Immune Reconstitution

免疫重建

• 批准号: 10262110
• 负责人: Ronald Gress
• 金额: $ 224.14万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262110
• 关键词: Acute; Address; Aging; Allogenic; Area; B-Cell Development; B-Lymphocytes; Biology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCR4 gene; Cell Aging; Cell Compartmentation; Cell Cycle Regulation; Cell surface; Cells; Clinical; Clinical Trials; Complex; Development; Disease; Distal; Dose; FLT3 ligand; Female; Gene Expression; Genes; Glucose; Goals; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homeostasis; Human; Image; Immune; Immune system; Interleukin 7 Receptor; Interleukin-7; Investigation; Isotopes; Kinetics; Maintenance; Malignant Neoplasms; Marrow; Mediating; Memory; Multiprotein Complexes; Mus; Natural regeneration; Organ; Pathogenesis; Pathway interactions; Patients; Pattern; Peripheral; Phenotype; Population; Premature aging syndrome; Proliferating; Proteins; Publishing; Regulation; Research; Role; Sensitivity and Specificity; Series; Signal Transduction; Stromal Cells; T cell reconstitution; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; TP53 gene; Therapeutic; Thymocyte Development; Thymus Gland; Transplantation; Work; base; cancer therapy; cell regeneration; chronic graft versus host disease; cytokine; experimental study; functional disability; immune reconstitution; interest; male; memory CD4 T lymphocyte; mouse model; neoplastic cell; notch protein; precursor cell; reconstitution; senescence; stem cells; thymocyte; uptake

The biology of reconstitution of T cell populations following acute loss remains incompletely characterized. Using murine models, we first identified two primary pathways of T cell immune reconstitution, the classic, thymic-dependent pathway, and a second, thymic-independent pathway. We then identified T cell surface markers which allowed identification, by phenotyping of reconstituted T cell populations, of the pathways which had given rise to them, and then applied this information to the characterization of T cell reconstitution in patients. This work showed an essential role for the thymus in regenerating CD4+ T cells quantitatively. CD8+ T cells can numerically be reconstituted by peripheral expansion for immune reconstitution, but both CD4+ and CD8+ T cells require thymic activity for maintenance or regeneration of repertoire diversity. These findings led in turn to a research emphasis on understanding mechanisms which control thymic function, and new treatments to treat cancer in the setting of a regenerating immune system. This work has progressed to the development of two new project areas of research -- one focused on points of regulation of thymus function and one on introducing agents into clinical trials. The work addressed in this project has also led to efforts in investigating IL-7 effects on the maturation of thymocytes. We have identified IL-7 as a negative regulator of thymopoiesis as well as being essential for thymocyte development. These dual roles are dose dependent and negative regulation at higher concentrations is mediated through control of Notch signaling -- which is central to T/B lineage commitment. At high doses, IL-7 favors B cell development and so turns the thymus towards a B cell-poietic organ. Additionally, we have worked to identify genes which might regulate the thymus and have characterized a gene called Tbata (previously SPATIAL) which is a negative regulator acting within the stromal cell compartment. It appears to exert its effect through control of cell cycle, specifically through regulation of the Nedd8 pathway. Recent results indicate that regulation of cell cycle by Tbata extends beyond Nedd8 and involves p53. This is due to involvement of the protein encoded by Tbata in a large multi-protein complex which controls gene expression. Interestingly, this may be reflected in differences of thymopiesis in female versus male mice. The difference is now clear from multiple experiments, and the mechanism is under investigation. Experiments are in progress to identify blockers of Tbata function that might have clincial applicability. The role of IL-7 as a possible regulator of thymus function was noted above; its role in peripheral homeostasis has been further investigated by characterizing IL-7 receptor regulation among T cell subsets. The work with IL-7 receptor modulation has shown a complex pattern of differential signaling regulation among subsets with the apparent effect of favoring the sustaining of primitive naive T cells. This is of special interest because it provides a basis for understanding how a single cytokine such as IL-7 can differentially regulate multiple distinct T cell subsets. Specifically, there is differential regulation between naive CD4 T cells and memory CD4 T cells. Differences in signaling distal to the receptor for IL-7 appear to mechanistically account for this differential regulation. We are now addressing the biology of signaling by the two primary homeostatic cytokines in the CD8 naive versus CD8 memory subsets in murine models and have found again differences at the level of T cell receptor turnover. These results are now published. We have also made the observation that in T cell immune reconstitution reliant on the thymus-independent pathway in humans, that such expansion results in premature aging of the T cells with resultant cellular senescence, a likely contributor to T cell functional impairment for years following transplant. Investigating the stem cell compartment in murine models, we showed that FLT3 ligand regulates thymic precursor cells and hematopoietic stem cells through interactions with CXCR4 and the marrow niche. Finally, a series of experiments using deuterated glucose to assess T cell subsets kinetics in the pathogenesis of chronic GVHD in murine models yielded information on such subsets and evolved into efforts to successfully image rapidly proliferating cells in that disease. This collaborative work has progressed to imaging of other rapidly proliferating cells, namely neoplastic cells. This imaging has sufficient sensitivity and specificity to be of clinical interest. It also may have therapeutic application in the treatment of disease by selective uptake of isotope based on proliferative activity.

急性损失后T细胞群重建的生物学特征仍然不完全。通过小鼠模型，我们首先确定了T细胞免疫重建的两种主要途径，一种是经典的胸腺依赖途径，另一种是胸腺独立途径。然后，我们确定了T细胞表面标记物，通过重组T细胞群的表型分析，可以识别产生它们的途径，然后将这些信息应用于患者T细胞重组的表征。这项工作显示了胸腺在定量再生CD4+ T细胞中的重要作用。CD8+ T细胞可以通过外周扩增进行免疫重建，但CD4+和CD8+ T细胞都需要胸腺活性来维持或再生库多样性。这些发现反过来又使研究重点转向了解控制胸腺功能的机制，以及在再生免疫系统的背景下治疗癌症的新疗法。这项工作已经发展到两个新的研究项目领域——一个专注于胸腺功能的调节，另一个专注于将药物引入临床试验。在这个项目中解决的工作也导致了研究IL-7对胸腺细胞成熟的影响的努力。我们已经确定IL-7是胸腺生成的负调节因子，也是胸腺细胞发育所必需的。这些双重作用是剂量依赖性的，高浓度的负调节是通过控制Notch信号传导介导的，这是T/B谱系承诺的核心。在高剂量下，IL-7有利于B细胞的发育，从而将胸腺转变为B细胞生成器官。此外，我们已经确定了可能调节胸腺的基因，并确定了一种名为Tbata（以前称为SPATIAL）的基因，它是一种在基质细胞内起作用的负调节作用。它似乎通过控制细胞周期，特别是通过调节Nedd8通路发挥作用。最近的研究结果表明，Tbata对细胞周期的调节超出了Nedd8，并涉及p53。这是由于Tbata编码的蛋白质参与了控制基因表达的大型多蛋白复合体。有趣的是，这可能反映在雌性和雄性小鼠胸腺功能的差异上。经过多次实验，这种差异现在已经很清楚了，其机制正在调查中。实验正在进行中，以确定可能具有临床适用性的Tbata功能阻滞剂。如上所述，IL-7可能是胸腺功能的调节因子；通过表征IL-7受体在T细胞亚群中的调节作用，进一步研究了其在外周稳态中的作用。IL-7受体调节的研究表明，在亚群中存在一种复杂的差异信号调节模式，其明显效果有利于维持原始幼稚T细胞。这是特别有趣的，因为它为理解单个细胞因子如IL-7如何差异调节多个不同的T细胞亚群提供了基础。具体来说，初始CD4 T细胞和记忆CD4 T细胞之间存在差异调节。IL-7受体远端信号的差异似乎在机制上解释了这种差异调节。我们现在正在研究小鼠模型中CD8初始和CD8记忆亚群中两种主要稳态细胞因子的信号传导生物学，并再次发现T细胞受体转换水平的差异。这些结果现已发表。我们还观察到，在依赖于人类胸腺非依赖性途径的T细胞免疫重建中，这种扩张导致T细胞过早衰老，从而导致细胞衰老，这可能是移植后多年T细胞功能受损的原因。在小鼠模型中研究干细胞区室，我们发现FLT3配体通过与CXCR4和骨髓生态位的相互作用调节胸腺前体细胞和造血干细胞。最后，在小鼠模型中使用氘化葡萄糖来评估慢性GVHD发病机制中的T细胞亚群动力学的一系列实验获得了这些亚群的信息，并演变为成功成像该疾病中快速增殖的细胞的努力。这项合作工作已经发展到其他快速增殖细胞的成像，即肿瘤细胞。该成像具有足够的敏感性和特异性，具有临床意义。根据增殖活性选择性摄取同位素，也可用于治疗疾病。