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取得了成功，但移植到所谓“高风险”眼睛中的异体角膜却失败了，这一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)为什么原发原位角膜异体移植具有如此良好的耐受性（即表现出免疫特权），以及(b)为什么移植在“高风险”眼睛中的效果如此之差。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”同种异体识别来识别供体同种异体抗原，而(b)“高风险”眼睛中的移植物同时被“直接”和“间接”同种异体反应T细胞排斥。我们已经证明，“高危”眼的排斥反应可以通过预先诱导ACAID来消除。此外，我们已经证明角膜移植物有助于其放置的免疫抑制微环境，并且这种微环境不再是高风险眼睛的“特权”。基于我们的研究结果，我们提出了三个相关的假设来指导我们未来5年的实验：角膜同种异体移植的成功或失败取决于(1)移植物显示免疫特权的能力；(2)前房和移植物床显示免疫特权的能力，以及(3)受体免疫系统识别移植物来源抗原并引发同种异体破坏或同种异体保护反应的能力。我们描述了三个具体目标：1。明确诱导角膜异体免疫的细胞和分子机制，对比异体破坏性免疫和异体保护性免疫的诱导和表达。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、非特权部位时，以及(b)当体外移植时。3. 根据具体目标1和2的结果，制定促进角膜异体移植接受的策略。我们的实验将使我们能够辨别角膜的免疫特权（作为一个组织）和前房的免疫特权（作为一个部位）在决定低风险和高风险眼睛的原位角膜异体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，以促进移植物接受在临床情况下，移植物失败是太常见了。

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.