Novel Approaches to Graft-versus-Host Disease Prevention

异基因造血干细胞移植(HSCT)是治疗许多慢性粒细胞白血病患者的唯一治疗方法。 恶性血液病和骨髓衰竭。移植相关因素限制了造血干细胞移植的全部潜力。 并发症--尤其是急性和慢性移植物抗宿主病(CGVHD)。控制GVHD的传统手段， 尤其是慢性移植物抗宿主病，只是部分有效。尽管急性GVHD得到了很好的控制，但50%-70%的患者 发展cGVHD。慢性移植物抗宿主病是HSCT的主要晚期并发症。的异构性 临床表现和发病晚导致研究落后于临床需要。这个 CGVHD的重要性越来越重要，因为1)HSCT技术的改进允许使用较老的 捐赠者移植老年患者，2)cGVHD的发生率增加，因为更多地使用外周血细胞 血液作为干细胞来源，以及3)支持性护理的改进导致更少的无复发死亡率和 因此，更多的患者在cGVHD发生的晚期存活。这是一个开始着手的机会 利用GVHD病理生物学方面的新信息进行的新研究。B细胞的重要性和 调节性T细胞(Treg)越来越清楚，但直接操纵B细胞和 Treg在人类中起作用。我们现在知道，B细胞与T细胞协同工作，以产生 CGVHD。项目1包括三个具体目标(SA)，其中包括5个制定新的预防战略的项目 治疗GVHD。SA1a是一种预防无活动性GVHD患者cGVHD的新方法 抗CD20单抗，靶向cGVHD的B细胞成分。在SA1b中，目标是消除钙调神经磷酸酶 来自GVHD预防的抑制剂(CNI)。CNI具有不良的内在毒性，它们抑制Treg在 适得其反的时尚。通过使用无CNI方案，Treg的扩展被促进以减少 同种异体和自身免疫，因此急性和慢性移植物抗宿主病的总体风险。在SA 2战略中，防止 对HSCT的主要并发症、肝脏VOD进行评估。在SA 3中，两种互补的治疗方法 激素耐药的cGVHD将被评估：1)通过协同抑制B和T细胞与低剂量的抗GVHD CD52单抗；2)用超低剂量IL-2扩增Treg。 相关性(请参阅说明)： CGVHD的重要性越来越重要，因为1)HSCT技术的改进允许使用 老年供者移植老年患者，2)cGVHD的发生率增加，因为更多地使用 外周血作为干细胞来源，以及3)支持性护理的改进导致不复发的减少 在慢性移植物抗宿主病发生的晚期，死亡率和活着的病人更多。这是一个机会，可以 开展新的研究，利用GVHD病理生物学的新信息

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for many patients with hematologic malignancies and marrow failure. The full potential of HSCT is limited by transplant related complications -particularly acute and chronic GVHD (cGVHD). Traditional means to control GVHD, particularly cGVHD, are only partially effective. Despite excellent control of acute GVHD, 50-70% of patients develop cGVHD. Chronic GVHD is the primary late complication of HSCT. The heterogeneity of manifestations and late onset has led to a situation where research lags behind clinical needs. The importance of cGVHD is increasingly relevant as 1) improvements in HSCT technology allow the use of older donors to transplant older patients, 2) the incidence of cGVHD increased due to greater use of peripheral blood as a stem cell source, and 3) improvements in supportive care result in less nonrelapse mortality and thus more patients alive in the late time periods when cGVHD occurs. This is an opportunity to embark on novel studies to leverage new information on the pathobiology of GVHD. The importance of B cells and regulatory T cells (Treg) is increasingly clear, but there has been little effort to directly manipulate B cell and Treg function in humans. We now know that B cells work with T cells in a coordinated fashion to produce cGVHD. Project 1 includes three Specific Aims (SA) including 5 projects to develop new strategies to prevent and treat GVHD. SA1a is a novel approach to prevent cGVHD in patients without active GVHD using monoclonal anti-CD20 to target the B cell component of cGVHD. In SA1b the goal is to eliminate calineurin inhibitors (CNI) from GVHD prophylaxis. CNI have undesirable intrinsic toxicity, and they inhibit Treg in a counterproductive fashion. By using CNI-free regimens, the expansion of Treg is facilitated to reduce both allo- and autoimmunity, and thus the overall risk of both acute and cGVHD. In SA 2 strategies to prevent a major complication of HSCT, hepatic VOD are assessed. In SA 3, two complementary approaches to treat steroid-resistant cGVHD will be evaluated: 1) by coordinately inhibiting both B and T cells with low dose anti- CD52 monoclonal antibody, and 2) by expansion of Treg with ultra low dose IL-2. RELEVANCE (See instructions): The importance of cGVHD is increasingly relevant as 1) improvements in HSCT technology allow the use of older donors to transplant older patients, 2) the incidence of cGVHD increased due to greater use of peripheral blood as a stem cell source, and 3) improvements in supportive care result in less nonrelapse mortality and thus more patients alive in the late time periods when cGVHD occurs. This is an opportunity to embark on novel studies to leverage new information on the pathobiology of GVHD