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: 9392628
• 负责人: Michael R. Verneris
• 金额: $ 35.77万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 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 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9392628
• 关键词: Acquired Immunodeficiency Syndrome; Adaptive Immune System; Address; Adult; Agonist; Allogenic; Antigens; Area; Aryl Hydrocarbon Receptor; Autoimmunity; B-Lymphocytes; 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; Goals; Helper-Inducer T-Lymphocyte; Hematopoiesis; Hematopoietic stem cells; Human; Immune; Immune response; Immune system; Immunity; Immunodeficient Mouse; Infection; Injury; International; Investigation; Knowledge; Laboratories; Laboratory Study; Lead; Life; Ligands; Ligation; Lymphocyte; Lymphoid Cell; Lymphoid Tissue; Malignant Neoplasms; Mediating; Membrane; Methods; Molecular; Morbidity - disease rate; Mus; NK Cell Activation; Natural Killer Cells; Nomenclature; Operative Surgical Procedures; Opportunistic Infections; Organogenesis; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Physiology; Play; Population; Positioning Attribute; Procedures; Production; Proto-Oncogene Protein c-kit; R-factor; 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; Transplantation; Tumor Necrosis Factor-Beta; Viral; antimicrobial; base; cell type; chemotherapy; clinical translation; cytokine; fetal; hematopoietic cell transplantation; improved; improved outcome; in vitro Model; in vivo; injured; interleukin-22; irradiation; leukemia; lymph nodes; mortality; mouse model; novel; pathogen; pre-clinical; preclinical study; prevent; programs; 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（alloc - hct）引发移植物对抗白血病反应，是治疗化疗难治性白血病的唯一方法。通过增强适应性免疫系统的恢复，这种治疗方法可以变得更加有效，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，这样更多的患者可以从这种手术中受益。次级淋巴组织（slt）是抗原特异性免疫反应针对病原体和癌症启动的地方。在allo-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。目前迫切需要修复受损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，也不知道它们在成年后是如何重塑的。淋巴组织诱导剂（LTi）细胞负责胎儿LN器官发生，在成人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，因此很难对它们进行研究，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（hsc）中产生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，我们可以产生大量的LTi细胞用于研究或潜在的临床应用。本建议的目标是

项目成果

Killing the killer: natural killer cells to treat Ewing's sarcoma.

• DOI: 10.1158/1078-0432.ccr-10-1368
• 发表时间: 2010-08-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Ahn YO;Weigel B;Verneris MR
• 通讯作者: Verneris MR

Is It Better to Be Rich or Relaxed? Sociobiology Meets Bone Marrow Transplant.

富有好还是轻松好？

• DOI: 10.1158/1078-0432.ccr-15-2112
• 发表时间: 2016
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Turcotte,LucieM;Verneris,MichaelR
• 通讯作者: Verneris,MichaelR

Natural killer cells and regulatory T cells: how to manipulate a graft for optimal GVL.

• DOI: 10.1182/asheducation-2013.1.335
• 发表时间: 2013
• 期刊: Hematology. American Society of Hematology. Education Program
• 作者: Verneris MR

KIR B or not to be?...that is the question for ALL.

KIR B 还是不？...这是所有人的问题。

• DOI: 10.1182/blood-2014-09-596395
• 发表时间: 2014
• 期刊: Blood
• 影响因子: 20.3
• 作者: Verneris,MichaelR;Miller,JeffreyS
• 通讯作者: Miller,JeffreyS