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以黏膜增厚、杯状细胞增多为特征， 增生，上皮下纤维化和炎性细胞包括嗜酸性粒细胞，嗜中性粒细胞， 巨噬细胞、浆细胞和淋巴细胞。炎性细胞的功能意义及 它们产生的生物活性因子与潜在的 病理学尚未明确定义或与疾病的因果关系。使用一种新的异种移植模型， 人鼻息肉组织在植入严重 免疫功能低下的NOD/SCID/IL 2 R缺失小鼠，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）与组织病理学的持续存在和进展有关。 将确定鼻息肉异种移植物。目标1和2通过监测和量化 炎症介质的选择性阻断或细胞因子和CD 4+的免疫耗竭的作用， CD 8 + T淋巴细胞、CD 68+巨噬细胞和CD 138+浆细胞在粘膜增厚、杯状 细胞增生、上皮下纤维化和鼻息肉内基因表达模式的变化 异种移植基于这些初步研究，目标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。战略首先设计和测试， 逆转T细胞受体信号传导阻滞，我们已经证明这是息肉相关T细胞的特征。 细胞接下来的方案被设计成将产生促炎细胞因子的T细胞重编程为T细胞 产生免疫抑制细胞因子。这些协议的设计是基于已证明的 人T细胞对细胞因子和抗细胞因子抗体的特定组合的响应的可塑性。在 最终目的是原位重新激活和/或重新编程T细胞以减少或完全阻止T细胞增殖的能力。 鼻息肉的进展，组织病理学，和相关的基因表达模式，在体内解决。 这是通过监测和量化的生长，组织病理学和基因表达的变化， 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 生物活性因子和鼻息肉病，并有望提供有价值的见解， 为这种慢性和使人衰弱的疾病设计更合理和有效的治疗方案， 选择性靶向和功能性改变息肉相关的免疫活性细胞。