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

项目摘要/摘要 大脑浸润性T淋巴细胞在各种神经疾病中被发现，包括多发性 硬化症(MS)、自身免疫性脑脊髓炎、创伤性脑损伤、帕金森氏病和神经官能症。 脑内浸润的CD4T淋巴细胞在多发性硬化症和自身免疫的病理过程中起着明确的致病作用 脑脊髓炎，并被认为是其他疾病的致病因素。因此，这些单元格表示 是治疗神经系统疾病的重要靶点。然而，尽管有这一切，仍然没有 体内观察和量化这些细胞的非侵入性方法。当前的成像方式，例如 MRI，只能间接测量炎症的影响，不能直接成像T淋巴细胞。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 针对这些细胞的治疗对患者有效。很明显，临床上需要新的 方法对脑内浸润性T淋巴细胞进行图像分析。 我们假设放射性示踪剂18F-FAC将选择性地积聚在大脑浸润性T细胞中。 淋巴细胞和18F-FAC PET显像可用于定量和可视化脑浸润性病变 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检验我们的假设。 脑脊髓炎(EAE)。我们设想，这项提案的成功完成将提供重要的 在患者身上测试这种方法的试点数据。这种方法在临床上的成功实施可以 为临床医生提供一种无创定量检测脑内浸润性T淋巴细胞的方法 神经疾病和监测治疗发展以抑制这些T淋巴细胞。 我们有重要的初步数据支持我们实现这一目标的可行性和能力 建议进行的研究。 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.量化18F-FAC在诱导和恢复过程中多个时间点的脑积聚 EAE小鼠模型的研究进展 具体目的2.确定18F-FAC PET是否可以作为一种功能性生物标志物 免疫抑制药物对EAE小鼠脑内作用的研究 特定目的3.确定导致EAE小鼠18F-FAC蓄积增加的白细胞类型 脑放射自显影、免疫组织化学、体内阻断和体外蓄积试验

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