IMMUNOBIOLOGY OF CORNEAL TRANSPLANTATION

角膜移植的免疫生物学

• 批准号: 7060797
• 负责人: Bruce R Ksander
• 金额: $ 43.06万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7060797
• 关键词: MHC class II antigen; confocal scanning microscopy; cornea; corneal epithelium; corneal stroma; eye transplantation; flow cytometry; fluorescence microscopy; gene targeting; genetically modified animals; histocompatibility; homologous transplantation; immunomodulators; isoantigen; keratoplasty; laboratory mouse; transplant rejection; transplantation immunology

DESCRIPTION: Whereas many primary, penetrating keratoplasties succeed in humans, an intolerably high proportion fails in "high-risk" eyes. Immune rejection is the major cause of allograft failure. Our long-term goals are to understand: (a) why primary orthotopic corneal allografts are so well tolerated (display immune privilege), and (b) why grafts in "high-risk" eyes fare so poorly. During the past 5 years we have made progress toward these goals by demonstrating that: (a) MHC class II and minor H, but not MHC class I, alloantigens are important barriers to corneal allograft acceptance, (b) direct and indirect alloreactive CD4+, but not CD8+, T cells are the dominant mediators of rejection, and (c) comeal endothelium, in part through expression of CD95L, displays inherent immune privilege. Based upon these findings, we have formulated two related hypotheses to guide our experiments: Hypothesis 1. Atypical expression of alloantigens and expression of immunomodulatory molecules on corneal cells contribute to the cornea's immune privileged status. These experiments will determine if expression of alloantigens and/or immunomodulatory molecules on corneal cells, rather than the special qualities of the surrounding graft bed in the eye, contributes to the cornea's status as an immune privileged tissue. Hypothesis 2. MHC class II and/or minor H alloantigen expression rob the corneal epithelium of its graft-acceptance promoting capacity. Our previous data indicated that syngeneic epithelium makes a positive contribution to immune privilege for orthotopic corneal allografts. These experiments will utilize composite comeal grafts composed of recipient epithelium layered over donor stroma/endothelium (and visa versa). We will determine the capacity of composite corneal allografts to induce allosensitization. Our experiments will enable us to discover novel cellular and molecular mechanisms with which to create protocols with greater power to promote graft acceptance in clinical situations where graft failure is all too common.

描述：虽然许多初次、穿透性角膜移植术在人类身上取得了成功，但在“高风险”眼睛中失败的比例却高得令人难以忍受。免疫排斥是同种异体移植失败的主要原因。我们的长期目标是了解：(a) 为什么原位同种异体角膜移植的耐受性如此良好（表现出免疫特权），以及 (b) 为什么“高风险”眼睛的移植效果如此差。在过去的 5 年里，我们在实现这些目标方面取得了进展，证明：(a) MHC II 类和次要 H，但不是 MHC I 类，同种抗原是角膜同种异体移植接受的重要障碍，(b) 直接和间接同种异体反应性 CD4+，但 CD8+ 除外，T 细胞是排斥反应的主要介质，并且 (c) 角膜内皮部分通过 CD95L 的表达表现出固有的免疫特权。基于这些发现，我们提出了两个相关的假设来指导我们的实验： 假设1.角膜细胞上同种抗原的非典型表达和免疫调节分子的表达有助于角膜的免疫特权状态。这些实验将确定角膜细胞上同种抗原和/或免疫调节分子的表达，而不是眼睛周围移植床的特殊品质，是否有助于角膜作为免疫特权组织的地位。假设 2. MHC II 类和/或次要 H 同种异体抗原的表达剥夺了角膜上皮的移植物接受促进能力。我们之前的数据表明，同基因上皮对原位角膜同种异体移植物的免疫特权做出了积极贡献。这些实验将利用由供体基质/内皮层上的受体上皮组成的复合角膜移植物（反之亦然）。我们将确定复合同种异体角膜移植物诱导异体致敏的能力。我们的实验将使我们能够发现新的细胞和分子机制，通过这些机制来创建更强大的方案，以在移植失败非常常见的临床情况下促进移植接受。