Immunobiology for Marrow Allografts for Leukemia

描述（由申请人提供）：我们提出一个综合的、多学科的基础和临床研究项目，解决同种异体造血干细胞移植用于治疗老年人和缺乏组织相容性供体的AML、ALL和MDS的成功挑战。该项目的中心主题是：探索新的方法，从而减少或预防由条件反射、感染和GVHD引起的正常宿主组织损伤，并选择性地增强对病原体和复发性白血病的抵抗力。该计划包括6个研究项目和3个核心。项目1研究NK细胞的发育，宿主和供体表达的HLA配体的KIR参与调节NK功能的作用，特别是激活KIR、2DS1和3Ds1对抵抗白血病复发和CMV感染的贡献。项目2研究控制单核细胞对来自微生物群的刺激反应的受体配体相互作用，包括它们的激活、动员和组织分布，以及它们刺激和参与GVHD的能力。项目3研究了在存在JAK-2抑制剂的情况下，同种异体单核细胞衍生的树突状细胞如何刺激t细胞进入持久的能量状态，以及JAK-2抑制剂对反应的影响，这些反应是由其他功能不同类型的树突状细胞呈现的肿瘤抗原。项目4评估IL-22的调控，其在刺激肠和胸腺上皮修复中的作用，以及其在降低毒性、调节GVHD和增强感染抵抗力方面的潜力。项目5测试针对WT1肽/HLA复合物的新型单克隆抗体，用于表达WT1/HLA复合物特异性tcr或嵌合抗原受体的长寿命EBV t细胞，以及用于WT-1+白血病过继免疫治疗的新型异源疫苗，项目6提出6项临床试验，测试新的调节和t细胞枯竭和脐带血HSCT，以减少毒性。增强造血和胸腺功能恢复，减少TRM和新的过继性t细胞治疗CMV感染或复发性白血病。这三个核心包括：核心A提供所有患者样本并评估HSCT前后的移植物，核心B生物统计学和核心C行政支持和监督。

DESCRIPTION (provided by applicant): We propose an integrated, multidisciplinary program of basic and clinical research addressing challenges to the success of allogeneic HSCT used to treat of AML, ALL and MDS in older adults and patients lacking a histocompatible donor. The program's central theme of this program is: The exploration of novel approaches whereby injuries to normal host tissues induced by conditioning, infection and GVHD can be reduced or prevented, and resistance to pathogens and recurrent leukemia selectively enhanced. The program includes 6 research projects and 3 cores. Project 1 examines NK cell development, the role of KIR engagement of HLA ligand expressed by host and donor in modulating NK function, and, particularly, the contributions of activating KIRs, 2DS1 and 3Ds1 to resistance against leukemic relapse and CMV infections. Project 2 examines receptor ligand interactions governing monocyte response to stimuli from the microflora including their activation, mobilization and tissue distribution, and their capacity to both stimulate and participate in GVHD. Project 3 examines how T-cells when stimulated with allogeneic monocyte-derived dendritic cells in the presence of JAK-2 inhibitors induced into a durable state of anergy and the effects of JAK-2 inhibitors on responses are tumor antigens presented by other functionally distinct types of dendritic cells. Project 4 evaluates the regulation of IL-22, its role in the stimulation of enteri and thymic epithelial repair and its potential to reduce toxicities, modulate GVHD and enhance resistance to infection. Project 5 tests new monoclonal antibodies specific for WT1 peptide/HLA complexes, long-lived EBV T-cells transduced to express TCRs or chimeric antigen receptors specific for WT1/HLA complexes and new heteroclitic vaccines for adoptive immunotherapy of WT-1+ leukemias, Project 6 proposes 6 clinical trials testing new conditioning and both T-cell depleted and cord blood HSCT to reduce toxicities, potentiate hematopoietic and thymopoietic recovery and reduce TRM and new adoptive T-cell therapies for CMV infections or recurrent leukemia . The 3 cores include: Core A which provides all patient samples and evaluate grafts pre and post HSCT, Core B Biostatistics and Core C administrative support and oversight.