New Therapeutics for Post-Transplant Lymphoproliferative Disorder

描述（由申请人提供）：虽然使用免疫抑制对实体器官移植的成功至关重要，但它也使患者容易增加感染和恶性肿瘤的发生率。eb病毒（EBV） B细胞淋巴瘤合并移植后淋巴细胞增生性疾病（PTLD）是移植受者中最具挑战性和最严重的并发症之一。目前，对于PTLD患者的治疗策略尚未达成共识，部分原因是所采用的方法疗效不一，而且我们无法预测哪种治疗方法对特定患者最有利。此外，复发和治疗相关死亡率是主要问题。我们的实验室一直致力于阐明EBV+ PTLD的潜在发病机制，以确定新的治疗靶点。我们发现PI3K/Akt/mTOR通路在PTLD患者的EBV+ B细胞淋巴瘤中具有组成性活性，EBV导致该通路失调。我们还发现EBV+ B细胞淋巴瘤的存活和增殖依赖于PI3K/Akt/mTOR通路，因为靶向通路成分的小分子抑制剂或siRNA显著抑制淋巴瘤生长。在本研究中，我们计划1)确定PI3K/Akt/mTOR通路在EBV+ B细胞淋巴瘤存活和生长中的作用，并确定针对该通路关键节点的合理治疗方法；2)确定靶向PI3K/Akt/mTOR通路是否影响同种异体器官移植和EBV的免疫反应。为了完成目标1，我们将对PTLD组织和B细胞淋巴瘤系进行生化、分子、细胞和药理学分析，以确定PI3K/Akt/mTOR通路中的“敏感”节点。我们还将研究病毒致癌基因、潜伏膜蛋白1和宿主细胞microRNA在该通路潜在失调中的作用。在Aim 2中，我们将利用小鼠异体心脏移植模型来确定PI3K/Akt/mTOR通路调节对异体移植免疫反应的影响。最后，我们将利用大量细胞术来确定PI3K/Akt/mTOR信号转导如何促进异体抗原特异性和ebv特异性的人类T细胞反应。这些研究将为改善EBV+ PTLD的治疗创造新的机会，也将增加我们对EBV+ B细胞淋巴瘤生物学、同种异体移植排斥以及同种异体抗原和EBV特异性人T细胞反应的基本认识。

DESCRIPTION (provided by applicant): While the use of immunosuppression is crucial to the success of solid organ transplantation, it also predisposes patients to an increased incidence of infection and malignancy. Epstein Barr virus (EBV) B cell lymphomas associated with post-transplant lymphoproliferative disorder (PTLD) represent one of the most challenging, and serious, complications in transplant recipients. Currently, there is no consensus on treatment strategies for patients with PTLD, in part because the approaches utilized vary in their efficacy and because we cannot predict which therapy will best benefit a given patient. Furthermore, relapse and treatment-related mortality are major concerns. Our laboratory has worked to elucidate the underlying pathogenesis of EBV+ PTLD as a strategy to identify novel therapeutic targets. We have discovered that the PI3K/Akt/mTOR pathway is constitutively active in EBV+ B cell lymphomas from patients with PTLD and that EBV contributes to dysregulation of this pathway. We have also shown that survival and proliferation of EBV+ B cell lymphomas depends upon the PI3K/Akt/mTOR pathway because small molecule inhibitors, or siRNA, that target pathway constituents significantly inhibit lymphoma growth. In this proposal we plan to 1) determine the role of the PI3K/Akt/mTOR pathway in survival and growth of EBV+ B cell lymphomas, and identify rational therapeutics for targeting key nodes in the pathway; 2) determine whether targeting the PI3K/Akt/mTOR pathway affects the immune response to organ allografts and to EBV. To accomplish Aim 1 we will perform biochemical, molecular, cellular, and pharmacologic analysis of PTLD tissue and B cell lymphoma lines to identify "sensitive" nodes within the PI3K/Akt/mTOR pathway. We will also investigate the role of the viral oncogene, latent membrane protein 1, and host cell microRNA in the underlying dysregulation of the pathway. In Aim 2 we will utilize a murine heterotopic heart allograft model to determine the effect of PI3K/Akt/mTOR pathway modulation on the immune responses to an allograft. Finally, we will utilize mass cytometry to determine how PI3K/Akt/mTOR signal transduction contributes to alloantigen-specific and EBV-specific human T cell responses. These studies will create new opportunities for improving the treatment of EBV+ PTLD, and will also increase our basic understanding of EBV+ B cell lymphoma biology, allograft rejection, and alloantigen- and EBV-specific human T cell responses.