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

移植中的缺血再灌注损伤：1-磷酸鞘氨醇受体和树突状细胞的作用

基本信息

批准号：
9337445
负责人：
Amandeep Bajwa
金额：
$ 7.9万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-25 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9337445
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Adverse effects Affect Agonist Allografting Animal Model Apoptosis Attenuated Bone Marrow Cadaver Cell Count Cell Maturation Cell Proliferation Cells Complex Complication Data Dendritic Cells Dendritic cell activation Development Dialysis procedure Dose Embryo Endothelial Cells Epithelial Cells Event FDA approved Family Flow Cytometry Future G-Protein-Coupled Receptors Harvest Healthcare Systems Image Immune Immunohistochemistry Immunosuppressive Agents Incidence Individual Infiltration Inflammation Injection of therapeutic agent Injury Innate Immune Response Ischemia Kidney Kidney Transplantation Knowledge Lead Length of Stay Lymphocyte Malignant Neoplasms Microscopy Modeling Mus Myelogenous Oliguria Operative Surgical Procedures Opportunistic Infections Organ Organ Donor Organ Survival Organ Transplantation Pathogenesis Patients Pharmaceutical Preparations Pharmacology Phenotype Physiological Play Postoperative Period Predisposition Procedures Proximal Kidney Tubules Publications Receptor Activation Receptor Cell Recovery Regulatory T-Lymphocyte Reperfusion Injury Reperfusion Therapy Risk Rodent Role Severities Speed Sphingolipids Sphingosine-1-Phosphate Receptor Spleen Splenectomy Supportive care Syndrome Testing Therapeutic Transgenic Mice Transplantation angiogenesis cell growth cost cytotoxicity delayed graft function edg-1 Protein effective therapy end-stage organ failure graft function hemodynamics immunogenicity immunoregulation migration neutrophil novel novel strategies novel therapeutic intervention novel therapeutics prevent protective effect public health relevance receptor response sphingosine 1-phosphate trafficking treatment strategy two-photon

项目摘要

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.

移植物功能延迟（DGF）是急性肾损伤（AKI）的一种形式，导致术后肾损伤。移植少尿、同种异体移植免疫原性增加和急性排斥反应的风险导致长期生存率下降。 DGF 需要在术后第一周进行透析接受尸体移植的患者中有 20% 至 50% 会发生这种情况。 DGF 通常是移植物在收获前或收获期间发生缺血性损伤的结果，并且进一步加剧再灌注综合征是一种多因素事件，多形核细胞在其中起主要作用角色。移植过程中缺血性再灌注损伤（IRI）的发病机制涉及改变的微循环血流动力学、内皮细胞和上皮细胞之间复杂的相互作用细胞和免疫细胞的浸润。树突状细胞 (DC) 在激活或抑制与 AKI 相关的先天性和适应性效应器。在肾脏 IRI 模型中，S1pr3-/- 的转移缺血前的骨髓衍生树突状细胞 (BMDC) 可保护小鼠肾脏免受损伤。这大多数转移的 S1pr3-/- BMDC 早在 30 分钟后就在脾脏中被发现。注射和先前的脾切除术消除了 S1pr3-/- BMDC 依赖性保护。在脾脏、S1pr3-/- BMDC 诱导 Tregs 增加，抑制先天免疫反应与 IRI 相关。因此，在移植中，来自 S1pr3-/- 小鼠的供体肾脏 DC 从移植的肾脏迁移到接收者的脾脏中。在脾脏中，来自供体 S1pr3-/- DC 会诱导受体 Tregs 增加，从而抑制先天免疫反应减弱与移植相关的IRI。因此，我们假设：1）供体 DC 激活控制肾移植中 AKI 的严重程度和 2) 药理调节供体 S1P1 可以保护肾脏免受 IRI 的影响。在具体目标 1 中，我们将检验以下假设：供体 DC 的 S1P1 受体激活可调节同基因小鼠肾移植中的 IRI。具体目标 2 将检验以下假设：用 FTY720 治疗供体可降低 IRI 同基因肾移植。这将使用啮齿动物肾移植模型进行检查。这这些具体目标的结果将产生有关 S1P1 对捐助者的作用的重要信息 DC 可以减弱或预防移植相关的 DGF。这些都是以前未探索过的可能揭示预防 DGF 并可能促进康复的新目标的问题 DCs S1P1 依赖的受体 Tregs 增加。通过这次获得的知识项目将构成独立出版物和个人 R01 申请的基础 PI。