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

• 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
• 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

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.

移植肾功能延迟恢复（DGF）是急性肾损伤（阿基）的一种形式，导致移植后肾功能衰竭。 移植少尿、同种异体移植物免疫原性增加和急性排斥反应发作风险 导致长期存活率下降。DGF需要在术后第一周进行透析 在接受尸体移植的患者中，20%至50%的患者会发生这种情况。DGF通常是 在收获之前或收获期间对移植物造成缺血性损伤的结果，并且由于 再灌注综合征是一种多因素事件，其中多形细胞起主要作用， 作用移植过程中缺血再灌注损伤（IRI）的发病机制涉及一个新的机制。 改变的微循环血流动力学、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）在活化或活化树突状细胞中起核心作用。 抑制参与阿基的先天和适应性效应物。在肾IRI模型中，S1 pr 3-/- 骨髓来源的DC（BMDCs）在缺血前保护小鼠肾脏免受损伤。的 大多数转移的S1 pr 3-/-BMDC早在接种后30分钟就在脾脏中发现。 注射和先前的脾切除消除了S1 pr 3-/- BMDC依赖性保护。在 脾，S1 pr 3-/- BMDCs诱导T细胞增加以抑制先天性免疫应答 与IRI有关。因此，在移植中，来自S1 pr 3-/-小鼠的供体肾DC将 从移植肾迁移到受体脾。在脾脏中，供体来源 S1 pr 3-/- DCs可诱导受体T淋巴细胞增加，从而抑制先天性免疫应答 减轻与移植相关的IRI。因此，我们假设：1）供体DC 活化控制肾移植中阿基的严重程度，以及2）药理学调节 供者S1 P1对IRI有保护作用。在具体目标1中，我们将检验以下假设： 供体DCs的S1 P1受体活化调节同基因小鼠肾移植中的IRI 具体目标2将检验用FTY 720治疗供体减少IRI的假设。 同基因肾移植这将使用啮齿动物肾移植模型进行检查。的 这些具体目标的结果将产生关于S1 P1对供体的作用的重要信息。 DC以减弱或预防移植相关的DGF。这些都是以前没有探索过的 这些问题可能会揭示预防DGF并可能促进康复的新目标， DCs S1 P1依赖性增加受体T细胞增殖。通过这个过程获得的知识 该项目将形成独立出版物和个人R 01应用的基础， Pi.