Apoptotic Regulation of Lymphocyte Responses

淋巴细胞反应的凋亡调节

• 批准号: 6880596
• 负责人: DAN V MOURICH
• 金额: $ 10.7万
• 依托单位: AVIBIOPHARMA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6880596
• 关键词: T lymphocyte; antigen presentation; antisense nucleic acid; apoptosis; autoimmunity; biological signal transduction; cell population study; cellular immunity; disease /disorder model; enzyme linked immunosorbent assay; experimental allergic encephalomyelitis; immunologic memory; immunopharmacology; immunoregulation; immunosuppression; immunotherapy; laboratory mouse; nonhuman therapy evaluation; therapy design /development; transport proteins

DESCRIPTION (provided by applicant): The response of lymphocytes to antigen stimulation is characterized by proliferation of an antigen-sensitive lymphocyte population, subsequent differentiation to subsets with effector cell function, and ultimately the retention of antigen-responsive lymphocytes with a memory cell phenotype. The initial increase of responsive lymphocytes is followed by an equally dramatic contraction of the responding population. The characteristic contraction of the number of responding lymphocytes that occurs following the antigen-driven expansion phase is caused, at the molecular level, by a change in the balance of intracellular proteins that are responsible for inhibiting or committing a cell to apoptosis via a programmed cell death pathway. Thus, during the initial antigen-driven expansion phase the level of anti-apoptotic protein(s) is increased and the cell is resistant to programmed cell death. Subsequently the level of these anti-apoptotic proteins declines placing the cell at risk for subsequent events conventionally termed activation-induced cell death. It is the hypothesis of this study that specific immune responses can be inhibited or destroyed at the clonal response level, by preventing the development of the increased level of anti-apoptotic protein(s) that develop during the initial response at the stage of antigen stimulation. Prevention of the production of the antigen response-induced anti-apoptotic proteins will place these cells at immediate risk for activation-induced cell death resulting in a selective deletion of the subset of antigen-responding lymphocytes. Such intervention will result in immunosuppression that is specific rather than global and will only affect those lymphocytes responding to antigen at the time anti-apoptotic protein production is prevented.

描述（由申请人提供）：淋巴细胞对抗原刺激的反应的特征是抗原敏感的淋巴细胞种群的增殖，随后与效应细胞功能的亚群的分化，最终是保留抗原反应性淋巴细胞具有记忆细胞表型。反应性淋巴细胞的初始增加之后，反应人群的收缩同样显着。在分子水平上，在抗原驱动的膨胀阶段发生的反应淋巴细胞数量的特征收缩是由于负责通过程序性细胞死亡途径抑制或承诺抑制细胞对凋亡的细胞内蛋白质的平衡而导致的。因此，在初始抗原驱动的膨胀阶段，抗凋亡蛋白的水平增加，细胞对程序性细胞死亡具有抗性。随后，这些抗凋亡蛋白的水平下降，将细胞置于随后的事件常规称为激活诱导的细胞死亡的风险。 这项研究的假设是，可以通过防止在抗原刺激阶段的初始反应中发展的抗凋亡蛋白水平升高，在克隆反应水平上抑制或破坏特定的免疫反应。预防抗原反应诱导的抗凋亡蛋白的产生将使这些细胞立即面临激活诱导的细胞死亡的风险，从而选择性缺失抗原反应淋巴细胞的子集。这种干预将导致免疫抑制是特定的，而不是全球性的，并且只会影响那些在抗凋亡蛋白产生时对抗原反应的淋巴细胞。