FAS L INDUCED APOPTOSIS IN CORNEA TRANSPLANTATION

角膜移植的接受率通常在80%-90%之间，角膜移植是最常见的移植类型之一。成功率如此之高的原因无疑与眼睛所处的独特环境有关。眼睛是表现出免疫豁免特性的几个器官之一。免疫豁免的特征是免疫反应的改变，就像同种异体移植物放置在免疫特权部位时表现出的延长存活的情况一样。虽然眼睛免疫豁免的确切机制尚不清楚，但已经表明，它可能依赖于多种因素共同作用，以保护这个重要的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，神经肽在眼部神经元中的定位，特殊抗原提呈细胞的战略性定位，以及眼内抗原提呈后全身免疫偏离的诱导。此外，最近发现，眼睛中的FasL可以杀死入侵的Fas+细胞，是保护这个器官的重要机制。此外，我们最近报道，几乎所有不表达功能性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%。Fas配体(FasL)在小鼠同种异体角膜移植的接受性中起着关键作用，本研究进一步证实了Fas配体(FasL)在小鼠角膜移植接受性中的关键作用，以确定增加FasL在角膜上的功能性表达是否会导致角膜移植接受性的增加。为此，我们将确定那些增加角膜FasL表达的试剂，并测试使用这些试剂治疗同种异体角膜移植物是否会增加角膜移植物的接受度。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。这将通过监测病变和受损的人类角膜中FasL的表达，并将其与在正常人类角膜中观察到的进行比较来实现。同时，我们将刺激小鼠的角膜疾病，并确定在疾病过程中，从炎症的初始阶段到疾病的解决，FasL的表达是否发生了变化。最后，初步数据表明，角膜新生血管的形成受功能性FasL的存在或缺失的影响。也就是说，不表达功能性FasL的小鼠比表达正常FasL的小鼠表现出更大程度的新生血管。因此，我们建议进行研究，以更好地确定Fas和FasL在角膜新生血管中所起的作用。

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.