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：新生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 以及世界范围内的发病率。虽然CM通常被认为是一种由免疫力低下引起的疾病，但有证据表明， 积累了旺盛的宿主免疫反应在CM发病机制中的重要作用。对这件事 最后，我们建立了一种CM小鼠模型，该模型复制了CM中枢神经系统炎性损伤的主要特征 患者发现，由超Th1极化的T细胞和 炎性单核细胞，促进严重的免疫病理和神经恶化。 调节性T细胞(Tregs)是这个免疫调节网络的关键组成部分，它们的功能障碍 与人类患者的CM炎症并发症有关。我们已出版和未出版的初步报告 现在的数据支持Treg在限制血管内的病理性炎症方面发挥了关键作用。 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特异性地表达趋化因子 CCR8受体和Treg募集动力学与CCR8配体趋化因子的上调平行 CCL1，支持CCL1/CCR8轴在调节Treg的中枢神经系统迁移中的重要性。我们证明了 在中枢神经系统内的所有细胞群中，Treg是免疫的主要(如果不是唯一的)产生者- 调节性细胞因子IL-10和两性调节蛋白(Areg)，已知促进伤口愈合和组织修复。 假设：CCL1/CCR8轴招募的Treg对严重的中枢神经系统损伤和 产生IL-10和ARG及Treg免疫疗法对CM小鼠后续死亡率影响 将降低CM小鼠的发病率和死亡率。为了测试这一假设的不同部分，我们将： 目的1.证明CCR8招募的Treg对CM大鼠脑组织的炎性病变具有保护作用 1.a.确定Treg是否能抑制CM期间过度的中枢神经系统炎症，特别是减少病理因素 CNS主机响应的 1.B.明确Treg是否以及如何减少CM患者脑内的神经病理过程 1.C.证明CCR8轴对CNS Treg聚集的依赖性及其在CM过程中的作用。 目的2：明确Treg在CM中的治疗效果 2.a.IL-2免疫复合体增强Treg对小鼠致死性心肌炎的保护作用 病理学 2.B.确定CCR8+与CCR8-Treg过继转移是否能保护小鼠免受致死性CM病理的影响 目的3：确定Treg抑制中枢神经系统炎症和促进炎症的机制 心肌梗死期间的神经修复 3.a.确定CM期间是否需要Treg来源的IL-10来限制病理性中枢神经系统炎症 3.B.明确Treg来源的ARG是否促进CM期间的神经修复。 研究计划和方法：本方案将使用我们建立的CM小鼠模型，该模型准确地 概述了新生葡萄球菌中枢神经系统感染患者经历的严重的矛盾免疫反应。 我们将操作Treg系统(移除或扩展T reg响应，以确定它们是否会恶化或 分别改善CM动物的状态)。我们还将进行一系列的领养迁移实验 用隔离的Tregs来确定他们的管理是否会缓解症状。最后，我们将使用T- 细胞限制性IL-10 KO小鼠和T细胞限制性两性调节蛋白KO小鼠的分子测定 它们的抗炎和中枢神经系统保护作用的机制及其对不同方面的影响 CM的中枢神经系统病理改变。总体而言，这些研究将为T细胞介导的病理学和 在真菌中枢神经系统感染期间，Tregs如何反对这一过程，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。

• DOI: 10.1101/2024.01.18.24301483
• 发表时间: 2024
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Hargarten,JessicaC;Ssebambulidde,Kenneth;Anjum,SeherH;Vaughan,MalcolmJ;Xu,Jintao;Song,Brian;Ganguly,Anutosh;Park,Yoon-Dong;Scott,Terri;Hammoud,DimaA;Olszewski,MichalA;Williamson,PeterR
• 通讯作者: Williamson,PeterR