2中,我们将阐明HS/IL-2如何作为IL-2 R信号转导的超激动剂。 在目标3中,我们将开发促进Treg诱导和免疫耐受的HS/IL-2复合物。 这些目标合在一起,有可能改变我们对促进发展的机制的理解。 外周组织的免疫稳态。

项目成果

期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
Reduced development of COVID-19 in children reveals molecular checkpoints gating pathogenesis illuminating potential therapeutics.
Sputum hyaluronan and versican in severe eosinophilic asthma.
Extracellular matrix components in the pathogenesis of type 1 diabetes.
  • DOI:
    10.1007/s11892-014-0552-7
  • 发表时间:
    2014-12
  • 期刊:
  • 影响因子:
    4.2
  • 作者:
    Bogdani, Marika;Korpos, Eva;Simeonovic, Charmaine J.;Parish, Christopher R.;Sorokin, Lydia;Wight, Thomas N.
  • 通讯作者:
    Wight, Thomas N.
Hyaluronan Controls the Deposition of Fibronectin and Collagen and Modulates TGF-β1 Induction of Lung Myofibroblasts.
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Paul L Bollky其他文献

Paul L Bollky的其他文献

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{{ truncateString('Paul L Bollky', 18)}}的其他基金

Circulating Bacteriophages for the Diagnosis of Sepsis
用于诊断脓毒症的循环噬菌体
  • 批准号:
    10673035
  • 财政年份:
    2022
  • 资助金额:
    $ 63.2万
  • 项目类别:
Studies on bacteriophages in respiratory diseases
噬菌体在呼吸系统疾病中的研究
  • 批准号:
    10525104
  • 财政年份:
    2022
  • 资助金额:
    $ 63.2万
  • 项目类别:
Circulating Bacteriophages for the Diagnosis of Sepsis
用于诊断脓毒症的循环噬菌体
  • 批准号:
    10510456
  • 财政年份:
    2022
  • 资助金额:
    $ 63.2万
  • 项目类别:
Studies on bacteriophages in respiratory diseases
噬菌体在呼吸系统疾病中的研究
  • 批准号:
    10669271
  • 财政年份:
    2022
  • 资助金额:
    $ 63.2万
  • 项目类别:
The Role of Hyaluronan and CD44 in the Pathogenesis of Type 2 Diabetes
透明质酸和 CD44 在 2 型糖尿病发病机制中的作用
  • 批准号:
    10578727
  • 财政年份:
    2020
  • 资助金额:
    $ 63.2万
  • 项目类别:
The Role of Hyaluronan and CD44 in the Pathogenesis of Type 2 Diabetes
透明质酸和 CD44 在 2 型糖尿病发病机制中的作用
  • 批准号:
    10359164
  • 财政年份:
    2020
  • 资助金额:
    $ 63.2万
  • 项目类别:
The Development of 4-methylumbelliferone Pro-drugs to Prevent Autoimmune Diabetes
预防自身免疫性糖尿病的 4-甲基伞形酮前药的开发
  • 批准号:
    9901521
  • 财政年份:
    2018
  • 资助金额:
    $ 63.2万
  • 项目类别:
Biofilms and Bacteriophages in Chronic Wound Infections
慢性伤口感染中的生物膜和噬菌体
  • 批准号:
    9375747
  • 财政年份:
    2017
  • 资助金额:
    $ 63.2万
  • 项目类别:
Extracellular matrix and the function and stability of FoxP3+ regulatory T-cells
细胞外基质与 FoxP3 调节性 T 细胞的功能和稳定性
  • 批准号:
    8345146
  • 财政年份:
    2012
  • 资助金额:
    $ 63.2万
  • 项目类别:
Extracellular matrix and the function and stability of FoxP3+ regulatory T-cells
细胞外基质与 FoxP3 调节性 T 细胞的功能和稳定性
  • 批准号:
    9135339
  • 财政年份:
    2012
  • 资助金额:
    $ 63.2万
  • 项目类别:

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  • 财政年份:
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