Lymphoid Tissue Inducer/NK22 Cells and Post-transplant Immune Recovery

淋巴组织诱导剂/NK22 细胞与移植后免疫恢复

• 批准号: 8660608
• 负责人: Michael R. Verneris
• 金额: $ 38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660608
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adult; Agonist; Allogenic; Antigens; Area; Aryl Hydrocarbon Receptor; Autoimmunity; B-Lymphocytes; Binding; Blocking Antibodies; Blood; Bone Marrow Transplantation; C-KIT Gene; Cell Proliferation; Cell Therapy; Cells; Cellular biology; Clinical; Cytokine Signaling; Data; Development; Differentiation Inducer; Engraftment; Environment; Epithelial Cells; FDA approved; Gastrointestinal tract structure; Genetic Programming; Goals; Helper-Inducer T-Lymphocyte; Hematopoiesis; Hematopoietic stem cells; Human; Immune; Immune response; Immune system; Immunity; Immunodeficient Mouse; Infection; Injury; Investigation; Knowledge; Laboratories; Laboratory Study; Lead; Life; Ligands; Ligation; Lymphocyte; Lymphoid Cell; Lymphoid Tissue; Malignant Neoplasms; Mediating; Membrane; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; NK Cell Activation; Natural Killer Cells; Nomenclature; Operative Surgical Procedures; Opportunistic Infections; Organogenesis; Outcome; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Physiology; Play; Population; Positioning Attribute; Procedures; Production; Proto-Oncogene Protein c-kit; Reaction; Reading; Recovery; Recovery of Function; Refractory; Relapse; Research; Risk; Role; Secondary to; Signal Transduction; Specimen; Stem Cell Factor; Stem cells; Stromal Cells; Structure; Structure of germinal center of lymph node; T-Lymphocyte; TNF gene; TNFSF4 gene; TRAMP protein; Testing; Thymus Gland; Translations; Transplantation; Tumor Necrosis Factor-Beta; Viral; antimicrobial; base; cell type; chemotherapy; cytokine; fetal; hematopoietic cell transplantation; immune function; improved; in vitro Model; in vivo; injured; interleukin-22; irradiation; leukemia; lymph nodes; mortality; novel; pathogen; pre-clinical; preclinical study; prevent; progenitor; public health relevance; reconstitution; repaired; research clinical testing; success; tissue repair; transcription factor

DESCRIPTION (provided by applicant): Allogeneic hematopoietic cell transplantation (allo-HCT) triggers graft vs. leukemia reactions that are uniquely curative for chemotherapy-refractory leukemia. This treatment approach can be made even more effective by enhancing the recovery of the adaptive immune system, thereby reducing the risks of opportunistic infection and relapse. Our long term goals are to make allo-HCT safer, so that more patients can benefit from this procedure. Secondary lymphoid tissues (SLTs) are where antigen-specific immune responses are initiated against pathogens and cancer. Chemotherapy and irradiation, used prior to allo-HCT, damage SLT (including lymph nodes [LN]). This injury delays post-transplant recovery of the adaptive immune system. Methods to repair injured SLTs are urgently needed. Until recently, it was not known how SLTs form during fetal life or how they are remodeled in adult life. Lymphoid tissue inducer (LTi) cells are responsible for fetal LN organogenesis and a related cell type is found in adult human SLT. In mice, adult LTi cells mediate SLT repair. Since LTi cells exist in SLTs, they are extremely difficult to study, especially in humans. As well, ther are considerable differences between murine and human LTi cells, potentially limiting the relevance of murine studies. Nearly all human LTi cell research has used clinical specimens obtained in the setting of pathology. To overcome these issues, we are the only laboratory to have generated LTi cells from human hematopoietic stem cells (HSCs). HSC-derived LTi cells are identical to those isolated from LNs. Using our newly discovered approach, we can generate large numbers of LTi cells for study or potential clinical use. The objectives of this proposal are to further determine the factors involved in LTi differentiation and the mechanisms of LTi-induced SLT repair. In specific aim 1 we will address the hypothesis that stem cell factor (SCF) plays a critical role in HSC commitment to the LTi lineage through the expression of aryl hydrocarbon receptor (AHR). We will also determine the role of soluble and membrane bound SCF on LTi development, survival and expansion. FDA- approved drugs with strong AHR agonist activity will be tested for LTi development or expansion activity. Additional studies will address whether death receptor 3 (DR3) signaling (via TNF ligand 1A (TL1A)) leads to LTi expansion. Our preliminary data shows that LTi cells interact with LN stroma to reorganize into germinal center-like structures and we further hypothesize that LTi cells can restore SLT injury. Lastly, we have found that LTi cells express TNF-superfamily molecules (including OX40L, CD70 LTa1b2 and BAFF) and hypothesize that they costimulate T, B and NK cell activation and proliferation. We will build on these preliminary findings to address whether LTi cells transferred into immunodeficient mice will facilitate human HSC engraftment and/or immune reconstitution. At the conclusion of this project, we will have determined the mechanisms responsible for the commitment of HSCs to the LTi lineage, the factors that lead to LTi cell expansion and whether they facilitate immune recovery in murine models, critical knowledge toward improving outcomes in allo-HCT.

描述（由申请人提供）：同种异体造血细胞移植（allo-HCT）引发移植物抗白血病反应，对化疗难治性白血病具有独特的疗效。通过增强适应性免疫系统的恢复，可以使这种治疗方法更加有效，从而降低机会性感染和复发的风险。我们的长期目标是让allo-HCT更安全，让更多患者能够从该手术中受益。次级淋巴组织 (SLT) 是针对病原体和癌症发起抗原特异性免疫反应的地方。在同种异体 HCT 之前使用的化疗和放疗会损害 SLT（包括淋巴结 [LN]）。这种损伤会延迟移植后适应性免疫系统的恢复。迫切需要修复受损 SLT 的方法。直到最近，人们还不知道 SLT 在胎儿时期是如何形成的，或者在成年后是如何重塑的。淋巴组织诱导 (LTi) 细胞负责胎儿 LN 器官发生，在成人 SLT 中发现了相关细胞类型。在小鼠中，成年 LTi 细胞介导 SLT 修复。由于 LTi 细胞存在于 SLT 中，因此研究起来极其困难，尤其是在人类中。此外，小鼠和人类 LTi 细胞之间存在相当大的差异，这可能限制了小鼠研究的相关性。几乎所有人类 LTi 细胞研究都使用在病理学背景下获得的临床标本。为了克服这些问题，我们是唯一一个从人类造血干细胞 (HSC) 中产生 LTi 细胞的实验室。 HSC 衍生的 LTi 细胞与从 LN 分离的细胞相同。使用我们新发现的方法，我们可以产生大量 LTi 细胞用于研究或潜在的临床用途。该提案的目标是 进一步确定参与LTi分化的因素以及LTi诱导的SLT修复的机制。在具体目标 1 中，我们将提出以下假设：干细胞因子 (SCF) 通过芳烃受体 (AHR) 的表达在 HSC 向 LTi 谱系的承诺中发挥关键作用。我们还将确定可溶性和膜结合 SCF 对 LTi 发育、存活和扩增的作用。 FDA 批准的具有强 AHR 激动剂活性的药物将进行 LTi 开发或扩展活性测试。其他研究将探讨死亡受体 3 (DR3) 信号传导（通过 TNF 配体 1A (TL1A)）是否会导致 LTi 扩增。我们的初步数据表明，LTi 细胞与 LN 基质相互作用，重组为生发中心样结构，我们进一步假设 LTi 细胞可以恢复 SLT 损伤。最后，我们发现 LTi 细胞表达 TNF 超家族分子（包括 OX40L、CD70 LTa1b2 和 BAFF），并假设它们共刺激 T、B 和 NK 细胞活化和增殖。我们将根据这些初步发现来解决 LTi 细胞是否转移的问题 进入免疫缺陷小鼠体内将促进人类 HSC 植入和/或免疫重建。在该项目结束时，我们将确定负责 HSC 向 LTi 谱系定型的机制、导致 LTi 细胞扩增的因素以及它们是否促进小鼠模型中的免疫恢复、改善同种异体结果的关键知识。血细胞CT。