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.

延迟移植功能（DGF）是一种急性肾脏损伤（AKI），导致后移植寡尿症，同种异体移植免疫原性和急性排斥发作的风险导致长期生存降低。 DGF需要在之后的第一周透析手术并发生在20％至50％的接受尸体移植的患者中。 DGF通常是收获之前或期间对移植的缺血性损害的结果，并进一步加剧了再灌注综合征，这是一个多因素事件，其中多形核细胞起主要的作用角色。移植过程中缺血性再灌注损伤（IRI）的发病机理涉及改变微循环血流动力学，内皮和上皮之间的复杂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AKI涉及的先天和适应性效应子。在肾脏IRI模型中，S1PR3的转移 - / - 缺血之前，骨髓衍生的DC（BMDC）可保护肾脏免受损伤。这大多数转移的S1PR3 - / - BMDC最早在脾中发现了30分钟注射和先前的脾切除术消除了S1PR3 - / - BMDC依赖性保护。在 Spleen，S1PR3 - / - BMDC诱导Treg的增加以抑制先天免疫反应与IRI相关。因此，在移植中，S1PR3 - / - 小鼠的供体肾脏DC将会从移植的肾脏迁移到收据脾脏中。在脾脏中，捐助者得出 S1PR3 - / - DCS将诱导受体Treg的增加以抑制先天免疫反应减轻与移植相关的IRI。因此，我们假设：1）供体DC 激活控制肾脏移植中AKI的严重程度和2）药理调节供体S1P1可以保护肾脏免受IRI的侵害。在特定目的1中，我们将检验以下假设。供体DC的S1P1受体激活调节同性小鼠肾移植中的IRI。具体目标2将检验以下假设：用fty720治疗供体会减少IRI 合成肾移植。将使用啮齿动物肾移植模型对此进行检查。这这些特定目标的结果将产生有关S1P1在捐助者中的作用的重要信息 DC减弱或预防与移植相关的DGF。这些以前是未开发的可能揭示新的目标的问题，以防止DGF，并可能促进由于 DCS S1P1依赖于受体Treg的增加。从中获得的知识项目将构成独立出版物的基础，并由 pi。