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

基本信息

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
项目类别：
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

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

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项目摘要

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有鼻息肉病的特征是粘膜增厚，杯状细胞增生，上皮纤维化以及通过包括嗜酸性粒细胞，嗜中性粒细胞的炎性细胞的浸润巨噬细胞，浆细胞和淋巴细胞。炎症细胞和他们相对于基础的生成和发展产生的生物活性因素病理学尚未与该疾病有良好的定义或因果关系。使用新颖的异种移植模型，其中人鼻息肉组织逐渐植入到严重的免疫功能低下的点头/SCID/IL2RγNull小鼠，淋巴细胞和单核细胞的贡献（以及他们产生的生物活性因素）到组织病理学的持续存在和进展将确定鼻息肉异种移植物。这是通过监视和量化目标1和2在目标1和2中实现的选择性阻断炎症介质或细胞因子和CD4+的免疫消耗的影响 CD8+ T淋巴细胞，CD68+巨噬细胞和CD138+等离子体细胞在粘膜增厚，杯状上细胞增生，上皮纤维化和鼻息内基因表达模式的变化异种移植物。基于这些初步研究，在AIM 3中将在体外设计和测试以改变鼻息肉相关的T细胞的功能特性。首先设计和测试策略扭转我们已证明与息肉相关T的特征的T细胞受体信号传导停滞细胞。接下来的方案旨在重新编程促炎细胞因子产生T细胞到T细胞中产生免疫抑制性细胞因子。这些协议的设计基于所证明的人类T细胞的可塑性响应细胞因子和抗周围因子抗体的特定组合。在最终目标是将T细胞在原位重新激活和/或重编程以减少或完全捕捉的能力鼻息肉进展，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生长，组织病理学和基因表达的变化来实现的响应细胞因子诱导的T细胞功能改变的鼻息肉异种移植物。这些预计研究将在淋巴细胞，巨噬细胞和血浆细胞产生的因果关系具有生物活性因素和鼻多发性因素，预计将提供有关的有价值的见解为这种慢性和使人衰弱的疾病设计的更有效和有效的治疗方案的设计有选择地靶向并在功能上改变了与息肉相关的免疫能力细胞。