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）：异基因造血细胞移植（allo-HCT）引发移植物抗白血病反应，可独特地治愈化疗难治性白血病。这种治疗方法可以通过增强适应性免疫系统的恢复而变得更加有效，从而降低机会性感染和复发的风险。我们的长期目标是使allo-HCT更安全，以便更多的患者可以从该手术中受益。次级淋巴组织（SLT）是针对病原体和癌症启动抗原特异性免疫应答的地方。在allo-HCT之前使用的化疗和放疗会损害淋巴结（包括淋巴结[LN]）。这种损伤延迟了移植后适应性免疫系统的恢复。修复受损的SLTs的方法是迫切需要的。直到最近，人们还不知道SLTs在胎儿期是如何形成的，也不知道它们在成人期是如何重塑的。类淋巴结组织诱导细胞（LTi）负责胎儿LN器官发生，在成人LN中发现了相关的细胞类型。在小鼠中，成年LTi细胞介导视网膜修复。由于LTi细胞存在于SLT中，因此它们非常难以研究，特别是在人类中。同样，鼠和人LTi细胞之间存在相当大的差异，可能限制了鼠研究的相关性。几乎所有的人类LTi细胞研究都使用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分离的那些相同。使用我们新发现的方法，我们可以产生大量的LTi细胞用于研究或潜在的临床用途。这项建议的目的是 以进一步确定参与LTi分化的因素和LTi诱导的细胞修复机制。在具体目标1中，我们将解决干细胞因子（SCF）通过芳烃受体（AHR）的表达在HSC向LTi谱系的定型中起关键作用的假设。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被测试LTi开发或扩展活性。其他研究将解决死亡受体3（DR 3）信号传导（通过TNF配体1A（TL 1A））是否导致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OX 40 L、CD 70 LTa 1b 2和BAFF），并假设它们共刺激T、B和NK细胞活化和增殖。我们将在这些初步研究结果的基础上， 移植入免疫缺陷小鼠将促进人HSC移植和/或免疫重建。在该项目结束时，我们将确定负责HSC向LTi谱系承诺的机制，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，这是改善allo-HCT结果的关键知识。