Pathogenesis of Murine Polyomavirus Allograft Nephropathy

描述（由申请人提供）：BK人多瘤病毒（BKV）在绝大多数健康个体中建立了一种沉默的、持续的感染。然而，在免疫抑制的情况下（如艾滋病、骨髓移植、肾移植），BKV的高水平复制可能随之而来，并导致一系列严重的尿路并发症。在肾移植的背景下，BKV感染已成为异体移植物功能障碍和失败的主要原因。由于多瘤病毒科的物种特异性，我们对肾移植后BKV肾病（BKVN）发病机制的理解以及有效治疗方法的开发受到缺乏可控制的动物模型的限制。为了解决这个问题，我们开发了一种独特的实验模型，模拟了临床移植中BKVN的许多重要特征，即肾移植后小鼠多瘤病毒感染。该模型的以下关键方面证明了为什么它对研究移植后BKV感染很有用：1)小鼠多瘤病毒（PyV）是一种普遍存在且无害的野生小鼠病原体，2)急性PyV感染通过CD8+ T细胞依赖过程被免疫能力强的宿主迅速清除，3)急性感染消退后，病毒在包括肾脏在内的许多组织中无限期存在，但不会引起病理。(4)急性PyV感染可显著加速移植小鼠同种异体移植肾的损伤，但对同种异体移植肾和原生肾无明显损伤。我们将使用小鼠pyv肾移植模型来解决三个具体目标。在第一个目标中，我们将评估PyV感染的来源和时间，以及临床相关免疫抑制剂和抗病毒治疗对PVAN发展的影响。异体移植物功能和存活的研究将通过受体抗病毒和抗供体免疫反应的分析来补充。在第二个目标中，我们将验证MHC匹配的假设，特别是MHC I类位点，将导致受体对PyV的免疫力提高，从而减少同种异体移植物损伤。此外，鉴于在临床移植中经常使用完全HLA错配的肾脏，我们将验证先天免疫有助于控制PyV感染的假设。在第三个目标中，我们将确定在PyV感染的情况下，抗病毒和抗供体T细胞免疫对同种异体移植物损伤的各自贡献。具体来说，我们将验证以下假设：1)直接的病毒细胞病变效应，2)由病毒介导的炎症诱导的抗供体T细胞反应，和/或3)由pyv特异性T细胞介导的免疫病理。使用我们的小鼠pyv肾移植模型将使我们能够控制许多变量，这些变量在临床上混淆了我们对BKVN发病机制的理解。这些研究的结果可能直接导致新的治疗方法的发展，以预防和治疗人类肾移植受者的BKV感染。人类多瘤病毒BK越来越被认为是移植肾功能障碍和衰竭的重要原因。由于BK病毒具有很强的物种特异性，因此无法在动物模型中进行研究，因此我们需要开发一种肾移植和天然小鼠多瘤病毒感染的联合模型。该小鼠模型将用于确定多瘤病毒导致移植肾衰竭的机制，并开发新的治疗干预措施。

DESCRIPTION (provided by applicant): The BK human polyomavirus (BKV) establishes a silent, persistent infection in the vast majority of healthy individuals. However, under conditions of immunosuppression (e.g., AIDS, BM transplantation, renal transplantation), high-level replication by BKV may ensue and result in a spectrum of severe urinary tract complications. In the setting of renal transplantation, BKV infection has emerged as a major cause of allograft dysfunction and failure. Due to the exquisite species specificity of Polyomaviridae, our understanding of the pathogenesis of BKV nephropathy (BKVN) following renal transplantation, as well as the development of effective therapies, is limited by the absence of a tractable animal model. To address this problem, we have developed an unique experimental model of polyomavirus infection in mice following kidney transplantation that mimics many of the important features of BKVN in clinical transplantation. The following key aspects of this model demonstrate why it is useful for studying BKV infection following transplantation: 1) mouse polyoma virus (PyV) is a ubiquitous and harmless pathogen wild mice, 2) acute PyV infection is rapidly cleared by immunocompetent hosts via a CD8+ T cell-dependent process, 3) following resolution of the acute infection, virus persists indefinitely in a number of tissues including the kidney but fails to cause pathology, and 4) acute PyV infection dramatically accelerates injury to allogeneic transplanted kidneys but not to syngeneic transplanted kidneys or native kidneys in transplanted mice. We will use the mouse PyV-kidney transplant model to address three specific aims. In the first aim we will evaluate the source and timing of PyV infection as well as the effects of clinically relevant immunosuppressive agents and anti-viral therapies on the development of PVAN. Studies of allograft function and survival will be complemented by analysis of the recipient anti-viral and anti-donor immune responses. In the second aim we will test the hypothesis that MHC matching, particularly at MHC class I loci, will result in improved recipient immunity to PyV and consequently reduced allograft injury. In addition, given the frequent use of fully HLA mismatched kidneys in clinical transplantation, we will test the hypothesis that innate immunity contributes to the control of PyV infection. In the third aim, we will determine the respective contributions of anti-viral and anti-donor T cell immunity to allograft injury in the setting of PyV infection. Specifically we will test the hypotheses that PVAN is mediated by 1) direct viral cytopathic effects, 2) an accentuated anti-donor T cell response induced by virally mediated inflammation, and/or 3) immunopathology mediated by PyV-specific T cells. The use of our mouse PyV-kidney transplant model will allow us to control many of the variables that have confounded our understanding of the pathogenesis of BKVN clinically. The results of these studies may directly lead to the development of new therapeutic approaches to prevent and treat BKV infection in human renal transplant recipients. PUBLIC HEALTH RELEVANCE The human polyomavirus BK is increasingly recognized as a significant cause of dysfunction and failure of transplanted kidneys. Due to its tight species specificity BK virus can not be studied in animal models necessitating our development of a combined model of kidney transplantation and infection by the natural mouse polyoma virus. This mouse model will be used to define the mechanisms by which polyomavirus causes the failure of transplanted kidneys and to develop novel therapeutic interventions.