Immunobiology of Corneal Allografts

描述（由申请人提供）：角膜移植是最常见的实体组织移植形式，在美国每年进行超过30，000例角膜移植术。尽管角膜移植术通常在不使用HLA分型或全身免疫抑制药物的情况下进行，但角膜移植术的首次接受者可以预期90%的成功率。角膜移植术的空前成功归因于眼睛的免疫赦免，其下调了对角膜移植物上的组织相容性抗原的免疫应答。该项目将评估两个重要的T调节细胞群体的作用，这些细胞被认为赋予角膜移植免疫豁免并促进其长期存活。尽管角膜移植取得了显著的成功，但免疫排斥反应仍然是角膜移植失败的主要原因。来自临床医生的轶事报告表明，过敏性结膜炎患者排斥角膜移植的风险明显更大。我们最近在穿透性角膜移植术的小鼠模型中证实了这一观察结果，并发现过敏性结膜炎产生显著的佐剂效应，导致对角膜移植物上组织相容性抗原的免疫反应增强，最终导致角膜移植排斥反应的发生率和克里思显著增加。该项目将描述过敏性结膜炎宿主对角膜组织相容性抗原的免疫反应增强的基础。研究还将检验这样一种假设，即其他形式的过敏，如过敏性哮喘，也会通过增强全身免疫反应，甚至在远处器官中，增加角膜移植免疫排斥的风险。了解调节性T细胞在促进角膜移植免疫豁免中的作用基础，将为开发新的免疫抑制剂以提高高危宿主角膜移植物存活率提供基础。过敏性疾病的发病率持续增长，因此是角膜移植物存活的一个越来越重要的风险因素。该项目将为理解角膜移植排斥反应的过敏相关风险的基础提供重要的见解，并确定其他形式的过敏是否也应该被视为角膜移植存活的风险因素。这些研究将导致重建角膜移植免疫豁免和抵消过敏性疾病对角膜移植命运的不利影响的改进策略。

DESCRIPTION (provided by applicant): Corneal transplantation is the most common form of solid tissue transplantation, with over 30,000 keratoplasties performed each year in the U.S. First-time recipients of corneal allografts can expect a 90% success rate, even though keratoplasty is usually performed without the use of HLA typing or systemic immunosuppressive drugs. The unparalleled success of keratoplasty is attributed to the immune privilege of the eye, which down-regulates the immune responses to the histocompatibility antigens on the corneal transplant. This project will evaluate the roles of two important populations of T regulatory cells that are believed to endow the corneal transplant with immune privilege and promote its long-term survival. Even though corneal transplants enjoy a remarkable success, immune rejection remains the leading cause of corneal graft failure. Anecdotal reports from clinicians suggest that patients with allergic conjunctivitis have a significantly greater risk for rejecting their corneal transplants. We recently confirmed this observation in a mouse model of penetrating keratoplasty and found that allergic conjunctivitis produces a remarkable adjuvant effect that results in a heightened immune response to the histocompatibility antigens on the corneal transplant, which culminates in a profound increase in the incidence and tempo of corneal allograft rejection. This project will characterize the basis for this heightened immune response to the corneal histocompatibility antigens that occurs in hosts with allergic conjunctivitis. Studies will also test the hypothesis that other forms of allergy, such as allergic asthma, also increase the risk for the immune rejection of corneal transplants by enhancing systemic immune responses, even in distant organs. Understanding the basis for the role of T regulatory cells in promoting immune privilege of corneal transplantation will provide a basis for developing new immunosuppressive agents for improving corneal graft survival in high risk hosts. The incidence of allergic diseases continues to grow and thus, is an increasingly important risk factor for corneal graft survival. This project will provide important insights into understanding the basis for the allergy-associated risk for corneal graft rejection and determine if other forms of allergy should also be considered as risk factors for corneal allograft survival. These studies will lead to improved strategies for re-establishing immune privilege of corneal transplants and offsetting the untoward effects of allergic diseases on the fate of corneal transplants.