HLA-Releasing Metalloproteinase in Allograft Rejection
HLA-Releasing Metalloproteinase in Allograft Rejection
批准号:
7769785
负责人:
YURI BUSHKIN
金额:
$32.77万
依托单位国家:
美国
项目类别:
财政年份:
2005
资助国家:
美国
项目状态:
已结题
起止时间:
2005-03-01 至 2012-02-28
关键词:
Adam15 geneAddressAllogenicAllograftingAlternative SplicingAntigen PresentationAvidityBiological AssayCD8B1 geneCell LineCellsChimera organismChimeric ProteinsCleaved cellCoculture TechniquesComplexCytomegalovirusDNA Microarray ChipDataDelayed HypersensitivityDisintegrinsEndothelial CellsEnzymesExpression LibraryFamily memberFibroblastsGenesGoalsGranulocyte-Macrophage Colony-Stimulating FactorHLA-A2 AntigenHomologous GeneHumanImmuneInfectionInterferon Type IIInterferonsLinkMajor Histocompatibility ComplexMeasuresMediatingMetalloproteasesMicroarray AnalysisModelingMonoclonal AntibodiesMusPathway interactionsPeptidesPeripheral Blood Mononuclear CellPhysiologicalProcessProteinsRegulationRoleScreening procedureSiteSmall Interfering RNAStimulusSubstrate InteractionSurfaceSystemT-LymphocyteTestingTissuesTransmembrane DomainTransplantationTransplantation Toleranceblastomere structurecytokinedesignenzyme activityenzyme substrateextracellularin vivoinhibitor/antagonistleukemiamonocytemutantnoveloverexpressionresponse
中文摘要
我们之前已经描述了金属蛋白酶介导的可溶性 MHC I 类释放途径
并提出了其在移植中的作用。我们发现可溶性 MHC I 类的释放是由
解整合素和金属蛋白酶家族成员 ADAM17。内皮细胞 (EC) 与
同种异体 T 细胞上调特定激活标记以及 ADAM 17 的表达和活性。
这种激活由干扰素 γ 驱动,最终导致可溶性 MHC I 类蛋白的释放
由欧共体。然而,至少另一种不同于 ADAM17 的金属蛋白酶完全能够释放
可溶性 MHC I 类。其活性可能受细胞因子以组织特异性方式调节。筛选
我们的单克隆抗体可阻断可溶性 MHC I 类的释放,从而构建人类白血病表达文库
鉴定出功能尚不清楚的新型蛋白质 BC036469。这种普遍表达的蛋白质
可能通过介导特定酶/底物参与可溶性 MHC I 类释放机制
相互作用及其功能可能受到不同组织中细胞特异性细胞因子的调节。三
独立目标旨在解决这些问题。首先,我们将识别细胞因子诱导的
能够通过使用一组 ADAM 缺陷细胞系和通过
DNA 微阵列分析。二、BC036469蛋白的功能将通过过表达来确定
野生型和缺失突变体,并通过用特定的方法破坏内源蛋白的表达
siRNA。最后,我们将确定有效酶/底物相互作用所需的位点
α 3 和 MHC I 类跨膜结构域,并测试特定肽抑制的能力
互动。可溶性 MHC I 类在抗原呈递中的预测作用将使用反式进行测试
HLA-A2-免疫调节连锁抑制模型体内迟发型超敏反应测定
限制性 CD8 低亲和力 T 调节细胞控制移植耐受。
英文摘要
We have previously described the metalloproteinase-mediated pathway of soluble MHC class I release
and proposed its role in transplantation. We found that the release of soluble MHC class I is mediated by a
disintegrin and metalloprotease family member, ADAM17. Endothelial cells (EC) co-cultured with
allogeneic T cells up-regulate specific activation markers and both the expression and activity of ADAM 17.
This activation is driven by interferon-gamma and culminates in the release of soluble MHC class I proteins
by EC. However, at least one other metalloproteinase distinct from ADAM17 is fully capable of releasing
soluble MHC class I. Its activity may be regulated by cytokines in a tissue-specific manner. Screening of a
human leukemia expression library with our mAb that blocks the release of soluble MHC class I led to
identification of a novel protein BC036469 with yet unknown function. This ubiquitously expressed protein
may participate in the mechanism of soluble MHC class I release by mediating specific enzyme/substrate
interactions and its function may be regulated by cell-specific cytokines in different tissues. Three
independent aims are designed to address these questions. First, we will identify cytokine-inducible
metalloproteinases capable of processing MHC class I by using a panel of ADAM-deficient cell lines and by
DNA microarray analysis. Second, the function of BC036469 protein will be determined by overexpressing
wild-type and deletion mutants, and by disrupting expression of the endogenous protein with specific
siRNA. Finally, we will determine the sites required for productive enzyme/substrate interactions within
alpha 3 and transmembrane domains of MHC class I and test the ability of specific peptides to inhibit the
interaction. The predicted role of soluble MHC class I in antigen presentation will be tested using the trans-
vivo delayed-type hypersensitivity assay in the linked suppression model of immune regulation by HLA-A2-
restricted CD8 low avidity T regulator cells controlling transplantation tolerance.
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海外基金