IMMUNOBIOLOGY OF CORNEAL ALLOGRAFTS

描述（由申请人提供）：角膜移植是最古老，最常见，也可以说是最成功的器官移植形式。仅在美国，每年就有超过45000例角膜移植手术。第一次手术中，不复杂的角膜移植手术只有不到10%会失败。相比之下，在血管化移植床上进行的第二次角膜异体移植或角膜成形术的排斥反应上升到65%以上。角膜移植失败的主要原因是免疫排斥，无论是发生在低风险的圆锥角膜患者，还是发生在先前拒绝角膜移植的高风险宿主。了解角膜移植排斥反应的免疫机制和制定预防同种免疫反应的策略对于保护大量患者的视力和预防失明至关重要。这两个目标将通过解决三个具体目标来实现。第一个目标是确定不涉及CD4+ T细胞参与的角膜移植排斥反应的免疫机制。干扰素- γ、肿瘤坏死因子- α和cd95诱导的细胞凋亡的作用将被进一步探讨。第二个具体目标是确定在“高风险”宿主中导致角膜移植排斥的免疫效应机制。根据我们实验室和其他人之前的研究，我们预测，在“高风险”宿主中引起角膜异体移植排斥的机制与在正常、首次宿主中介导排斥的机制有着根本的不同。第三个具体目标将进一步表征口服免疫作为降低角膜移植排斥风险策略的临床参数。口服同种异体角膜移植供体的同种异体抗原细胞可诱导对供体同种异体抗原的免疫反应下调，从而提高同种异体移植的存活率。这种现象被称为“口服耐受”，有望降低“高风险”患者角膜异体移植排斥反应的风险。所有这三个目标将在穿透性角膜移植术的小鼠模型中得到解决。

DESCRIPTION (provided by applicant): Corneal transplantation is the oldest, most common, and arguably, the most successful form of organ transplantation. In the United States alone, over 45,000 corneal transplants are performed annually. Less than 10% of first time, uncomplicated keratoplasties will fail. By contrast, the rejection of second corneal allografts or keratoplasties performed on vascularized graft beds rises to over 65%. The leading cause of corneal graft failure - whether it occurs in the low risk keratoconus patient or the high risk host who has rejected a previous corneal transplant - is immune rejection. Understanding the immune mechanisms of corneal graft rejection and developing strategies to prevent alloimmune responses are of paramount importance in preserving vision and preventing blindness in a very large population of patients. These two goals will be pursued by addressing three specific aims. The first aim will determine the immune mechanisms of corneal graft rejection that do not involve the participation of CD4+ T cells. The roles of interferon-gamma, tumor necrosis factor-alpha, and CD95-induced apoptosis will be explored prospectively. The second specific aim will ascertain the immune effector mechanisms that culminate in corneal graft rejection in "high-risk" hosts. Based on previous studies from our laboratory and others, we predict that the mechanisms invoked to reject corneal allografts in "high-risk" hosts are fundamentally different from those mediating rejection in normal, first-time hosts. The third specific aim will further characterize the clinical parameters of oral immunization as a strategy for reducing the risk of corneal graft rejection. Oral administration of alloantigenic cells from corneal allograft donors induces the down-regulation of immune responses to donor alloantigens and as a result, enhances allograft survival. This phenomenon is termed "oral tolerance" and holds promise for reducing the risk of corneal allograft rejection in the "high-risk" patients. All three of these aims will be addressed in a well-characterized mouse model of penetrating keratoplasty.