IMMUNOBIOLOGY OF CORNEAL ALLOGRAFTS

描述(摘自申请者摘要)：角膜移植是 最古老和最常见的实体器官移植形式。在 在美国，每年进行的角膜移植手术超过4万例。尽管 角膜移植成功率高，10%-15%会因 免疫排斥反应。在这些患者中，移植失败的风险飙升至 65%-75%用于后续的角膜移植。免疫抑制药物经常 在这种高风险的寄主面前失败，即使他们阻止了拒绝，他们也会 有严重的副作用，包括肾脏和肝脏毒性。因此，新的 而毒性较小的免疫抑制策略需要用于 “高危”宿主或不能耐受当前免疫抑制的宿主 毒品。该项目将解决两个具体目标：(1)确定和 描述同种异体角膜移植的免疫机制 拒绝，以及(2)开发和评估两种新的预防策略 同种异体角膜移植的免疫排斥反应这两个目标都将在#年实现 一种具有良好特性的穿透性角膜移植小鼠模型。实验 将利用穿孔素基因敲除小鼠来确定细胞毒性T细胞的作用 细胞在角膜移植排斥反应中的作用其他实验将利用选择性 重组穿孔素基因敲除小鼠以确定其作用 迟发性超敏反应与肿瘤坏死因子-α 调节角膜移植排斥反应。第二个具体目标将制定和实施 评价两种有前景的预防免疫的新策略 同种异体角膜移植排斥反应：(1)供体特异性口服免疫 细胞，以及(2)阻断T细胞激活的共刺激通路。 因为口服免疫会对角膜移植物产生严重的抑制作用 排斥，研究将确定最佳方案，移植物的寿命 抗原饲喂的增强和作用方式。其他调查 将决定阻断T细胞共刺激通路的效果 活化及其对同种异体角膜移植存活的影响。这两种策略 获得抗原特异性的宿主免疫反应抑制，并应 事实证明，它在预防角膜移植排斥反应方面很有用。

DESCRIPTION (Adapted from applicant's abstract): Corneal transplantation is the oldest and most common form of solid organ transplantation. In the U.S., over 40,000 corneal transplants are performed each year. Although the success rate of corneal transplants is high, 10-15 percent will fail due to immune rejection. In these patients, the risk for graft failure soars to a 65-75 percent for subsequent corneal grafts. Immunosuppressive drugs often fail in such "high-risk" hosts and even when they prevent rejection, they carry serious side effects including renal and hepatic toxicity. Thus, new and less toxic immunosuppressive strategies are needed for use in "high-risk" hosts or in hosts who cannot tolerate current immunosuppressive drugs. This project will address two specific aims: (1) identify and characterize the immune mechanisms responsible for corneal allograft rejection, and (2) develop and evaluate two novel strategies for preventing the immune rejection of corneal allografts. Both aims will be addressed in a well-characterized mouse model of penetrating keratoplasty. Experiments will employ perforin knockout mice to determine the role of cytotoxic T cells in corneal graft rejection. Other experiments will utilize selective reconstitution of perforin knockout mice to determine the role of delayed-type hypersensitivity and tumor necrosis factor-alpha (TNF-alpha) in mediating corneal graft rejection. The second specific aim will develop and evaluate the two promising novel strategies for preventing the immune rejection of corneal allografts: (1) oral immunization with donor-specific cells, and (2) blockade of costimulatory pathways of T cell activation. Since oral immunization produces a profound inhibition of corneal graft rejection, studies will identify the optimal protocol, longevity of graft enhancement and the mode of action of antigen feeding. Other investigations will determine the efficacy of blocking costimulatory pathways of T cell activation and its effect on corneal allograft survival. Both strategies procure antigen-specific suppression of host immune responses and should prove useful in preventing corneal graft rejection.