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(申请人提供)：异基因造血细胞移植(allo-hct)触发移植物对白血病的反应，对化疗难治的白血病是唯一有效的。通过加强适应性免疫系统的恢复，从而减少机会性感染和复发的风险，这种治疗方法可以变得更加有效。我们的长期目标是使allo-HCT更安全，这样更多的患者可以从这一过程中受益。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反应的地方。在allo-HCT前使用的化疗和放疗会损害SLT(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。修复损伤的SLT的方法迫在眉睫。直到最近，人们还不知道SLT在胎儿时期是如何形成的，或者它们在成年生活中是如何重塑的。淋巴组织诱导物(LTI)细胞负责胎儿LN器官的发生，在成人SLT中发现了一种相关的细胞类型。在小鼠中，成年LTI细胞介导SLT修复。由于LTI细胞存在于SLT中，因此对它们的研究非常困难，特别是在人类中。此外，小鼠和人类的LTI细胞之间也有相当大的差异，潜在地限制了小鼠研究的相关性。几乎所有的人类LTI细胞研究都使用了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(HSCs)中培养出LTI细胞的实验室。HSC来源的LTI细胞与分离自LNS的LTI细胞相同。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应用。这项提议的目标是 进一步确定LTI分化的相关因素及LTI诱导SLT修复的机制。在具体目标1中，我们将解决干细胞因子(SCF)通过芳香烃受体(AHR)的表达在HSC对LTI谱系的承诺中发挥关键作用的假设。我们还将确定可溶性和膜结合的SCF在LTI的发育、存活和扩增中的作用。FDA批准的具有强大AHR激动剂活性的药物将接受LTI开发或扩展活性测试。其他研究将解决死亡受体3(DR3)信号(通过肿瘤坏死因子配体1A(TL1A))是否导致LTI扩大。我们的初步数据显示，LTI细胞与LN间质相互作用，重组为生发中心样结构，并进一步假设LTI细胞可以修复SLT损伤。最后，我们发现LTI细胞表达肿瘤坏死因子超家族分子(包括OX40L、CD70LTa1b2和BAFF)，并假设它们共同刺激T、B和NK细胞的激活和增殖。我们将在这些初步发现的基础上解决LTI细胞是否转移 移植到免疫缺陷小鼠中将促进人类HSC的植入和/或免疫重建。在本项目结束时，我们将确定导致造血干细胞向LTI谱系承诺的机制，导致LTI细胞扩张的因素，以及它们是否促进小鼠模型的免疫恢复，以及改善allo-HCT预后的关键知识。