THE IMMUNOBIOLOGY OF CORNEAL ALLOGRAFTS

描述（由申请人提供）：角膜移植是最古老、最常见、也是最成功的实体组织移植形式。仅在美国，每年就有超过4万例角膜移植手术。即使不进行HLA分型，局部皮质类固醇是唯一使用的免疫抑制剂，90%的角膜移植将存活第一年。在相同条件下，没有其他形式的实体器官移植可以拥有如此高的成功率。然而，尽管有这种免疫豁免，角膜移植物可能失败，免疫排斥是角膜移植物失败的主要原因。因此，该项目的长期目标是更好地了解角膜移植免疫豁免的潜在机制，并表征并有望逆转那些剥夺角膜移植免疫豁免并导致移植排斥的条件。将在前瞻性研究中使用穿透性角膜移植术的小鼠模型，根据这些长期目标，研究三个具体目标。第一个特定的目标是探索免疫机制，过敏性疾病，如哮喘和过敏性结膜炎，取消角膜免疫豁免，并大大增加角膜移植排斥反应的发生率和克里思。第二个具体目标是探讨Th 1细胞因子干扰素-γ（IFN-γ）在不同类型的不匹配角膜移植物中的显著不同作用。在MHC +多种轻微组织相容性（H）不匹配的移植物的情况下，移植物存活需要IFN-y。相比之下，在MHC匹配、轻微H不匹配的移植物中，IFN-γ促进角膜同种异体移植物排斥。第三个具体目标描述了最近发现的一项发现，该发现表明角膜手术危及后续角膜同种异体移植物的存活，甚至危及来自与角膜同种异体移植物供体完全无关的供体的角膜同种异体移植物的存活，甚至更令人印象深刻的是，危及放置在对侧眼中的角膜同种异体移植物的存活！我们把这种现象称为“免疫抑制的交感神经消除”（SAIP）。SAIP可能导致角膜移植排斥反应的急剧增加， 来自与第一角膜同种异体移植物的供体无关的供体的后续角膜同种异体移植物。

DESCRIPTION (provided by applicant): Corneal transplantation is the oldest, most common, and arguably, the most successful form of solid tissue grafting. In the U.S. alone, over 40,000 corneal transplants are performed each year. Even though HLA typing is not performed and topical corticosteroids are the only immunosuppressive agents used, 90% of the corneal transplants will survive the first year. No other form of solid organ transplantation can boast thi success rate under the same conditions. However, in spite of this immune privilege, corneal allografts can fail, with immune rejection being the leading cause of corneal allograft failure. Thus, the long-range goal of this project is to better understand the underlying mechanisms that contribute to immune privilege of corneal allografts and to characterize and hopefully, reverse those conditions that rob the corneal allograft of its immune privilege and lead to allograft rejection. A mouse model of penetrating keratoplasty will be used in prospective studies that address three specific aims pursuant to these long range goals. The first specific aim explores the immune mechanisms whereby allergic diseases such as asthma and allergic conjunctivitis abolish corneal immune privilege and profoundly increase the incidence and tempo of corneal allograft rejection. The second specific aim explores the dramatically different roles of theTh1 cytokine, interferon-y (IFN-y) in different categories of mismatched corneal allografts. In the case of MHC + multiple minor histocompatibility (H)-mismatched grafts, IFN-y is required for graft survival. By contrast, in MHC-matched, minor H mismatched grafts IFN-y promotes corneal allograft rejection. The third specific aim characterizes a recently discovered finding, which demonstrates that corneal surgery jeopardizes the survival of subsequent corneal allografts, even corneal allografts from donors completely unrelated to the donor of the corneal allograft and even more impressively, in corneal allografts placed in the contralateral eye! We have termed this phenomenon "Sympathetic Abrogation of Immune Privilege" (SAIP). SAIP may contribute to the sharp increase in corneal allograft rejection that occurs in patients who receive subsequent corneal allografts from donors unrelated to the donors of the first corneal allograft.