Immune Reconstitution

免疫重建

• 批准号: 8763129
• 负责人: Ronald Gress
• 金额: $ 106.76万
• 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/8763129
• 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; 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; Peripheral; 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 cliniocal trial with androgen blockade is in progress.

急性损失后T细胞种群重建的生物学仍然没有完全表征。使用鼠模型，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个胸腺独立途径。然后，我们确定了T细胞表面标记，通过表型来识别重组的T细胞种群，对引起它们产生的途径的途径，然后将此信息应用于患者中T细胞重建的表征。最初的工作确定了这种方法对年轻人的T细胞种群再生研究的适用性。最近的工作验证了该方法的有效性，并确定了成人人类在长时间内的两种主要途径中的T细胞免疫重建过程。这项工作表现出胸腺定量再生CD4+ T细胞的重要作用。 CD8+ T细胞在数值上可以通过外周膨胀以进行免疫重建，但是CD4+和CD8+ T细胞都需要胸腺活性来维持或再生曲目多样性。这些发现又导致研究重点是理解控制胸腺功能的机制，以及在重生免疫系统中治疗癌症（包括疫苗策略）的新治疗方法。已经开发了四种胸腺调节模型；这项工作已发展为两个新的研究项目领域的发展 - 一项侧重于调节胸腺功能的点，另一个侧重于将代理引入临床试验中。该项目中涉及的工作还导致了研究IL-7对胸腺细胞成熟的影响的努力。我们已经将IL-7确定为胸腺甲基膜的负调节剂，并且对于胸腺细胞发育至关重要。这些双重作用是剂量依赖性，在较高浓度下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。此外，我们还努力鉴定可能调节胸腺的基因，并表征了一个称为TBATA（以前空间）的基因，该基因是作用在基质细胞室内的负调节剂。它似乎通过控制细胞周期，特别是通过调节NEDD8途径来发挥作用。表征了雄激素信号阻滞和IGF-1调节胸腺功能的细胞和分子机制，并调节胸腺上皮细胞室的增殖点的映射点。已经开发了一种新的转基因鼠模型来研究该调节中涉及的信号通路。这个新模型涉及能够在没有辅助组织损伤的情况下耗尽周围T细胞室的能力。使用胸腺调节的关键控制点的信息是对胸腺上皮细胞增殖的控制，以固定的时间间隔在分离的细胞上进行基因阵列，以鉴定分裂的活化细胞途径。同时，LC/MS被用于鉴定可能充当识别途径的配体的新蛋白质物种。上面指出了IL-7作为胸腺功能的可能调节剂的作用。通过对T细胞亚群中的IL-7受体调节进行表征，进一步研究了其在外围稳态中的作用。在所有这些研究中，目的是了解T细胞稳态的生物学，以开发针对T细胞群体耗尽的患者的新方法，并导致免疫力受损。迄今为止，已经在人类中引入了IL-7，并且正在进行雄激素阻滞的临床试验。