Acute Kidney Injury and Double Negative T Cells

描述(由申请人提供)：急性肾损伤(AKI)与高死亡率、发病率和增加的医疗费用有关。在自体肾和移植肾中，AKI最常见的病因之一是缺血再灌注损伤(IRI)，目前尚无特效治疗方法。IRI也是导致心肌缺血和中风的主要过程。IRI的早期损伤和恢复的机制是复杂的，仍然不完全清楚。IRI涉及多种细胞类型的先天免疫系统和获得性免疫系统，其中一些会造成损害，而另一些会促进损伤修复。了解肾脏中处于稳定状态或损伤后招募的不同免疫细胞的个体和协同作用，对于开发有效的策略来改善与IRI相关的肾脏损害具有重要意义。我们有新的数据表明，一种相当新发现且知之甚少的细胞类型，属于TCR？+CD4-CD8-双阴性(DN)T细胞亚群，优先在正常肾脏中大量定位，并随年龄和缺血而变化。这些细胞可以抗炎，具有大量糖尿病肾病T细胞的转基因小鼠可免受IRI。我们假设，糖尿病肾病T细胞介导独特的免疫功能，这是维持稳定状态下局部免疫反应和肾小管上皮细胞动态平衡所必需的，同时也保护肾脏免受损伤，促进IRI后的恢复。我们将通过以下具体目标开始检验这一新假说：在目标1中，我们将检验局部DNT细胞通过抑制激活的常规T细胞来维持免疫动态平衡的假说。我们还将研究对构成肾细胞主体的肾小管上皮细胞(RTECs)的影响。在目标2中，我们将验证这样一种假设，即DNT细胞直接保护IRI后的早期损伤并促进修复。我们还将阐明其作用机制。研究结果将为这种新发现的肾脏细胞提供新的信息，并有可能利用一种新的细胞用于针对缺血再灌注损伤的细胞治疗。 公共卫生相关性：免疫细胞是缺血再灌注损伤(IRI)的主要参与者，IRI是自体肾脏和移植肾脏的主要问题。我们计划研究一种新的T细胞亚群的功能，这种T细胞亚群在正常肾脏中大量存在，但在IRI后逐渐减弱。这些研究将有助于更好地了解肾脏的免疫动态平衡，并有可能找到新的治疗方法来减少肾脏IRI后的损伤和炎症。

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is associated with a high mortality, morbidity, and increased health care cost. Among the most common etiologies of AKI in both native and transplanted kidneys is ischemia-reperfusion injury (IRI), which has no specific therapy. IRI is also a major process underlying myocardial ischemia and stroke. Mechanisms of early injury and recovery from IRI are complex and remain incompletely understood. IRI involves diverse cell types of the innate and adaptive immune systems, some of which cause damage while others promote injury repair. Efforts to understand the individual and collaborative roles of the different immune cells that reside in the kidney in the steady state or recruited after injury are important for laying the foundation for developing effective strategies o ameliorate renal damage associated with IRI. We have novel data that a fairly newly identified and poorly understood cell type that belong to the TCR¿¿+CD4-CD8- double negative (DN) T cell subset, preferentially localizes in large numbers in the normal kidney and changes with age and ischemia. These cells can be anti-inflammatory and genetically modified mice with large quantities of DN T cells are protected from IRI. We hypothesize that DN T cells mediate unique immune functions that are necessary for maintaining local immune responses and renal tubular epithelial cell homeostasis in the steady state, while also protecting from injury and enhancing recovery after IRI. We will begin to test this novel hypothesis through the following specific Aims: In Aim 1, we will test the hypothesis that local DN T cells maintain immune homeostasis by suppression of activated conventional T cells. We will also study effects on renal tubular epithelial cells (RTECs), which make up the bulk of the kidney cells. In Aim 2, we will test the hypothesis that DN T cells directly protect from early injury and accelerate repair after IRI. We will also elucidate mechanisms of action. Results will provide novel information on this newly identified kidney cell and has the potential to harness a novel cell for cell therapy directed to ischemia reperfusion injury. PUBLIC HEALTH RELEVANCE: Immune cells are major players in ischemia reperfusion injury (IRI), a major problem in both native and transplanted kidneys. We plan to investigate the function of a novel T cell subset that resides in significant numbers in normal kidney but wane down after IRI. These studies would lead to better understanding of the kidney immune homeostasis and potentially new therapeutics to decrease injury and inflammation after kidney IRI.