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

慢性增生性鼻窦炎合并鼻息肉的特点是粘膜增厚、杯状细胞 增生，上皮下纤维化和炎症细胞的渗透，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。炎性细胞和血管内皮细胞的功能意义 它们产生的生物活性因子与潜在疾病的发生和发展有关 病理还没有明确定义，也没有与这种疾病有因果关系。使用一种新的异种移植模型 人鼻息肉组织植入重度鼻息肉后逐渐扩张 免疫低下的NOD/SCID/IL2R；基因缺失小鼠，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)对组织病理学的持续存在和进展 鼻息肉异种移植将被确定。在目标1和目标2中，通过监测和量化 选择性阻断炎症介质或免疫耗竭细胞因子和CD_4、CD_4的作用 粘膜增厚的CD8 T淋巴细胞、CD68巨噬细胞和CD138浆细胞 鼻息肉组织中细胞增殖、上皮下纤维化和基因表达模式的变化 异种移植物。在这些初步研究的基础上，将在AIM 3中设计并在体外测试方案以改变 鼻息肉相关T细胞的功能特性。战略首先被设计和测试以 逆转我们已经证明的息肉相关T细胞受体信号停滞的特征 细胞。NEXT方案被设计为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。这些协议的设计是基于演示的 人类T细胞对细胞因子和抗细胞因子抗体特定组合的可塑性。在……里面 最终目标是在原位重新激活和/或重新编程T细胞以减少或完全停止 鼻息肉进展，组织病理学，以及相关的基因表达模式，在体内进行了讨论。 这是通过监测和量化在生长、组织病理学和基因表达方面的变化来实现的 已建立的鼻息肉异种移植是对细胞因子引起的T细胞功能改变的反应。这些 研究有望确定淋巴细胞、巨噬细胞和浆细胞产生的因果联系。 生物活性因子和鼻息肉病，并有望提供关于以下方面的宝贵见解 通过设计更合理和更有效的治疗方案来治疗这种慢性和衰弱的疾病 选择性靶向和功能改变息肉相关的免疫活性细胞。

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.