Imaging DTH, IFN gamma responses & GA in human arteries

成像 DTH、IFN γ 反应

• 批准号: 6659332
• 负责人: JEFFREY R. BENDER
• 金额: $ 17.75万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6659332
• 关键词: SCID mouse; angiography; arteriosclerosis; autoradiography; bioimaging /biomedical imaging; blood vessel transplantation; cell adhesion molecules; cytokine receptors; delayed hypersensitivity; human subject; human tissue; interferon gamma; laboratory mouse; peptide library; platelet derived growth factor; radioimmunoassay; radionuclide imaging /scanning; technology /technique development; transplant rejection

Imaging DTH, IFN-gamma Responses and GA in Human Arteries. Graft arteriosclerosis (GA) is the major cause of late graft failure in cardiac transplantation. Reliable non-invasive tools for the detection of GA, specifically in its early form, do not currently exist. Coronary angiography and myocardial perfusion imaging are routinely performed but have limited detection accuracy for early disease. However, the detected neointima is not predictive of the clinical course. The overall goal of this project is to develop non-invasive, nuclear imaging-based modalities for early GA detection, based upon the immunopathogenesis. Our approaches will be closely linked to the Project 1 and 2 hypotheses, that TH1 cells are potent stimulators of the GA response through the elaboration of IFN-gamma which in turn, induces chemokine production, growth factor receptor expression and smooth muscle cell (SMC) activation/proliferation. We have recently established small animal imaging models which target modulated membrane markers in pathologic states, including an arterial injury model in mice. Specific proposals now include: (1) to define expression levels of known, carefully chosen candidates target molecules, including CXCR3 and CCR5 (T cells), PDGFbeta-R, alphavbeta3 and VCAM-1 (endothelial cells and SMC), IP- 10 and Mig (secreted), on CD4+ TH1 cells, IFN-gamma activated SMC and EC, in (a) cell culture, (b) organ culture, (c) human-to-mouse vascular transplant segments in a SCID mouse model, and (d) human specimens of chronic vascular rejection; (2) to select novel potential imaging ligands using a peptide phage display library and biopanning, in vitro, ex vivo, and in vivo, directing the phage biopanning at the same spectrum of immune-activated cells/tissues; (3) to radiolabel chosen ligands (antibodies, peptides and other small molecules) and determine their pharmacologic properties both in vitro and in vivo, using radioimmunoassays and autoradiography; and (4) to perform gamma camera-based in vivo imaging in the human arterial transplant to SCID mouse model, using a limited number of radiotracers selected in 1-3, above. Defined targeted imaging approaches will be the foundation for patient-based studies in the future. Ultimately, the ability to detect early pathogenetic features of GA may provide prognostic data and generate a new paradigm for treatment of transplant patients.

人体动脉中的 DTH、IFN-γ 反应和 GA 成像。移植物动脉硬化（GA）是心脏移植中晚期移植失败的主要原因。目前尚不存在用于检测 GA（特别是早期形式）的可靠非侵入性工具。冠状动脉造影和心肌灌注成像是常规检查，但对早期疾病的检测准确性有限。然而，检测到的新内膜并不能预测临床病程。该项目的总体目标是开发基于免疫发病机制的非侵入性、基于核成像的早期 GA 检测方式。我们的方法将与项目 1 和项目 2 的假设密切相关，即 TH1 细胞通过 IFN-gamma 的形成，成为 GA 反应的有效刺激剂，而 IFN-gamma 反过来又诱导趋化因子的产生、生长因子受体的表达和平滑肌细胞 (SMC)激活/增殖。我们最近建立了小动物成像模型，以病理状态下的调节膜标记为目标，包括小鼠动脉损伤模型。现在的具体建议包括：（1）定义已知的、精心挑选的候选靶分子的表达水平，包括CXCR3和CCR5（T细胞）、PDGFbeta-R、alphavbeta3和VCAM-1（内皮细胞和SMC）、IP-10和Mig（分泌），在 CD4+ TH1 细胞、IFN-γ 激活的 SMC 和 EC 上，在 (a) 细胞培养物、(b) 器官培养物、(c) 人对小鼠中SCID 小鼠模型中的血管移植片段，以及 (d) 慢性血管排斥的人类标本； (2) 使用肽噬菌体展示库和体外、离体和体内生物淘选来选择新型潜在成像配体，将噬菌体生物淘选引导至相同谱的免疫激活细胞/组织； (3) 使用放射免疫测定法和放射自显影术对选定的配体（抗体、肽和其他小分子）进行放射性标记并确定其体外和体内药理学特性； (4) 使用上述 1-3 中选择的有限数量的放射性示踪剂，对 SCID 小鼠模型的人动脉移植物进行基于伽玛相机的体内成像。明确的靶向成像方法将成为未来基于患者的研究的基础。最终，检测 GA 早期发病特征的能力可能会提供预后数据并为移植患者的治疗提供新的范例。