IMMUNOBIOLOGY OF CORNEAL TRANSPLANATION

虽然绝大多数初级穿透性角膜成形术在人类身上成功，但移植到所谓的高危眼睛的同种异体角膜却有高得令人无法忍受的比例失败。免疫排斥被认为是移植物失败的主要原因。我们的长期目标是了解细胞和分子免疫过程，这些过程决定了(A)为什么初级同种异体角膜移植耐受性如此之好(即表现出免疫特免权)，以及(B)为什么植入高危眼球的移植效果如此之差。在过去的4年里，我们通过证明：(A)主要负责低危角膜移植排斥反应的T细胞通过“间接途径”同种异体识别供体抗原，而(B)“高危”眼的移植物被“直接”和“间接”同种异体反应性T细胞排斥，从而朝着这些目标取得进展。我们已经证明，“高危”眼的排斥反应可以通过先发制人的ACAID诱导来消除。此外，我们还证明了角膜移植物有助于其所处的免疫抑制微环境，并且该微环境不再是高危眼睛的“特权”。根据我们的发现，我们提出了三个相关的假设来指导我们未来5年的实验：同种异体角膜移植的成败取决于(1)移植物展示免疫豁免的能力；(2)前房和移植物床展示免疫豁免的能力；(3)受者免疫系统识别移植物衍生的抗原和启动同种或同种异体保护反应的能力。我们描述了三个特定的目标：1.确定诱导同种异体角膜移植免疫的细胞和分子机制，比较同种异体破坏性免疫的诱导和表达与同种异体保护性免疫的诱导。2.确定角膜作为免疫特权组织的功能程度(A)当放置在异位的非特权部位时，以及(B)当在体外移植时。3.根据特定目标1和2的结果制定促进同种异体角膜移植接受性的策略。我们的实验将使我们能够辨别角膜(作为组织)的免疫豁免和前房(作为部位)的免疫豁免在决定低风险和高风险眼原位角膜移植成功方面的相对重要性。此外，我们预计，我们的结果将提出新的策略，可以用于治疗，以促进移植物在临床情况下的接受性，移植物失败是非常常见的。

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.