Memory CD4 T cell-mediated immunopathology in influenza infection

流感感染中记忆 CD4 T 细胞介导的免疫病理学

• 批准号: 7391867
• 负责人: Donna L. Farber
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391867
• 关键词: Activities of Daily Living; Address; Adult; Affect; Alveolar; Body Weight decreased; CD28 gene; Cause of Death; Cell physiology; Cells; Child; Exhibits; Generations; Goals; Homing; Immune; Immune response; Immunity; Immunomodulators; Immunotherapy; Individual; Infection; Infiltration; Inflammatory; Inflammatory Infiltrate; Influenza; Influenza A Virus, H5N1 Subtype; Interferons; Interleukin-17; Laboratories; Lead; Lung; Lymphoid; Lymphoid Tissue; Mediating; Memory; Modeling; Mus; Nature; Numbers; Other Finding; Pathologic; Pathology; Pathway interactions; Personal Satisfaction; Pneumonia; Population; Process; Production; Reaction; Reagent; Regulation; Research; Rheumatoid Arthritis; Risk; Role; Signal Transduction; Site; Structure of parenchyma of lung; System; T memory cell; T-Lymphocyte; TNF gene; Tissues; Variant; Viral; Viral Proteins; Viremia; Virulent; Virus; anti-influenza; base; clinically relevant; cytokine; flu; immunopathology; in vivo; inhibitor/antagonist; interest; memory CD4 T lymphocyte; mouse model; novel; pandemic disease; pandemic influenza; pathogen; response

DESCRIPTION (provided by applicant): The immune response to highly pathogenic viruses such as influenza, is a double edged sword. In response to influenza infection, innate and adaptive immune components coordinate elimination of the pathogen from the lung; however, these same processes can generate pathological reactions including excessive cytokine production and destruction of lung airways now believed to be the leading cause of death and pneumonia from the 1918 pandemic influenza (H1N1) and avian influenza (H5N1) strains. This dual nature of the immune response, with the ability to promote protection and immunopathology, is well-documented in diverse viral systems, suggesting that immunomodulating strategies that promote a protective or beneficial immune response while suppressing an undesired immune response would be an ideal treatment strategy for new pandemic influenza strains. However, mechanisms for the immunopathology observed in adult immune responses to influenza and strategies to regulate such responses remain unknown. My laboratory has developed a novel mouse model in which immunity to influenza is driven by memory CD4 T cells, that also has significant clinical relevance given that most older children and adults have been exposed to influenza and can maintain memory T cells to invariant viral determinants, and that ample number of memory T cells reside in the lung and can therefore provide a "first-line" response at the site of infection. We have found that memory CD4 T cells can coordinate both protective and pathologic responses to influenza manifested by rapid viral clearance in the presence of extensive lung immune infiltration and tissue damage -features not observed in flu-infected naive mice lacking specific memory T cells. We also have obtained preliminary evidence that the CD28 costimulatory pathway may be instrumental in controlling this bipartite nature of the memory CD4 T cell response to influenza, in that blocking CD28 costimulation with the inhibition reagent CTLA4Ig maintains protection while lessening the lung damage and weight-loss pathology observed during infection. In the proposed research, we will build on these interesting preliminary findings to delve into the mechanism for memory CD4 T cell-induced immunopathology during influenza challenge, and how interfering with the CD28 costimulatory pathway on memory CD4 T cells may be the optimal immunomodulator for enhancing protection while abrogating immunopathology. Given the clinical relevance of examining memory T cell responses to influenza as a model for adult immune responses, and the fact that CTLA4Ig is already used clinically to lessen immunopathology in rheumatoid arthritis, the proposed research could lead to a readily translatable strategy for regulating deleterious immune responses to virulent pathogens via modulation of memory T cells.

描述（由申请人提供）：对高度致病性病毒（例如流感）的免疫反应是双层剑。为了响应流感感染，先天和适应性免疫成分会坐落从肺部消除病原体。但是，这些相同的过程可以产生病理反应，包括过度的细胞因子产生和肺气道的破坏，现在据信是1918年大流行性流感（H1N1）和禽流感（H5N1）菌株的死亡和肺炎的主要原因。免疫反应的这种双重性质具有促进保护和免疫病理学的能力，在各种病毒系统中有充分的证明，这表明促进促进保护性或有益免疫反应的免疫调节策略同时抑制了不良的免疫反应，这将是新pandemic型流行性流行性流行性流行性型菌株的理想治疗策略。但是，在成人对流感的免疫反应中观察到的免疫病理学的机制和调节此类反应的策略尚不清楚。我的实验室开发了一种新型的小鼠模型，在该模型中，对流感的免疫力是由记忆CD4 T细胞驱动的，鉴于大多数大多数年龄较大的儿童和成年人都暴露于流感，并且可以维持记忆T细胞不变性的病毒决定因素，并且可以在肺中含有大量的记忆T细胞，因此可以在肺中含有大量的记忆T细胞，因此可以在肺中居住，并且可以为您提供“第一线”的响应，从而可以保持记忆T细胞。我们发现，记忆CD4 T细胞可以在存在广泛的肺免疫浸润和组织损伤的情况下，在缺乏特定特定记忆T细胞中未观察到的天真小鼠中未观察到的广泛的肺免疫浸润和组织损伤的情况下，对流感的保护性和病理反应均可表现为受病毒的快速清除。我们还获得了初步证据，表明CD28的刺激途径可能有助于控制记忆CD4 T细胞对流感的两分性质，因为阻止CD28与抑制作用CTLA4IG的结肠刺激能保持保护，同时减少肺部损伤和体重减轻的病理，并在感染过程中降低了体重减轻的病理学。在拟议的研究中，我们将以这些有趣的初步发现为基础，以深入研究记忆CD4 T细胞诱导的流感挑战期间的免疫病理学的机制，以及如何干扰记忆CD4 T细胞的CD28 costimulation途径可能是最佳的免疫调节剂，以增强免疫病理学的保护，以增强免疫病理学的保护。鉴于检查对流感的记忆T细胞反应作为成人免疫反应的模型的临床相关性，并且CTLA4IG在临床上已经用于减少类风湿关节炎的免疫病理学，因此提出的研究可能会导致可容易翻译的策略，用于调节有害的免疫反应，通过调节毒性病原体，通过模块的模块模型，这一策略。