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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

基本信息

批准号：
8114018
负责人：
Midhat H Abdulreda
金额：
$ 5.3万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/8114018
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 Regimen Reporting Research Resolution Shapes Signal Transduction Site Speed Surface T-Lymphocyte Techniques Technology Testing Therapeutic Therapeutic Intervention Time Tissue Grafts Tissues Transplantation Transplanted tissue Work allograft rejection anterior chamber cell motility cytotoxic fluorescence imaging graft function imaging modality implantation improved in vivo islet islet allograft novel prevent tool two-photon

项目摘要

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）：移植治愈 1 型糖尿病后胰岛细胞的存活率主要受到免疫介导的限制拒绝。因此，实时原位监测移植物排斥反应对于正确干预至关重要。目前的成像方式缺乏空间和时间分辨率，因此只有在发生宏观移植物损伤时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，可以无创地监测并原位研究活体受体中免疫介导的移植组织排斥反应。该项目旨在将胰岛移植到小鼠眼前房中，作为移植同种异体胰岛免疫排斥的双光子荧光成像模型。眼睛的前房提供了一个自然的身体窗口，可以对同一胰岛进行纵向无创监测。该假设是，尽管有免疫特权，但免疫介导的胰岛同种异体移植物的眼内排斥仍然发生，并且可以很容易地进行非侵入性实时成像。该项目将首次实现体内早期排斥反应的实时研究。它将能够研究胰岛同种异体移植排斥期间的细胞运动和动力学。申请人提供的试验数据揭示了同种异体胰岛的排斥，并证明了眼内胰岛功能和排斥成像的强度和可行性。这些数据首次显示个体免疫细胞在体内募集到移植部位以及胰岛移植物的主动浸润。申请人提出以下具体目标：（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性炎症，最终由效应 T 淋巴细胞引起； (2) 确定同种异体胰岛移植物眼内排斥的细胞机制。目前的假设是，排斥过程需要胰岛移植物中炎症细胞与同种异体特异性效应 T 细胞的紧密结合。据预测，胰岛细胞死亡发生在这些细胞复合物附近。这些研究将揭示胰岛同种异体移植物的免疫介导的眼内排斥的动力学和动力学，并将提供一个平台来测试和完善旨在增强胰岛存活和移植物的长期接受性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能够进行早期干预，并将解决胰岛移植作为治疗 1 型糖尿病的疗法的主要限制。该项目允许对排斥反应进行早期检测和研究，从而更好地了解排斥反应的过程，并能够及时进行干预，以提高胰岛细胞的存活率和长期移植物的接受度。