FAS L INDUCED APOPTOSIS IN CORNEA TRANSPLANTATION

FAS L 在角膜移植中诱导细胞凋亡

• 批准号: 6179299
• 负责人: Patrick M Stuart
• 金额: $ 26.94万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6179299
• 关键词: CD95 molecule; apoptosis; clinical research; cornea; eye transplantation; gene expression; homologous transplantation; human subject; immunosuppression; keratoplasty; laboratory mouse; nonsurgical revascularization; organ culture; tissue inhibitor of metalloproteinases; transplant rejection; transplantation immunology

The acceptance rate for corneal transplantation, one of the most common types of transplantation performed, is typically between 80- 90%. The reasons for this remarkably high success rate are undoubtedly related to the unique environment of the eye. The eye is one of several organs that manifests properties of immune privilege. Immune privilege is characterized by altered immune responses as is seen in the case of allografts which display prolonged survival when placed into an immune privileged site. While the exact mechanism responsible for immune privilege in the eye is at yet unknown, it has been shown that it probably relies on multiple factors which work together to protect this vital organ from rampant inflammatory processes. These include the production of immunosuppressive cytokines, the localization of neuropeptides in ocular neurons, the strategic placement of specialized antigen presenting cells, and the induction of systemic immune deviation following antigen presentation in the eye. Additionally, it has recently been found that FasL in the eye kills invading Fas+ cells and is a significant protective mechanism for this organ. Furthermore, we have recently reported that virtually all corneas that fail to express functional FasL are rejected by their allogeneic hosts, a compared to a 50% rejection rate for corneas expressing functional FasL. The present application extends our previous observations that Fas ligand (FasL) plays a critical role in murine corneal allograft acceptance to determining whether increasing the functional expression of FasL on the cornea leads to concomitant increase in acceptance of corneal allografts. To that end we will identify those reagents that increase corneal FasL expression and test whether treatment of corneal allografts with such reagents leads to increased cornea allograft acceptance. We will also determine whether FasL expression and function are altered by the immunological state of the cornea. This will be accomplished by monitoring FasL expression in diseased and damaged human corneas and comparing this to that observed in normal human corneas. In parallel, we will stimulate cornea disease in mice and determine whether, over the course of the disease, there are changes in FasL expression from the initial stages of inflammation to the resolution of disease. Finally, preliminary data suggests that neovascularization of the cornea is effected by the presence or absence of functional FasL. Namely, that mice which do not express functional FasL display neovascularization to a greater extent than do mice with normal FasL. Consequently, we propose studies to better define the role that Fas and FasL play in corneal neovascularization.

角膜移植是最常见的移植类型之一，其接受率通常在 80-90% 之间。成功率如此之高的原因无疑与眼睛独特的环境有关。眼睛是表现出免疫特权特性的几个器官之一。免疫特权的特点是免疫反应改变，正如同种异体移植物在置于免疫特权位点时表现出延长的存活期的情况所示。虽然导致眼睛免疫豁免的确切机制尚不清楚，但研究表明，它可能依赖于多种因素，这些因素共同作用来保护这个重要器官免受猖獗的炎症过程的影响。这些包括免疫抑制细胞因子的产生、神经肽在眼神经元中的定位、特殊抗原呈递细胞的战略放置以及抗原呈递在眼中后诱导全身免疫偏差。此外，最近发现眼睛中的 FasL 可以杀死入侵的 Fas+ 细胞，是该器官的重要保护机制。此外，我们最近报道，几乎所有不能表达功能性 FasL 的角膜都会被其同种异体宿主排斥，相比之下，表达功能性 FasL 的角膜的排斥率为 50%。本申请扩展了我们之前的观察，即Fas配体（FasL）在小鼠角膜同种异体移植接受中发挥关键作用，以确定增加角膜上FasL的功能表达是否导致角膜同种异体移植接受的伴随增加。 为此，我们将鉴定那些增加角膜 FasL 表达的试剂，并测试用此类试剂处理同种异体角膜是否会增加角膜同种异体移植的接受度。我们还将确定 FasL 的表达和功能是否会因角膜的免疫状态而改变。 这将通过监测患病和受损的人角膜中的 FasL 表达并将其与正常人角膜中观察到的进行比较来实现。 与此同时，我们将刺激小鼠角膜疾病，并确定在疾病过程中，从炎症初始阶段到疾病消退，FasL 表达是否存在变化。 最后，初步数据表明，角膜的新血管形成受功能性 FasL 存在或不存在的影响。即，不表达功能性FasL的小鼠比具有正常FasL的小鼠表现出更大程度的新血管形成。 因此，我们建议进行研究以更好地确定 Fas 和 FasL 在角膜新生血管形成中的作用。