Immunoregulatory Mechanisms to Combat CNS Pathology During Infection

感染期间对抗中枢神经系统病理的免疫调节机制

• 批准号: 10485452
• 负责人: Michal A Olszewski
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10485452
• 关键词: Acceleration; Adoptive Transfer; Affect; Amphiregulin; Animal Model; Animals; Anti-Inflammatory Agents; Antifungal Agents; Antifungal Therapy; Antigen-Antibody Complex; Biological Markers; Brain; Brain Injuries; CCL1 gene; CCR8 gene; Cellular immunotherapy; Central Nervous System; Central Nervous System Fungal Infections; Central Nervous System Infections; Cessation of life; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; Cytoprotection; Data; Dependence; Deterioration; Development; Disease; Elements; Epidermal Growth Factor; Exposure to; Functional disorder; General Population; Goals; HIV; Homeostasis; Human; Immune; Immune response; Immunity; Immunocompromised Host; Immunosuppression; Immunotherapeutic agent; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-2; Investigation; Kinetics; Knockout Mice; Ligands; Link; Lung; Malaria; Mediating; Medical; Meningeal Tuberculosis; Meningoencephalitis; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Nervous System Physiology; Nervous System Trauma; Neurologic; Neurologic Symptoms; Pathogenesis; Pathologic; Pathology; Patients; Pharmacotherapy; Play; Population; Process; Production; Publishing; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Role; Series; System; T cell response; T cell therapy; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Up-Regulation; Veterans; Virus; central nervous system injury; chemokine; chemokine receptor; combat; cytokine; disability; experience; experimental study; fungus; immunomodulatory therapies; immunopathology; immunoregulation; immunostimulatory therapy; improved; infection risk; insight; migration; monocyte; mortality; mouse model; neuropathology; novel therapeutic intervention; pathogen; pathogenic fungus; pre-clinical; prevent; protective effect; recruit; reduce symptoms; repaired; response; tissue repair; translation to humans; wound healing

Objectives: Cryptococcus neoformans is the most important fungal pathogen causing CNS-related mortality and morbidity world-wide. Although CM is generally viewed as a disease caused by weak immunity, evidence accumulates that exuberant host immune responses significantly contribute to the pathogenesis of CM. To this end, we developed a murine model of CM that reproduces major features of inflammatory CNS injury in CM patients and found that the exuberant CNS inflammation, driven by ultra Th1-polarized T cells and inflammatory monocytes, promotes severe immunopathology with neurological deterioration. Regulatory T cells (Tregs) are the crucial component of this immunoregulatory network, and their dysfunction is linked to inflammatory complications of CM in human patients. Our published and unpublished Preliminary Data now support that Treg play crucial roles in limiting the pathological inflammation within the Cryptococcus-infected CNS. Our preliminary data further show that Treg specifically express chemokine receptor CCR8 and that Treg-recruitment kinetics is paralleled by the upregulation of CCR8 ligand chemokine CCL1, supporting the importance of the CCL1/CCR8 axis in mediating CNS migration of Treg. We show that among all cellular populations within the CNS, Treg are the major, if not sole producer of the immune- regulatory cytokine IL-10 and Amphiregulin (Areg), factor known to promote wound healing and tissue repair. Hypothesis: Hypothesis that CCL1/CCR8-axis-recruited Treg protect against severe CNS damage and subsequent mortality in mice with CM via production of IL-10 and Areg and that Treg-based immunotherapies will reduce morbidity and mortality in mice with CM. To test distinct parts of this hypothesis we will: Aim 1. To demonstrate that CCR8-recruited Treg protect the brain from inflammatory pathology in CM 1.a. determine if Treg limit excessive CNS inflammation during CM, especially reducing pathological elements of the CNS host response 1.b. define whether and how Treg reduce neuropathological processes in the CM-afflicted brain 1.c. demonstrate the dependence of the CCR8 axis for CNS Treg accumulation and their function during CM. Aim 2: To define the therapeutic effects of Treg in CM 2.a. demonstrate that Treg enhancement by IL-2 immune complex therapy protects mice from fatal CM pathology 2.b. determine if CCR8+ versus CCR8- Treg adoptive transfer protects mice from fatal CM pathology Aim 3: To determine the mechanisms by which Treg limit CNS inflammation and promote neurological repair during CM 3.a. determine if Treg-derived IL-10 is required for limiting pathological CNS inflammation during CM 3.b. define whether Treg-derived Areg promotes neurological repair during CM. Research Plan and Methods: This proposal will use our established mouse model of CM, which accurately recapitulates severe paradoxical immune responses experienced by patients with C. neoformans CNS infection. We will manipulate Treg system (remove or expand T reg responses, to determine if they would worsen or improve condition of CM animals, respectively). We will also perform a series of adoptive transfer experiments with isolated Tregs to determine if their administration would alleviate the symptoms. Finally, we will use T- cell restricted IL-10 KO mice and T-cell-restricted Amphiregulin KO mice to determine the molecular mechanism of their anti-inflammatory and CNS protective effect and how they will affect different aspects of CNS pathology in CM. Overall, these studies will provide significant insight on T cell mediated pathology and how Tregs oppose this process during fungal CNS infections, that down the road will likely identify new biomarkers or therapeutic opportunities.

目的：新型隐球菌是导致中枢神经系统相关死亡的最重要的真菌病原体 和全世界的发病率。尽管 CM 通常被视为一种由免疫力低下引起的疾病，但有证据表明 累积表明，旺盛的宿主免疫反应对 CM 的发病机制有显着贡献。对此 最后，我们开发了一种 CM 小鼠模型，该模型再现了 CM 炎症性中枢神经系统损伤的主要特征 患者，发现由超 Th1 极化 T 细胞驱动的旺盛的中枢神经系统炎症和 炎症性单核细胞，促进严重的免疫病理学和神经系统恶化。 调节性 T 细胞 (Treg) 是免疫调节网络的重要组成部分，其功能障碍 与人类患者的 CM 炎症并发症有关。我们已发表和未发表的初步 现在的数据支持 Treg 在限制体内病理性炎症方面发挥着至关重要的作用 隐球菌感染的中枢神经系统。我们的初步数据进一步表明Treg特异性表达趋化因子 受体 CCR8 并且 Treg 募集动力学与 CCR8 配体趋化因子的上调平行 CCL1，支持 CCL1/CCR8 轴在介导 Treg 中枢神经系统迁移中的重要性。我们表明 在中枢神经系统内的所有细胞群中，Treg 是免疫细胞的主要（如果不是唯一的）产生者。 调节细胞因子 IL-10 和双调蛋白 (Areg)，已知可促进伤口愈合和组织修复的因子。 假设：假设 CCL1/CCR8 轴募集的 Treg 可以防止严重的 CNS 损伤并 通过产生 IL-10 和 Areg 以及基于 Treg 的免疫疗法，导致 CM 小鼠随后死亡 将降低 CM 小鼠的发病率和死亡率。为了检验这个假设的不同部分，我们将： 目标 1. 证明 CCR8 招募的 Treg 可以保护大脑免受 CM 炎症病理的影响 1.a.确定 Treg 是否限制 CM 期间过度的 CNS 炎症，特别是减少病理因素 CNS 宿主反应 1.b.定义 Treg 是否以及如何减少患有 CM 的大脑中的神经病理过程 1.c.证明 CCR8 轴对 CNS Treg 积累的依赖性及其在 CM 期间的功能。 目标 2：确定 Treg 在 CM 中的治疗作用 2.a.证明 IL-2 免疫复合物疗法增强 Treg 可保护小鼠免受致命性 CM 的侵害 病理 2.b.确定 CCR8+ 与 CCR8- Treg 过继转移是否可以保护小鼠免受致命 CM 病理的影响 目标 3：确定 Treg 限制 CNS 炎症和促进的机制 CM期间的神经修复 3.a.确定 Treg 衍生的 IL-10 是否需要限制 CM 期间的病理性 CNS 炎症 3.b.定义 Treg 衍生的 Areg 是否促进 CM 期间的神经修复。 研究计划和方法：本提案将使用我们建立的 CM 小鼠模型，该模型准确地 概括了新型隐球菌中枢神经系统感染患者所经历的严重矛盾的免疫反应。 我们将操纵Treg系统（删除或扩大Treg反应，以确定它们是否会恶化或 分别改善 CM 动物的状况）。我们还将进行一系列的收养转移实验 与分离的 Tregs 一起确定它们的给药是否会减轻症状。最后，我们将使用 T- 细胞限制性 IL-10 KO 小鼠和 T 细胞限制性双调蛋白 KO 小鼠以确定分子 它们的抗炎和中枢神经系统保护作用的机制以及它们如何影响不同方面 CM 中的中枢神经系统病理学。总体而言，这些研究将为 T 细胞介导的病理学和 Tregs 在真菌中枢神经系统感染期间如何对抗这一过程，未来可能会发现新的 生物标志物或治疗机会。

项目成果

JAK/STAT Signaling Predominates in Human and Murine Fungal Post-infectious Inflammatory Response Syndrome.

JAK/STAT 信号传导在人类和小鼠真菌感染后炎症反应综合征中占主导地位。

• 发表时间: 2024-01-21
• 作者: Hargarten, Jessica C;Ssebambulidde, Kenneth;Anjum, Seher H;Vaughan, Malcolm J;Xu, Jintao;Song, Brian;Ganguly, Anutosh;Park, Yoon;Scott, Terri;Hammoud, Dima A;Olszewski, Michal A;Williamson, Peter R
• 通讯作者: Williamson, Peter R