Strategies to enhance immune reconstitution after BMT

BMT 后增强免疫重建的策略

• 批准号: 7691047
• 负责人: Marcel R M van den Brink
• 金额: $ 9.81万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7691047
• 关键词: Adoptive Transfer; Age; Allogenic; Allografting; Antigens; Apoptosis; Biological Assay; Cell Therapy; Cell physiology; Chimerism; Development; Disease; Dose; Graft-Versus-Tumor Induction; Growth Factor; Hematopoietic Stem Cell Transplantation; Homing; Immune; In Vitro; Incidence; Infection; Interleukin-7; Kinetics; Ligands; Listeria monocytogenes; Malignant - descriptor; Modeling; Morbidity - disease rate; Mus; Natural Killer Cells; Non-Malignant; Numbers; Peripheral; Recovery; Relapse; Role; Site; Stromal Cells; System; T-Cell Development; T-Lymphocyte; Testing; Time; Transplantation; antimicrobial; cytokine; design; graft vs host disease; improved; in vivo; keratinocyte growth factor; middle age; mortality; notch protein; novel; preclinical study; reconstitution; research study

DESCRIPTION (provided by applicant): Strategies to enhance post-transplant T and NK cell reconstitution could decrease the incidence of fatal infectious complications and malignant relapse, and significantly improve the overall survival of recipients of a hematopoietic stem cell transplantation (HSCT). We propose studies in murine allogeneic HSCT models to analyze the effects on post-transplant T cell reconstitution of the adoptive transfer of ex vivo expanded T cell precursors to HSCT recipients. Large numbers of T cell precursors can be generated using a novel culture system using stromal cells expressing the Notch ligand Delta-like 1 (OP9-DL1). In preliminary studies we found that the adoptive transfer of OP9-DL1 derived T cell precursors to recipients of a T cell-depleted allograft can enhance early post-transplant T and NK cell reconstitution and donor chimerism. This improvement in post-transplant T and NK cell reconstitution results in significant graft-versus-tumor (GVT) activity without graft-versus-host disease (GVHD), and better antimicrobial activity against Listeria monocytogenes. Adoptive transfer of T cell precursors to HSCT recipients treated with keratino growth factor (KGF) had an additive effect on T cell reconstitution. We will assess the kinetics of T and NK cell reconstitution in recipients with varying degrees of MHC disparity, recipients with or without GVHD, young vs. middle-aged recipients, as well as the effects of varying doses of T cell precursors, the role of homing molecules, the effects of the timing of administration and multiple doses of T cell precursors, and the site of T cell development (thymic vs. extrathymic). In addition, we will test combination strategies using administration of T cell precursors and immunostimulatory cytokines/growth factors such as lnterleukin-7 (IL-7) and KGF. In addition to in vitro functional T and NK cell assays, we will assess the effects of T cell precursor administration to HSCT recipients on anti-microbial activity against Listeria monocytogenes and GVT activity in vivo. These preclinical studies could result in the development of a safe and effective adoptive cell therapy using transfer of T cell precursors in combination with cytokines/growth factors to decrease post-transplant morbidity and mortality from infections and relapse in HSCT recipients.

描述（由申请人提供）：增强移植后T和NK细胞重建的策略可能会降低致命感染并发症和恶性复发的发生率，并显着提高造血干细胞移植受体的总体存活率（HSCT）。我们提出了对鼠同种异体HSCT模型的研究，以分析对移植后T细胞重建的影响，从而将过体的T细胞前体扩展到HSCT受体。可以使用表达Notch配体Delta样1（OP9-DL1）的基质细胞使用新型培养系统（OP9-DL1）生成大量T细胞前体。在初步研究中，我们发现，OP9-DL1衍生的T细胞前体的过继转移到耗尽T细胞的同种异体移植物的受体可以增强移植后T和NK细胞重建后的早期早期，以及供体嵌合。移植后T和NK细胞重建的这种改善导致没有移植物与宿主病（GVHD）（GVHD）和对单核细胞增生李斯特菌的抗菌活性更好的移植物及其肿瘤（GVT）活性。将T细胞前体转移到接受Keratino生长因子（KGF）治疗的HSCT受体对T细胞重建的附加作用。我们将评估具有不同程度的MHC差异的受体中T和NK细胞重建的动力学，具有或不具有GVHD的受体，年轻人与中年接受者，中年与中年的受体以及不同剂量的T细胞前体的影响外激体）。此外，我们将使用T细胞前体和免疫刺激性细胞因子/生长因子（例如Lnterleukin-7（IL-7）和KGF）测试组合策略。除了体外功能性T和NK细胞测定外，我们还将评估T细胞前体给予HSCT受体对抗微生物菌活性对单核细胞增生李斯特菌的抗菌活性和体内GVT活性的影响。这些临床前研究可能会导致使用T细胞前体与细胞因子/生长因子结合转移的安全有效的收养细胞疗法，从而降低移植后的发病率和感染中的死亡率以及HSCT接受者的复发。