HLA-RELEASING METALLOPROTEINASE IN ALLOGRAFT REJECTION

描述(改编自申请人的摘要)：这些调查的重点是 I类重链特异性基因的遗传和生化特征 金属蛋白酶(含锌酶)及其在间接免疫反应中的作用 同种异体识别途径。可溶性MHC-I类抗原参与了 通过间接途径启动CD4+T细胞，导致排斥反应 MHC I类不同的移植物。研究人员描述了一种新的机制 在体外活化细胞中产生可溶性MHC-I类分子 在活体内。MHC I类分子解离产生的游离重链 细胞表面的复合体被蛋白水解性切割并释放到 含有完整胞外结构域的可溶性分子，能够 与溶液中的β2微球蛋白重新结合，由锌离子介导的释放 依赖膜结合的金属蛋白酶。从细胞中释放出大量可溶性的人类白细胞抗原 体内的同种异体移植依赖于这种酶的活性。三大战略 将被用来分离合适的基因。酶底物关系 分离的金属蛋白酶基因产物与游离态重金属 链将被建立，而金属蛋白酶在 将在小鼠皮肤和大鼠身上测试同种异体移植排斥的间接途径 同种异体心脏移植模型。动物将被用金属蛋白酶治疗 抑制剂BB-94和免疫活性评估。

DESCRIPTION (adapted from applicant's abstract): These investigations focus on the genetic and biochemical characterization of class I heavy chain specific metalloproteinases (Zn-containing enzymes) and their role in the indirect pathway of allorecognition. Soluble MHC class I antigens are involved in priming CD4+ T cells through the indirect pathway, resulting in rejection of MHC class I disparate grafts. The investigators describe a novel mechanism of generation of soluble MHC class I which operates in activated cells in vitro and in vivo. Free heavy chains originated by disassociation of MHC class I complexes on the cell surface are proteolytically cleaved and released to soluble molecules containing intact extracellular domains and capable of reassociating with beta2 microglobulin in solution, a release mediated by Zn2+ dependent membrane bound metalloproteinase. Much soluble HLA released from the allograft in vivo is dependent upon activity of this enzyme. Three strategies will be used to isolate the appropriate gene. The enzyme substrate relationship between the product of the isolated metalloproteinase gene and free heavy chains will be established, and the role of the metalloproteinase in the indirect pathway of allograft rejection will be tested in mouse skin and rat cardiac allograft models. Animals will be treated with the metalloproteinase inhibitor BB-94 and immune activity assessed.