Acute Kidney Injury and Double Negative T Cells

项目摘要 急性肾损伤(AKI)与自然肾脏的高死亡率有关， 同种异体移植物在移植中的存活率以及非常高的医疗费用。其中最常见的 自体肾和移植肾AKI的病因均为缺血再灌注损伤(IRI)。 尽管医疗护理取得了进步，但与IRI后AKI相关的死亡率和发病率 保持高水平，没有特定的治疗方法。一个主要的未知因素是不同的T细胞类型在 导致/防止组织损伤或改善/恶化修复。详细了解 不同T细胞类型的作用在这两种机制的阐明上都有很大的希望 潜在的IRI，以及设计新的战略来改善AKI。一种这样的策略是 改变T细胞平衡，有利于保护T细胞类型，而不是致病T细胞类型。 因此，研究不同类型的T细胞在人群中的居住和运输是非常重要的。 并研究它们在稳态和IR条件下的作用。我们队已经有了 长期以来，人们一直有兴趣使用实验性动物模型研究AKI中的免疫细胞 翻译潜力。我们最近发现了一种独特的CD4-CD8-Double群体 阴性(DN)CD3 TCRab T细胞占据了abT细胞隔间的很大一部分。 正常小鼠肾脏，并在急性肾损伤过程中发生明显变化。然而，它们的功能 在正常肾脏和AKI的发病机制尚不清楚。基于强大的 关于糖尿病肾病细胞的初步数据，我们的主要假设是肾脏糖尿病肾病T细胞发挥着 稳定状态下调节肾脏免疫细胞稳态的独特作用 在AKI之后。我们的具体目标是：1)研究稳定的机制和意义 肾小管上皮细胞增殖状态。2)研究糖尿病肾病T细胞对IRI的免疫反应性 诱导AKI。3)检测糖尿病肾病T细胞预防AKI和/或利用GAIN促进修复的能力 和功能丧失策略。为以前不受重视的这一点确立职能角色 肾脏的细胞类型将极大地促进我们对肾脏免疫学的了解 并可能导致科学概念范式的转变。

Project Summary Acute kidney injury (AKI) is associated with a high mortality in native kidneys, decreased allograft survival in transplants, and very high health care costs. Among the most common etiologies of AKI in both native and transplanted kidneys is ischemia-reperfusion injury (IRI). Despite advances in medical care, the mortality and morbidity associated with AKI after IRI remain high, with no specific therapy. A major unknown is the role of different T cell types in either causing/preventing tissue damage or improving/worsening repair. Detailed understanding of the roles of different T cell types holds great promise in both elucidating mechanisms underlying IRI and also in devising new strategies to ameliorate AKI. One such strategy is to shift the T cell balance in favor of protective T cell types and away from pathogenic ones. Therefore, it is important to study different T cell types residing and trafficking to the kidney and investigate their roles in the steady state and IR conditions. Our team has had a long-standing interest in studying immune cells in AKI using experimental animal models with translational potential. We recently discovered a unique population of CD4-CD8- double negative (DN) CD3+TCRab+ T cells that occupies a large niche of the ab T cell compartment in the normal mouse kidney and undergoes marked changes during AKI. However, their functions in the normal kidney and AKI pathogenesis remain relatively unknown. Based on strong preliminary data on DN cells, our overarching hypothesis is that kidney DN T cells play a major and unique role in regulating renal immune cell homeostasis in the steady state and after AKI. Our specific Aims are: 1) Investigate mechanisms and significance of steady state proliferation of kidney DN T cells. 2) Investigate immunoreactivity of DN T cells to IRI induced AKI. 3) Test the ability of DN T cells to prevent AKI and/or accelerate repair using gain and loss-of-function strategies. Establishing a functional role for this previously unappreciated cell type in the kidney will substantially advance our understanding of the kidney immunology and could lead to paradigm shifting scientific concepts.