Innate Immunity and Viral Renal Allograft Injury

先天免疫和病毒性同种异体肾移植损伤

基本信息

批准号：
8513454
负责人：
Masako Shimamura
金额：
$ 36.23万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8513454
关键词：
Activated Natural Killer Cell Acute Adverse event Affect Alloantigen Allogenic Allografting Animal Model Animals Antibody Formation Antigen-Presenting Cells Antiviral Agents Biopsy Cell physiology Cells Childhood Clinical Complex Cytolysis Cytomegalovirus Cytomegalovirus Infections Data Databases Dendritic Cells Event Functional disorder Future Ganciclovir Genes Goals Graft Survival Histology Human Immunosuppression Infection Inferior Infiltration Injury Interferons Kidney Kidney Failure Kidney Transplantation Lead Licensing Longevity Lymphocyte Mediating Modeling Modification Murid herpesvirus 1 Mus NK Cell Activation Natural Immunity Natural Killer Cells Outcome Pathogenesis Patients Population Production Quality of life Relative (related person)Role Sampling Satellite Viruses Staining method Stains T-Lymphocyte Time Tissues Transplant Recipients Transplantation Viral Virus Virus Diseases Work base experience graft function improved kidney allograft killings mutant novel strategies patient population prevent response translational approach transmission process virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): Despite excellent short-term outcomes in renal transplant recipients resulting from advances in immunosuppression and management, long-term allograft survival has not substantially improved over the past few decades. Viral infections, particularly human cytomegalovirus (HCMV), are associated epidemiologically with inferior transplant outcomes. The pathogenesis behind these observations is not known; however, CMV infection is well recognized to activate innate effectors such as natural killer (NK) cells. The function of NK cells in allograft loss has not been clearly defined: in animal models, NK cells can contribute to either rejection (by promoting activation and differentiation of dendritic cells and alloreactive T lymphocytes), or tolerance (by killing donor antigen presenting cells). CMV infection in animal models can reverse NK mediated tolerance to allografts by unknown mechanisms. An understanding of the pathogenesis of virus associated allograft injury could lead to new approaches to improve allograft survival and function in CMV-infected transplant recipients. To better understand how CMV infection contributes to renal allograft loss, we have developed a murine transplant model in which murine CMV (MCMV) infected donor kidneys are transplanted into MCMV native recipient mice, resembling the mode of viral transmission in transplant patients. MCMV infected allografts demonstrated accelerated and intensified tissue damage compared to uninfected grafts, and this damage was associated with increased intragraft NK cell infiltration. Pharmacologic inhibition of viral replication resulted in decrease NK infiltration and improvement in allograft histology. In this application, we will use this model to determine whether NK cells in MCMV infected allografts induce direct antiviral-directed graft damage, or whether virus-induced NK activity might exacerbate allogeneic responses. Findings from the animal model will then be used to guide and focus analysis of archival human renal transplant biopsies to identify likely pathogenic mechanisms and predictors of virus-associated graft dysfunction. Since not all patients with CMV infection experience allograft loss, it is likel that many factors contribute to allograft outcome. It is intended that the work in the animal model will identify potential factors of relevance to outcome in CMV infected transplant patients, so that analysis of the patient samples can be directed toward likely parameters that may be correlated with virus-associated allograft injury. The long-term goal of these studies is to identiy predictors of patients likely to develop virus-associated allograft dysfunction, and to suggest future strategies to improve graft function by modifying these virus-associated mechanisms of allograft injury.

描述（由申请人提供）：尽管由于免疫抑制和管理方面的进步，肾移植受者取得了优异的短期结果，但在过去几十年中，同种异体移植物的长期存活率并未得到实质性改善。病毒感染，特别是人类巨细胞病毒（HCMV），在流行病学上与较差的移植结果相关。这些观察结果背后的发病机制尚不清楚；然而，人们普遍认为 CMV 感染会激活自然杀伤 (NK) 细胞等先天效应细胞。 NK 细胞在同种异体移植物丢失中的功能尚未明确定义：在动物模型中，NK 细胞可以有助于排斥（通过促进树突状细胞和同种异体反应性 T 淋巴细胞的活化和分化）或耐受（通过杀死供体抗原呈递细胞）。动物模型中的 CMV 感染可以通过未知机制逆转 NK 介导的对同种异体移植物的耐受性。了解病毒相关同种异体移植物损伤的发病机制可能会带来改善CMV感染移植受者同种异体移植物存活和功能的新方法。为了更好地了解 CMV 感染如何导致同种异体移植肾损失，我们开发了一种小鼠移植模型，其中将受 CMV (MCMV) 感染的小鼠供体肾脏移植到 MCMV 天然受体小鼠中，类似于移植患者中的病毒传播模式。与未感染的移植物相比，MCMV 感染的同种异体移植物表现出加速和强化的组织损伤，并且这种损伤与移植物内 NK 细胞浸润的增加有关。病毒复制的药物抑制导致 NK 浸润减少和同种异体移植物组织学改善。在这个应用程序中，我们将使用这个模型以确定 MCMV 感染的同种异体移植物中的 NK 细胞是否会诱导直接抗病毒定向的移植物损伤，或者病毒诱导的 NK 活性是否可能加剧同种异体反应。然后，动物模型的研究结果将用于指导和集中分析存档的人类肾移植活检，以确定可能的致病机制和病毒相关移植物功能障碍的预测因素。由于并非所有 CMV 感染患者都会出现同种异体移植物丢失，因此可能有许多因素会影响同种异体移植物的结果。动物模型的工作旨在确定与 CMV 感染的移植患者的结果相关的潜在因素，以便对患者样本的分析可以针对可能与病毒相关的同种异体移植损伤相关的可能参数。这些研究的长期目标是确定可能发生病毒相关同种异体移植物功能障碍的患者的预测因子，并提出通过修改这些病毒相关同种异体移植物损伤机制来改善移植物功能的未来策略。