New Therapeutics for Post-Transplant Lymphoproliferative Disorder

描述（由申请人提供）：虽然免疫抑制剂的使用对实体器官移植的成功至关重要，但它也使患者感染和恶性肿瘤的发生率增加。Epstein巴尔病毒（EBV）B细胞淋巴瘤与移植后淋巴组织增生性疾病（PTLD）相关，是移植受者中最具挑战性和最严重的并发症之一。目前，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在疗效上各不相同，而且我们无法预测哪种疗法对特定患者最有益。此外，复发和治疗相关的死亡率也是主要关切问题。我们的实验室致力于阐明EBV+ PTLD的潜在发病机制，作为确定新治疗靶点的策略。我们已经发现PI 3 K/Akt/mTOR通路在PTLD患者的EBV+ B细胞淋巴瘤中是组成性活性的，并且EBV有助于该通路的失调。我们还表明，EBV+ B细胞淋巴瘤的存活和增殖取决于PI 3 K/Akt/mTOR途径，因为靶向途径成分的小分子抑制剂或siRNA显著抑制淋巴瘤生长。在该提案中，我们计划1）确定PI 3 K/Akt/mTOR通路在EBV+ B细胞淋巴瘤的存活和生长中的作用，并确定靶向通路中的关键节点的合理疗法; 2）确定靶向PI 3 K/Akt/mTOR通路是否影响对器官同种异体移植物和EBV的免疫应答。为了实现目标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，以鉴定PI 3 K/Akt/mTOR通路内的“敏感”节点。我们还将研究病毒癌基因、潜伏膜蛋白1和宿主细胞microRNA在该途径潜在失调中的作用。在目的2中，我们将利用鼠异位心脏同种异体移植物模型来确定PI 3 K/Akt/mTOR通路调节对同种异体移植物的免疫应答的影响。最后，我们将利用质谱流式细胞术来确定PI 3 K/Akt/mTOR信号转导如何促进同种异体抗原特异性和EBV特异性人T细胞应答。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、同种异体移植物排斥、同种异体抗原和EBV特异性人类T细胞应答的基本理解。

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.