HLA-RELEASING METALLOPROTEINASE IN ALLOGRAFT REJECTION

描述（改编自申请人摘要）：这些研究的重点是 I类重链特异性的遗传和生化表征 金属蛋白酶（含锌酶）及其在间接免疫中的作用 异源识别途径。可溶性MHC I类抗原参与了 通过间接途径引发CD 4 + T细胞，导致排斥反应。 MHC I类不同移植物。研究人员描述了一种新的 产生在体外活化细胞中起作用的可溶性MHC I类 和体内。由MHC I类解离产生的游离重链 细胞表面上的复合物被蛋白水解切割并释放， 含有完整的细胞外结构域的可溶性分子， 与溶液中的β 2微球蛋白重新结合，由Zn 2+介导的释放 依赖性膜结合金属蛋白酶。大量可溶性HLA从 同种异体移植物在体内的存活依赖于该酶的活性。三大战略 将用于分离合适的基因酶底物关系 在分离的金属蛋白酶基因的产物和游离重链之间 链将建立，和金属蛋白酶的作用， 将在小鼠皮肤和大鼠中测试同种异体移植物排斥的间接途径 心脏移植模型。动物将接受金属蛋白酶处理 抑制剂BB-94和评估的免疫活性。

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.