IMMUNOBIOLOGY OF CORNEAL TRANSPLANATION

尽管绝大多数的原发性穿透性角膜移植术在人类身上都取得了成功，但移植到所谓的“高危”眼睛中的同种异体角膜失败的比例高得令人难以忍受。免疫排斥反应被认为是移植失败的主要原因。我们的长期目标是了解细胞和分子免疫过程，这些免疫过程决定了（a）为什么原发性原位角膜同种异体移植物耐受性如此好（即显示免疫豁免），以及（B）为什么植入“高危”眼的移植物效果如此差。在过去的4年中，我们已经朝着这些目标取得了进展，证明了（a）主要负责低风险角膜移植排斥反应的T细胞通过“间接途径”同种异体识别供体同种异体抗原，而（B）“高风险”眼中的移植物被“直接”和“间接”同种异体反应性T细胞排斥。 我们已经表明，排斥反应在“高风险”的眼睛可以废除的ACAID的先发制人的诱导。 此外，我们已经证明，角膜移植有助于免疫抑制微环境中，它被放置，而微环境不再是“特权”在高危眼睛。基于我们的发现，我们提出了三个相关的假设来指导我们未来5年的实验：（1）角膜移植的成功或失败取决于移植物显示免疫豁免的能力;（2）前房和移植床显示免疫赦免的能力，和（3）受体免疫系统识别移植物衍生抗原和产生同种异体破坏性或同种异体保护性应答的能力。我们描述了三个具体目标：1。明确诱导角膜移植免疫的细胞和分子机制，对比同种异体破坏性免疫和同种异体保护性免疫的诱导和表达。 2.确定角膜作为免疫豁免组织（a）放置在异位、非豁免部位时和（B）体外培养时的功能程度。 3.根据特定目标1和2的结果制定策略以促进角膜移植物的接受。我们的实验将使我们能够辨别角膜（作为一种组织）的免疫豁免和前房（作为一个部位）的免疫豁免在决定低风险和高风险眼的原位角膜同种异体移植成功率方面的相对重要性。 此外，我们预计我们的研究结果将提出新的策略，可用于治疗，以促进移植物的接受在临床情况下，移植失败是太常见了。

Whereas the great majority of primary, penetrating keratoplasties succeed in human beings, an intolerably high proportion of allogeneic corneas grafted into so-called "high-risk" eyes fail. Immune rejection is regarded as the major cause of graft failure. Our long term goal is to understand the cellular and molecular immune processes that dictate (a) why primary orthotopic corneal allografts are so well tolerated (i.e. display immune privilege), and (b) why grafts placed in "high-risk" eyes fare so poorly. During the past 4 years we have made progress toward these goals by demonstrating that (a) the T cells primarily responsible for low-risk corneal graft rejection recognize donor alloantigens by the "indirect pathway" allorecognition, whereas (b) grafts in "high-risk" eyes are rejected by both "direct" and "indirect" alloreactive T cells. We have shown that rejection in "high-risk" eyes can be abrogated by pre-emptive induction of ACAID. In addition, we have demonstrated that the cornea graft contributes to the immunosuppressive microenvironment in which it is placed, and that that microenvironment is no longer "privileged" in high-risk eyes. Based on our findings, we have formulated three related hypotheses to guide our experiments for the next 5 years: Success or failure of orthotopic corneal allografts is dictated by (1) the capacity of the graft to display immune privilege; (2) the capacity of the anterior chamber and the graft bed to display immune privilege, and (3) the capacity of the recipient immune system to recognize graft-derived antigens and to mount an allodestructive or an alloprotective response. We describe three Specific Aims: 1. Define the cellular and molecular mechanisms that induce corneal allograft immunity, contrasting the induction and expression of allodestructive immunity with the induction of alloprotective immunity. 2. Determine the extent to which the cornea functions as an immune privileged tissue (a) when placed at a heterotopic, non-privileged site, and (b) when explanted in vitro. 3. Develop strategies to promote corneal allograft acceptance based on results accruing from Specific Aims 1 and 2. Our experiments will enable us to discern the relative importances that immune privilege of the cornea (as a tissue), and immune privilege of the anterior chamber (as a site) play in dictating success of orthotopic corneal allografts in both low- and high-risk eyes. Moreover, we anticipate that our results will suggest novel strategies that could be used therapeutically to promote graft acceptance in clinical situations where graft failure is all too common.