Role of Memory T Cells in Pathogenesis and Resolution of Inflammatory Diseases

记忆 T 细胞在炎症性疾病发病机制和解决中的作用

• 批准号: 8018802
• 负责人: RICHARD B BANKERT
• 金额: $ 39.63万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018802
• 关键词: Address; Antibodies; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Characteristics; Chronic; Communicable Diseases; Disease; Epithelial; Fibrosis; Gene Expression; Generations; Goblet Cells; Growth; Histopathology; Human; Hyperplasia; Immune; Immunocompetent; Immunocompromised Host; Immunosuppressive Agents; In Situ; In Vitro; Infiltration; Inflammation Mediators; Inflammatory; Inflammatory Response; Knockout Mice; Link; Lymphocyte; Mediator of activation protein; Monitor; Nasal Polyps; Nose; Pathogenesis; Pathology; Pattern; Plasma Cells; Polyps; Property; Protocols documentation; Receptor Signaling; Regulatory T-Lymphocyte; Resolution; Role; Sinusitis; T memory cell; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Tissues; Xenograft Model; Xenograft procedure; base; chronic rhinosinusitis; cytokine; design; eosinophil; implantation; in vitro testing; in vivo; insight; macrophage; monocyte; neutrophil; novel; polyposis; response; tissue processing

Chronic hyperplastic sinusitis with nasal polyposis is characterized by mucosal thickening, goblet cell hyperplasia, subepithelial fibrosis and by the infiltration of inflammatory cells including eosinophils, neutrophils, macrophages, plasma cells and lymphocytes. The functional significance of the inflammatory cells and the biologically active factors they produce with respect to the generation and progression of the underlying pathology has not been well- defined or causally linked to the disease. Using a novel xenograft model in which human nasal polyp tissues expand progressively following their implantation into severely immunocompromised NOD/SCID/IL2Rγnull mice, the contributions of lymphocytes and monocytes (and the biologically active factors they produce) to the sustained presence and progression of the histopathology of the nasal polyp xenografts will be determined. This is achieved in Aims 1 and 2 by monitoring and quantifying the effect of the selective blockade of inflammatory mediators or immune-depletion of cytokines and CD4+ and CD8+ T lymphocytes, CD68+ macrophages, and CD138+ plasma cells upon the mucosal thickening, goblet cell hyperplasia, sub-epithelial fibrosis and changes in gene expression patterns within the nasal polyp xenografts. Based upon these initial studies, in Aim 3 protocols will be designed and tested in vitro to change the functional properties of the nasal polyp-associated T cells. Strategies are first designed and tested to reverse the T cell receptor signaling arrest that we have shown to be characteristic of the polyp-associated T cells. Next protocols are designed to reprogram proinflammatory cytokine producing T cells into T cells producing immunosuppressive cytokines. The design of these protocols is based upon the demonstrated plasticity of human T cells in response to specific combinations of cytokines and anti-cytokine antibodies. In the final aim the ability of reactivating and/or reprogramming of T cells in situ to reduce or completely arrest nasal polyp progression, histopathology, and the associated gene expression patterns, is addressed in vivo. This is achieved by monitoring and quantifying changes in the growth, histopathology, and gene expression of established nasal polyp xenografts in response to the cytokine induced alterations in T cell functions. These studies are expected to establish a causal link between lymphocyte-, macrophage- and plasma cell-produced biologically active factors and nasal polyposis, and are expected to provide valuable insights with respect to the design of more rationale and effective therapeutic protocols for this chronic and debilitating disease by selectively targeting and functionally altering polyp-associated immunocompetent cells.

慢性增生性鼻窦炎伴鼻息肉病，特点是粘膜增厚，杯状细胞增多。 增生、上皮下纤维化以及炎症细胞（包括嗜酸性粒细胞、中性粒细胞、 巨噬细胞、浆细胞和淋巴细胞。炎症细胞和炎症细胞的功能意义 它们产生的生物活性因子与潜在的产生和进展有关 病理学尚未明确定义或与该疾病存在因果关系。使用一种新颖的异种移植模型，其中 人类鼻息肉组织在植入严重后逐渐扩大 免疫功能低下的 NOD/SCID/IL2Rγ 小鼠，淋巴细胞和单核细胞的贡献（以及 它们产生的生物活性因子）对组织病理学的持续存在和进展 将确定鼻息肉异种移植物。这是通过监测和量化目标 1 和 2 来实现的 选择性阻断炎症介质或细胞因子和 CD4+ 的免疫耗竭的作用 粘膜增厚、杯状时 CD8+ T 淋巴细胞、CD68+ 巨噬细胞和 CD138+ 浆细胞 鼻息肉内细胞增生、上皮下纤维化和基因表达模式的变化 异种移植物。基于这些初步研究，Aim 3 方案将在体外设计和测试，以改变 鼻息肉相关 T 细胞的功能特性。首先设计并测试策略 逆转 T 细胞受体信号传导阻滞，我们已证明这是息肉相关 T 细胞的特征 细胞。接下来的方案旨在将产生促炎细胞因子的 T 细胞重新编程为 T 细胞 产生免疫抑制细胞因子。这些协议的设计基于已证明的 人类 T 细胞对细胞因子和抗细胞因子抗体的特定组合做出反应的可塑性。在 最终目标是原位重新激活和/或重新编程 T 细胞以减少或完全停滞的能力 鼻息肉的进展、组织病理学和相关的基因表达模式在体内得到解决。 这是通过监测和量化生长、组织病理学和基因表达的变化来实现的。 建立鼻息肉异种移植物以响应细胞因子诱导的 T 细胞功能改变。这些 研究预计将建立淋巴细胞、巨噬细胞和浆细胞产生的物质之间的因果关系 生物活性因子和鼻息肉病，并有望提供有关以下方面的宝贵见解 为这种慢性衰弱性疾病设计更合理、更有效的治疗方案 选择性靶向和功能改变息肉相关免疫活性细胞。