Ischemic Reperfusion injury in Transplantation: Role of Sphingosine 1-phosphate receptors and dendritic cells

移植物功能延迟(DGF)是急性肾损伤(AKI)的一种形式，可导致移植后肾功能障碍。 移植物少尿、移植物免疫原性增强和急性排斥反应的风险 导致长期存活率下降。DGF需要在术后第一周进行透析 在接受身体移植的患者中，有20%到50%的患者会发生这种情况。DGF通常是 移植物在收获前或收获过程中的缺血性损伤，并进一步加重 再灌注综合征，一种多因素事件，其中多形核细胞在其中起主要作用 角色。移植过程中缺血再灌注损伤(IRI)的发病机制涉及 微循环血流动力学改变与内皮和上皮的复杂相互作用 细胞，以及免疫细胞的渗透。树突状细胞(DC)在激活血管紧张素转换酶(OR) 抑制AKI中涉及的先天和适应性效应器。在肾脏IRI模型中，S1pr3-/-的转移 缺血前的骨髓来源树突状细胞(BMDCs)对小鼠肾脏具有保护作用。这个 大多数转移的S1pr3-/-BMDCs早在30分钟后就在脾中被发现 注射和之前的脾切除取消了S1pr3-/-BMDC的依赖保护。在 脾，S1pr3-/-BMDCs诱导Treg增加以抑制先天免疫反应 与IRI相关联。因此，在移植中，来自S1pr3-/-小鼠的供体肾脏DC将 从移植的肾脏移植到受者的脾中。在脾中，供体来源于 S1pr3-/-树突状细胞可诱导受体树突状细胞增多以抑制先天免疫反应 以减轻与移植相关的IRI。因此，我们假设：1)捐赠者DC 激活控制肾移植急性肾损伤的严重程度和2)药物调节 供体S1P1对肾脏有保护作用。在具体目标1中，我们将检验假设 供体DC的S1P1受体激活调节同基因小鼠肾移植中的IRI。 特定目标2将检验FTY720治疗供者降低IRI的假说。 同基因肾移植。这将通过啮齿动物肾脏移植模型进行检验。这个 这些特定目标的结果将产生关于S1P1在供体中的作用的重要信息 以减轻或预防移植相关的DGF。这些都是以前未曾开发过的 可能揭示预防DGF并可能促进恢复的新目标的问题 DCs S1P1依赖受体树突状细胞的增加。通过这一过程获得的知识 该项目将成为独立出版物的基础，并将由 圆周率。

Delayed graft function (DGF) is a form of acute kidney injury (AKI) resulting in post- transplantation oliguria, increased allograft immunogenicity and risk of acute rejection episodes resulting in decreased long-term survival. DGF necessitates dialysis in the first week after surgery and occurs in 20% to 50% of patients receiving a cadaver graft. DGF is usually the result of ischemic damage to the graft before or during harvesting and is further aggravated by the reperfusion syndrome, a multifactorial event in which polymorphonuclear cells play a major role. The pathogenesis of ischemic reperfusion injury (IRI) during transplantation involves a complex interaction between altered microcirculatory hemodynamics, endothelial and epithelial cells, and infiltration of immune cells. Dendritic cells (DCs) play a central role in activating or inhibiting innate and adaptive effectors involved in AKI. In kidney IRI model, transfer of S1pr3-/- bone marrow derived DCs (BMDCs) prior to ischemia protects mice kidneys from injury. The majority of transferred S1pr3-/- BMDCs are found in the spleen as early as 30 minutes after injection and prior splenectomy abrogates the S1pr3-/- BMDC dependent protection. In the spleen, S1pr3-/- BMDCs induce an increase in Tregs to inhibit innate immune response associated with IRI. Therefore, in transplantation, donor kidney DCs from S1pr3-/- mice will migrate out of the transplanted kidney into the receipt spleen. In the spleen, donor derived S1pr3-/- DCs will induce an increase in recipient Tregs to suppress the innate immune response to attenuate IRI associated with transplantation. Accordingly, we hypothesize that: 1) donor DC activation controls severity of AKI in kidney transplantation and 2) pharmacological modulation of donor S1P1 can protect kidneys from IRI. In Specific aim 1 we will test the hypothesis that S1P1 receptor activation of donor DCs regulates IRI in syngeneic mouse kidney transplant. Specific Aim 2 will test the hypothesis that treatment of the donor with FTY720 reduces IRI in syngeneic kidney transplant. This will be examined using a rodent kidney transplant model. The results of these specific aims will yield important information about the role of S1P1 on donor DCs to attenuate or prevent transplant associated DGF. These are previously unexplored questions that may reveal novel targets to prevent DGF and possibly promote recovery due to the DCs S1P1 dependent increase in recipient Tregs. The knowledge gained through this project will form the basis of independent publications and an individual R01 application by the PI.