Immune Reconstitution

免疫重建

• 批准号: 8937763
• 负责人: Ronald Gress
• 金额: $ 138.08万
• 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/8937763
• 关键词: Acute; Address; Adult; Aging; Allogenic; Androgens; Area; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Cycle Regulation; Cell surface; Cells; Clinical Trials; Complex; Dose; Epithelial Cell Proliferation; Epithelial Cells; Genes; Goals; Hematopoietic Stem Cell Transplantation; Homeostasis; Human; Immune; Immune system; Immunity; Injury; Insulin-Like Growth Factor I; Interleukin-7; Ligands; Maintenance; Malignant Neoplasms; Maps; Mediating; Modeling; Molecular; Mus; Natural regeneration; Pathway interactions; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Phenotype; Population; Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; Stromal Cells; T-Lymphocyte; T-Lymphocyte Subsets; Thymic epithelial cell; Thymocyte Development; Thymus Gland; Time; Tissues; Transgenic Organisms; Vaccines; Work; cancer therapy; liquid chromatography mass spectrometry; notch protein; novel strategies; receptor; reconstitution; senescence; thymocyte; time interval

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. Initial work established the applicability of this approach to the study of T cell population regeneration in humans who were young. Recent work verified validity of the approach and established the course of T cell immune reconstitution in adult humans over an extended period time for each of the two primary pathways. 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 have led in turn to a research emphasis on understanding mechanisms which control thymic function, and new treatments, including vaccine strategies, to treat cancer in the setting of a regenerating immune system. Four models of thymic regulation have been developed; this work has progressed to the developoment 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. 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. The cellular and molecular mechanisms by which androgen signaling blockade and IGF-1 modulate thymus function were characterized and map points of regulation of proliferation to the epithelial cell compartment of the thymus. A new transgenic murine model has been developed to investigate signaling pathways involved in this regulation. This new model involves the ability to deplete the peripheral T cell compartment without ancillary tissue injury. Using the information that a key control point of thymus regulation is the control of thymic epithelial cell proliferation, gene arrays are being carried out at fixed time intervals on isolated cells to identify activated cell pathways of division. In parallel, LC/MS is being used to identify new protein species that may act as ligands for those identified pathways. 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 characteizing IL-7 receptor regulation among T cell subsets. The purpose in all of these studies is to understand the biology of T cell homeostasis in order to develop new approaches to therapy for patients in whom T cell populations are depleted with consequences of impaired immunity. To date, IL-7 has been introduced in humans and a clinical trial with androgen blockade is in progress. The IL-7 trials was interrupted due to lack of drug supply; the trial is to resume within the next year. The trial with androgen blockage shows early positive results which need to be confirmed as the trial continues. The work with IL-7 receptor modulation has shown a complex pattern of differential receptor regulation among subsets with the apparent effect of favoring the sustaining of primitive naive T cells.

急性丧失后T细胞群重建的生物学特征仍不完全。使用小鼠模型，我们首先确定了T细胞免疫重建的两种主要途径，经典的胸腺依赖性途径和第二种胸腺非依赖性途径。然后，我们确定了T细胞表面标志物，其允许通过对重建的T细胞群体进行表型分析来识别产生它们的途径，然后将这些信息应用于患者T细胞重建的表征。最初的工作建立了这种方法在年轻人T细胞群体再生研究中的适用性。最近的工作验证了该方法的有效性，并建立了两种主要途径中的每一种在成年人中T细胞免疫重建的过程。这项工作显示了胸腺在定量再生CD 4 + T细胞中的重要作用。CD 8 + T细胞可以通过外周扩增在数量上重建以用于免疫重建，但CD 4+和CD 8 + T细胞都需要胸腺活性以维持或再生库多样性。这些发现反过来又导致研究重点放在了解控制胸腺功能的机制，以及新的治疗方法，包括疫苗策略，以在再生免疫系统的背景下治疗癌症。胸腺调节的四种模型已经开发出来;这项工作已经进展到两个新的研究项目领域的发展-一个集中在胸腺功能的调节点和一个在临床试验中引入代理。在这个项目中解决的工作也导致了在研究IL-7对胸腺细胞成熟的影响的努力。我们已经确定了IL-7作为胸腺生成的负调节因子以及对于胸腺细胞发育是必需的。这些双重作用是剂量依赖性的，并且在更高浓度下的负调节是通过Notch信号传导的控制介导的，Notch信号传导是T/B谱系定型的中心。此外，我们还努力鉴定可能调节胸腺的基因，并鉴定了一种名为Tbata（以前称为SPATIAL）的基因，它是一种在基质细胞室中起作用的负调节因子。它似乎通过控制细胞周期，特别是通过调节Nedd 8途径发挥其作用。雄激素信号传导阻断和IGF-1调节胸腺功能的细胞和分子机制的特点和地图点的增殖调节上皮细胞室的胸腺。一种新的转基因小鼠模型已被开发，以调查参与这种调节的信号通路。这种新模型涉及在没有辅助组织损伤的情况下耗尽外周T细胞隔室的能力。利用胸腺调节的关键控制点是胸腺上皮细胞增殖的控制这一信息，以固定的时间间隔对分离的细胞进行基因阵列，以鉴定活化的细胞分裂途径。与此同时，LC/MS被用于鉴定可能作为这些已鉴定途径的配体的新蛋白质种类。IL-7作为胸腺功能的可能调节剂的作用在上文中提到;其在外周稳态中的作用已通过表征T细胞亚群中的IL-7受体调节而进一步研究。所有这些研究的目的是了解T细胞稳态的生物学，以开发新的方法来治疗T细胞群耗尽导致免疫力受损的患者。迄今为止，IL-7已被引入人体，雄激素阻断的临床试验正在进行中。IL-7试验由于缺乏药物供应而中断;试验将在明年恢复。雄激素阻断试验显示了早期阳性结果，需要随着试验的继续进行确认。IL-7受体调节的工作显示了亚群之间差异受体调节的复杂模式，具有有利于维持原始幼稚T细胞的明显作用。