Immunodeficiencies that impair lymphocyte survival

损害淋巴细胞存活的免疫缺陷

• 批准号: 6630173
• 负责人: Robert Thomas Woodland
• 金额: $ 27.83万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6630173
• 关键词: B lymphocyte; biological signal transduction; flow cytometry; gene targeting; genetically modified animals; immunocytochemistry; immunodeficiency; laboratory mouse; leukocyte activation /transformation; ligands; polymerase chain reaction; receptor expression; southern blotting; spleen; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): The size and diversity of the immune repertoire found in naive peripheral lymphocytes must be maintained at a sufficient capacity to mount effective immune responses to new infectious agents. This repertoire is constantly diminished by pathogen challenge. It is currently postulated the naive B cell pool is maintained through interactions with ligands in the environment that promote lymphocyte survival. We have recently demonstrated that adoptively transferred B lymphocytes actively replicate in B cell deficient hosts and maintain their naive phenotype. This homeostatic proliferation (HP) of mature B cells requires Bruton's tyrosine kinase is T cell and antigen independent, inhibited at high B cell densities and displays signaling requirements distinct for those for antigen/mitogen induced activation or for peripheral B cell survival. We propose that homeostatic B cell proliferation is ongoing, not just confined to lymphopenic settings and constitutes an antigen-independent mechanism for maintaining and expanding the immune repertoire of the naive B cell pool. Understanding the regulation of this homeostatic mechanism could provide important new therapies for effecting the reconstitution of immune systems debilitated by chemotherapy, virus infection or aging. We propose to elucidate this homeostatic mechanism using the following rationale and experimental approaches. Extensive B cell traffic to the spleen makes it an ideal site for monitoring peripheral B cell density and providing the cells and ligands necessary to initiate HP. Aim 1 will determine if all B cell subpopulations can undergo HP, the accessory cells and microarchitectural elements in the spleen required for HP and if sites outside the spleen can support HP. Basal signals from the BCR are necessary for B cell survival and intensification or costimulation of these signals may induce HP. In Aim 2 we will determine if the BCR is necessary for HP, if HP can be initiated in any B cell or is confined to a cohort with a restricted BCR repertoire and the signaling pathways required to induce HP. B cell survival is also dependent on stimulation by the TNF-related ligand BLyS. Aim 3 will use adenovirus-mediated gene transfer to determine if costimulation with BLyS is required for or enhances HP, which of the BLyS receptors is necessary for this stimulation and the effect, on mature B cell homeostasis, of selectively inhibiting the expression of BLyS receptors TACI or BR3.

描述（由申请方提供）：在初始外周淋巴细胞中发现的免疫库的大小和多样性必须保持足够的能力，以产生对新感染因子的有效免疫应答。这一库不断减少病原体的挑战。目前假设幼稚B细胞池通过与环境中促进淋巴细胞存活的配体相互作用来维持。我们最近已经证明过继转移的B淋巴细胞在B细胞缺陷的宿主中积极复制并保持其幼稚表型。成熟B细胞的这种稳态增殖（HP）需要布鲁顿酪氨酸激酶是T细胞和抗原非依赖性的，在高B细胞密度下被抑制，并且显示出与抗原/有丝分裂原诱导的活化或外周B细胞存活不同的信号传导要求。我们认为稳态B细胞增殖是持续的，而不仅仅局限于淋巴细胞减少的情况，并且构成了维持和扩大幼稚B细胞库的免疫库的抗原非依赖性机制。了解这种自我平衡机制的调节可以为重建因化疗、病毒感染或衰老而衰弱的免疫系统提供重要的新疗法。我们建议使用以下原理和实验方法来阐明这种稳态机制。广泛的B细胞运输到脾脏使其成为监测外周B细胞密度和提供启动HP所需的细胞和配体的理想部位。目的1将确定是否所有B细胞亚群都可以经历HP，HP所需的脾中的辅助细胞和微结构元件，以及脾外的位点是否可以支持HP。来自BCR的基础信号对于B细胞存活是必需的，并且这些信号的增强或共刺激可诱导HP。在目标2中，我们将确定BCR是否是HP所必需的，HP是否可以在任何B细胞中启动或仅限于具有有限BCR库和诱导HP所需的信号传导途径的队列。B细胞存活也依赖于TNF相关配体BLyS的刺激。目的3将使用腺病毒介导的基因转移来确定与BLyS的共刺激是否是HP所需的或增强HP，哪种BLyS受体是这种刺激所必需的，以及选择性抑制BLyS受体TACI或BR 3的表达对成熟B细胞稳态的影响。