Noninvasive two-photon imaging of pancreatic islet graft rejection in the eye

眼部胰岛移植排斥反应的无创双光子成像

• 批准号: 7743864
• 负责人: Midhat H Abdulreda
• 金额: $ 4.74万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743864
• 关键词: Active Sites; Address; Allogenic; Allografting; Animals; Apoptosis; Bioluminescence; Cell Communication; Cell Death; Cell Survival; Cells; Clinical; Complex; Data; Development; Diabetes Mellitus; Diagnosis; Early Diagnosis; Early treatment; Endothelial Cells; Event; Extravasation; Eye; Fluorescence Microscopy; Goals; Graft Rejection; Graft Survival; Homologous Transplantation; Hyperglycemia; Image; Imaging Techniques; Immune; Immune Targeting; Immune response; Immune system; Immunobiology; Immunohistochemistry; Immunologic Monitoring; In Situ; Individual; Infiltration; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Kinetics; Label; Life; Lymphoid; Magnetic Resonance Imaging; Measures; Mediating; Methods; Modality; Modeling; Modification; Monitor; Morphology; Movement; Mus; Myelogenous; Ophthalmologist; Pattern; Positron-Emission Tomography; Process; Publications; Recurrence; Reporting; Research; Resolution; Shapes; Signal Transduction; Site; Speed; Surface; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Grafts; Tissues; Transplantation; Transplanted tissue; Treatment Protocols; Work; anterior chamber; cell motility; cytotoxic; fluorescence imaging; graft function; imaging modality; implantation; improved; in vivo; islet; islet allograft; novel; prevent; tool; two-photon

DESCRIPTION (provided by applicant): Islet cell survival after transplantation to cure type 1 diabetes is limited primarily by immune-mediated rejection. Therefore, in situ monitoring of graft rejection in real time is critical for proper intervention. Current imaging modalities lack spatial and temporal resolution and consequently immune attack of the islets is only be detected once macroscopic graft damage has occurred. The long-term goal of this application is to establish a high resolution imaging approach where immune-mediated rejection of graft tissue in live recipients can be monitored noninvasively and studied in situ. This project aims to establish pancreatic islet transplantation into the murine anterior chamber of the eye as a model for two-photon fluorescence imaging of immune rejection of transplanted allogeneic islets. The anterior chamber of the eye provides a natural body window that allows noninvasive monitoring of the very same islets longitudinally. The hypothesis is that immune-mediated intraocular rejection of islet allografts occurs despite immune privilege and can be readily imaged noninvasively in real time. For the first time, this project will enable studying in vivo early rejection in real time. It will enable the study of cellular motility and dynamics during islet allograft rejection. Pilot data provided by the applicant revealed rejection of allogeneic islets and demonstrated the strength and feasibility of imaging intraocular islet function and rejection. These data showed for the first time in vivo recruitment of individual immune cells to the graft site and active infiltration of the islet grafts. The applicant proposes the following specific aims: (1) Establish intraocular transplantation as a rejection model for transplanted pancreatic islets. The working hypothesis is that islet rejection is mediated by early and persistent inflammation and ultimately by effector T lymphocytes; and (2) Identify the cellular mechanisms of intraocular rejection of islet allografts. The working hypothesis is that the rejection process requires the close association of inflammatory cells with allospecific effector T cells in the islet grafts. It is predicted that islet cell death occurs near these cell complexes. These studies will reveal the kinetics and dynamics of immunemediated intraocular rejection of islet allografts and will provide a platform to test and refine novel and existing therapeutic regimens aimed at enhancing islet survival and long-term acceptance of grafts. Being able to monitor the fate of islet grafts in real time would enable early intervention and will address the major limitation to pancreatic islet transplantation as a therapy to cure type 1 diabetes. This proposed project allows the early detection and study of rejection providing a better understanding of the process and the ability for a timely intervention to improve islet cell survival and long-term graft acceptance.

描述（由申请人提供）： 移植到1型糖尿病后的胰岛细胞存活主要受到免疫介导的限制 拒绝。因此，实时监测接枝拒绝对于正确干预至关重要。当前的成像方式缺乏空间和时间分辨率，因此仅一旦发生宏观移植损伤才能检测到胰岛的免疫攻击。该应用的长期目标是建立一种高分辨率成像方法，可以非侵入性地监测活物体中的接枝组织的免疫介导的排斥反应并原位研究。该项目旨在将胰岛移植到眼前的鼠前腔中，作为两光子荧光成像的模型，以免疫排斥的同种异体胰岛的免疫排斥。眼睛的前室提供了一个自然的体窗，可以纵向对同一小岛进行非侵入性监测。假设是，尽管免疫特权，也会发生免疫介导的胰岛移植的眼内排斥反应，并且可以实时无创地成像。该项目将首次实时研究体内早期拒绝。它将能够研究同种异体移植排斥期间的细胞运动和动力学。申请人提供的试点数据显示，同种异体胰岛的排斥反应，并证明了成像眼内胰岛功能和排斥的强度和可行性。这些数据首次在体内募集单个免疫细胞到移植部位和胰岛移植物的主动浸润。申请人提出以下特定目的：（1）建立眼内移植作为移植胰岛的排斥模型。工作假设是胰岛排斥是由早期和 持续的炎症，最终通过效应T淋巴细胞； （2）确定同种异体移植的眼内排斥反应的细胞机制。工作假设是，拒绝过程需要炎症细胞与胰岛移植物中同种效应T细胞的密切关联。可以预测，胰岛细胞死亡发生在这些细胞复合物附近。这些研究将揭示免疫介导的胰岛眼内排斥反应的动力学和动力学，并将提供一个平台，以测试和完善旨在增强胰岛存活和长期接纳的新型和现有治疗方案。能够实时监测胰岛移植物的命运将使早期干预，并将针对胰岛移植的主要限制作为治疗1型糖尿病的治疗。该提出的项目允许对排斥的早期检测和研究，从而更好地理解该过程，并及时干预改善胰岛细胞存活和长期移植物的能力。