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: 8575441
• 负责人: Michael R. Verneris
• 金额: $ 35.72万
• 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/8575441
• 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; 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）触发移植物与白血病反应，这些反应可用于化学疗法 - 性疗法 - 性治疗性白血病。通过增强自适应免疫系统的恢复，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。我们的长期目标是使Allo-HCT更安全，以便更多的患者可以从此手术中受益。继发性淋巴组织（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Allo-HCT之前使用的化学疗法和辐照，损害SLT（包括淋巴结[LN]）。这种伤害延迟了自适应免疫系统的移植后恢复。迫切需要修复受伤的SLT的方法。直到最近，还不知道在胎儿生活中SLTS如何形成或在成人生活中如何重塑。淋巴组织诱导剂（LTI）细胞负责胎儿LN器官发生，并且在成人人类SLT中发现了相关的细胞类型。在小鼠中，成年LTI细胞介导SLT修复。由于LTI细胞存在于SLT中，因此很难研究它们，尤其是在人类中。同样，鼠和人类LTI细胞之间存在很大的差异，可能限制了鼠研究的相关性。几乎所有人类LTI细胞研究都使用了在病理环境中获得的临床标本。为了克服这些问题，我们是唯一从人造血干细胞（HSC）产生LTI细胞的实验室。 HSC衍生的LTI细胞与从LNS分离的LTI细胞相同。使用我们新发现的方法，我们可以生成大量的LTI细胞进行研究或潜在的临床用途。该提议的目标是 进一步确定LTI分化涉及的因素以及LTI诱导的SLT修复的机理。在特定目标1中，我们将解决以下假设：干细胞因子（SCF）通过芳基烃受体（AHR）的表达在HSC承诺中起关键作用。我们还将确定可溶性和膜结合SCF在LTI发育，生存和扩张中的作用。具有强大AHR激动剂活性的FDA-批准的药物将用于LTI开发或扩张活性。其他研究将解决死亡受体3（DR3）信号传导（通过TNF配体1A（TL1A））是否导致LTI膨胀。我们的初步数据表明，LTI细胞与LN基质相互作用以重组成生发中心样结构，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-Superfamily分子（包括OX40L，CD70 LTA1B2和BAFF），并假设它们可以刺激T，B和NK细胞的激活和增殖。我们将基于这些初步发现，以解决LTI单元是否转移 进入免疫缺陷的小鼠将有助于人类HSC植入和/或免疫重建。在该项目的结论结束时，我们将确定负责HSC对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鼠模型中的免疫恢复，以及改善Allo-HCT的关键知识。