Non-invasive imaging of brain infiltrating T lymphocytes in a mouse model of experimental autoimmune encephalomyelitis with PET

实验性自身免疫性脑脊髓炎小鼠模型中脑浸润 T 淋巴细胞的 PET 无创成像

• 批准号: 9925850
• 负责人: Peter Michael Clark
• 金额: $ 33.32万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925850
• 关键词: Alzheimer' s Disease; Anatomy; Animals; Area; Autoradiography; Biochemical Pathway; Biodistribution; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Brain; Brain imaging; CD4 Positive T Lymphocytes; Cell physiology; Cells; Clinic; Clinical; Companions; Data; Demyelinations; Deoxycytidine Kinase; Diagnosis; Disease; Dose; Encephalitis; Enzymes; Experimental Autoimmune Encephalomyelitis; Hour; Human; Image; Imaging technology; Immunohistochemistry; Immunomodulators; Immunosuppressive Agents; Infiltration; Inflammation; Injections; Leukocytes; Literature; Lymphocytic Infiltrate; Magnetic Resonance Imaging; Measures; Methods; Monitor; Multiple Sclerosis; Mus; Myelin; Neurologic; Nucleosides; Parkinson Disease; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Process; Reading; Reporting; Research; Role; T-Lymphocyte; Tauopathies; Testing; Time; Tracer; Traumatic Brain Injury; attenuation; clinical translation; clinically relevant; drug efficacy; experimental study; human disease; imaging approach; imaging modality; immunomodulatory therapies; in vivo; mouse model; nervous system disorder; non-invasive imaging; pre-clinical; radiotracer; therapeutic target; therapy development; tool

PROJECT SUMMARY / ABSTRACT Brain infiltrating T lymphocytes are found in a variety of neurological disorders, including multiple sclerosis (MS), autoimmune encephalomyelitis, traumatic brain injury, Parkinson's disease, and tauopathies. Brain infiltrating CD4 T lymphocytes have a clear, causative role in the pathology of MS and autoimmune encephalomyelitis and have been suggested to contribute to other diseases. As such, these cells represent an important therapeutic target in the treatment of neurological disorders. Yet despite all of this, there remains no non-invasive method for visualizing and quantifying these cells in vivo. Current imaging modalities, such as MRI, can only indirectly measure the effects of inflammation and cannot directly image T lymphocytes. This makes it challenging to further validate the contribution of these cells to human disease and to identify whether therapies meant to target these cells are effective in patients. There is a clear clinical need for new methods to image brain infiltrating T lymphocytes. We hypothesize that the radiotracer 18F-FAC will selectively accumulate in brain infiltrating T lymphocytes and that PET imaging with 18F-FAC can be used to quantify and visualize brain infiltrating T lymphocytes. We propose to test our hypothesis in a preclinical mouse model of experimental autoimmune encephalomyelitis (EAE). We envision that the successful completion of this proposal would provide important pilot data for testing this approach in patients. Successful implementation of this approach in the clinic could provide clinicians with a non-invasive method for quantifying brain infiltrating T lymphocytes in patients with neurological diseases and for monitoring treatments developed to suppress these T lymphocytes. We have significant preliminary data to support the feasibility of and our ability to accomplish the proposed studies. We propose to test our hypothesis through the following three Specific Aims: Specific Aim 1. To quantify 18F-FAC brain accumulation across multiple time points during the induction and progression of EAE in a mouse model Specific Aim 2. To determine whether 18F-FAC PET can be used as a functional biomarker of immunosuppressant drug efficacy in the brains of EAE mice Specific Aim 3. To identify the leukocyte type that causes increased 18F-FAC accumulation in EAE mouse brains using autoradiography, immunohistochemistry, in vivo blocking, and ex vivo accumulation assays

项目总结/摘要 脑浸润性T淋巴细胞存在于多种神经系统疾病中，包括多种神经系统疾病。 硬化症（MS）、自身免疫性脑脊髓炎、创伤性脑损伤、帕金森病和tau蛋白病。 脑浸润性CD 4 T淋巴细胞在MS和自身免疫性疾病的病理学中具有明确的致病作用。 脑脊髓炎，并已被认为有助于其他疾病。因此，这些细胞代表 在神经系统疾病的治疗中是重要的治疗靶点。然而，尽管如此， 非侵入性的方法，用于可视化和量化这些细胞在体内。当前的成像模式，例如 MRI只能间接测量炎症的影响，不能直接对T淋巴细胞成像。这 这使得进一步验证这些细胞对人类疾病的贡献以及确定是否 旨在靶向这些细胞的疗法在患者中是有效的。有明确的临床需求， 方法脑浸润性T淋巴细胞显像。 我们假设放射性示踪剂18F-FAC将选择性地在脑浸润性T细胞中积聚， 18F-FAC的PET成像可用于定量和可视化脑浸润 T淋巴细胞。我们建议在实验性自身免疫的临床前小鼠模型中测试我们的假设。 脑脊髓炎（EAE）。我们预计，该提案的成功完成将提供重要的 在患者中测试这种方法的试点数据。在临床上成功实施这种方法可以 为临床医生提供了一种非侵入性的方法，用于定量患者的脑浸润T淋巴细胞， 神经系统疾病和监测治疗开发抑制这些T淋巴细胞。 我们有重要的初步数据来支持的可行性和我们的能力，以实现 建议的研究。 我们建议通过以下三个具体目标来检验我们的假设： 具体目标1.在诱导期间的多个时间点定量18F-FAC脑蓄积， EAE在小鼠模型中的进展 具体目标2。为了确定18F-FAC PET是否可以用作功能性生物标志物， EAE小鼠脑中的免疫抑制剂药物功效 具体目标3。鉴定引起EAE小鼠18F-FAC蓄积增加的白细胞类型 使用放射自显影术、免疫组织化学、体内阻断和离体蓄积测定的脑