In vivo imaging of diabetogenic cytotoxic T-lymphocytes

致糖尿病细胞毒性 T 淋巴细胞的体内成像

• 批准号: 6918608
• 负责人: ANNA MOORE
• 金额: $ 26.56万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-05 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918608
• 关键词: NOD mouse; T cell receptor; bioimaging /biomedical imaging; crosslink; cytotoxic T lymphocyte; genetically modified animals; imaging /visualization /scanning; immunomagnetic separation; insulin dependent diabetes mellitus; leukocyte activation /transformation; magnetic field; magnetic resonance imaging; noninvasive diagnosis; pancreatic islets; pathologic process

DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop a non-invasive method to detect the infiltration of CD8+ T-cells responsible for beta-cell destruction in pancreatic islets in Type 1 Diabetes (IDDM) by MR imaging. In vivo imaging of immune cells infiltration in real time would have significant impact in managing clinical IDDM, pancreas and/or islet cell transplantation and the understanding of the pathogenesis of IDDM. Unfortunately, such non-invasive techniques are currently not available. Based on our prior experience in cell labeling with crosslinked, superparamagnetic, monocrystalline iron oxide nanoparticles, we synthesized a novel MR imaging probe with high affinity ligands to T cell autoantigenic markers that allowed for high-efficiency intracellular magnetic labeling of the cells with subsequent detection by MRI. This probe specifically binds to highly diabetogenic TCR on CD8+ T cells from NOD transgenic mice, but does not recognize CD8+ T cells from healthy NOD mice. Furthermore, in our initial imaging experiments in vivo we were able to see gradual accumulation of labeled CD8+ T cells in mouse pancreas after adoptive transfer. In the current proposal we are going to conduct imaging experiments using this probe to answer highly relevant biological questions regarding the mechanisms that drive the recruitment, activation and differentiation of autoreactive CD8+ T cells. Specifically, we propose to image in vivo tracking of CD8+ T cell recruitment to the islets and beta-cell mass loss depending on the avidity of recruited killer cells. The proposed studies are a logical extension of the feasibility experiments, and if successful, a transition of this research would be tested in clinical trials.

描述（由申请人提供）：本提案的总体目标是开发一种非侵入性方法，通过 MR 成像检测负责 1 型糖尿病 (IDDM) 胰岛中 β 细胞破坏的 CD8+ T 细胞的浸润。免疫细胞浸润的实时体内成像将对治疗临床 IDDM、胰腺和/或胰岛细胞移植以及了解 IDDM 的发病机制产生重大影响。不幸的是，目前还没有这种非侵入性技术。基于我们之前使用交联超顺磁性单晶氧化铁纳米粒子进行细胞标记的经验，我们合成了一种新型磁共振成像探针，其具有与 T 细胞自身抗原标记物高亲和力的配体，可对细胞进行高效的细胞内磁性标记，并随后通过核磁共振成像。该探针特异性结合 NOD 转基因小鼠 CD8+ T 细胞上高度致糖尿病的 TCR，但不识别健康 NOD 小鼠的 CD8+ T 细胞。此外，在我们最初的体内成像实验中，我们能够看到过继移植后小鼠胰腺中标记的 CD8+ T 细胞逐渐积累。在当前的提案中，我们将使用该探针进行成像实验，以回答有关驱动自身反应性 CD8+ T 细胞招募、激活和分化的机制的高度相关的生物学问题。具体来说，我们建议根据招募的杀伤细胞的亲合力对 CD8+ T 细胞招募到胰岛和 β 细胞质量损失进行体内成像跟踪。拟议的研究是可行性实验的逻辑延伸，如果成功，这项研究的转变将在临床试验中进行测试。