T cell modulation of renal ischemia reperfusion injury.

描述（由申请人提供）：肾缺血再灌注损伤（IRI）是自体肾和同种异体肾中急性肾衰竭（ARF）的主要原因。我们和其他人已经证明了T细胞在实验性肾ARF以及其他器官的IRI中的重要调节作用。尽管有强有力的证据支持这一概念，但关于T细胞在肾IRI中的作用机制的信息很少。本课题旨在阐明T细胞调节肾脏IRI的机制。我们的重点将是在体内的整合机制，因此，拟议的研究将在一个既定的ARF小鼠模型进行。具体目标1：研究构成传统T细胞应答的第一个信号的主要分子“信号1”是否在T细胞参与肾IRI中发挥作用。我们将使用已建立的肾IRI小鼠模型和特异性基因敲除小鼠，然后评价肾功能、结构、分子和细胞反应。我们将进行T细胞过继转移研究并开发骨髓嵌合体。具体目标二：研究肾IRI中T细胞的功能是否是由于T细胞直接浸润到肾中，或者T细胞功能和浸润是否可以分离。我们将使用免疫组织化学和白细胞分离纯化技术评估T细胞进入缺血后肾脏的早期运输和这些T细胞的表型。我们将比较T细胞运输与其他白细胞的运输，并将这些发现与损伤的功能，结构和分子终点相关联。我们将进行血清和T细胞转移研究，以评估是否浸润到肾脏中，这对介导T细胞的作用至关重要。具体目标3：研究T细胞是否通过与其他淋巴细胞的相互作用调节肾脏IRI。我们将使用缺乏B细胞和特化T细胞的小鼠，并使用可溶性和细胞因子进行过继转移研究。这是一个新的方向，应该导致新的见解非常早期的细胞步骤，启动缺血后炎症。长期的目标将是确定抗原和分子途径，燃料损伤过程中的ARF和发展有针对性的治疗。

DESCRIPTION (provided by applicant): Kidney ischemia reperfusion injury (IRI) is a major cause of acute renal failure (ARF) in both the native and allograft kidney. We and others have demonstrated an important modulatory role for T cells in experimental kidney ARF as well as in IRI of other organs. Despite strong evidence for this concept, there is minimal information on the mechanisms underlying the role for T cells in renal IRI. The Aims of this project are to elucidate the mechanisms by which T cells modulate kidney IRI. Our focus will be on integrative in vivo mechanisms, thus the studies proposed will be performed in an established murine model of ARF. Specific Aim 1: To investigate if the major molecules that constitute the first signal for conventional T cell responses, "Signal 1," play a role in the T cell's participation in renal IRI. We will use an established mouse model of renal IRI and mice with specific knockouts, and then evaluate kidney function, structure, molecular and cellular responses. We will perform T cell adoptive transfer studies and develop bone marrow chimeras. Specific Aim 2: To investigate if the function of the T cell in renal IRI is due to the direct infiltration of T cells into the kidney or if T cell function and infiltration can be disassociated. We will evaluate the early trafficking of T cells into post ischemic kidney and phenotype these T cells using immunohistochemistry and a leukocyte isolation and purification technique. We will compare T cell trafficking with trafficking of other leukocytes, and correlate these findings with functional, structural and molecular endpoints for injury. We will perform serum and T cell transfer studies to evaluate if infiltration into kidney which is essential to mediate the T cell's role. Specific Aim 3: To investigate if the T cell is modulating kidney IRI by interactions with other lymphocytes. We will use mice deficient in B cells and specialized T cells, and perform adoptive transfer studies using soluble and cellular factors. This is a novel direction that should lead to new insights into the very early cellular steps that initiate post ischemic inflammation. The long term goal will be to identify the antigens and molecular pathways that fuel the injury processes in ARF and develop targeted therapies.