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Role of Class II MHC Antigens in Neurologic Diseases

II 类 MHC 抗原在神经系统疾病中的作用

基本信息

批准号：
6920706
负责人：
Jenny P Ting
金额：
$ 32.61万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-15 至 2007-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6920706
关键词：
MHC class II antigen T lymphocyte biological signal transduction disease /disorder model gene induction /repression genetically modified animals laboratory mouse leukocyte activation /transformation macrophage microglia myelinopathy

项目摘要

DESCRIPTION (provided by applicant): MHC class II molecules are expressed in the central nervous system (CNS) during a number of neurologic disorders and demyelinating disease. In a majority of these diseases, T cells are generally absent in the affected CNS. To address the importance of class II MHC in CNS disorders, we have characterized two models of demyelination that exhibit class II MHC hyper-expression on microglial cells. Characterizations of these disease models show that the deletion of class II MHC caused the alleviation of overt symptoms, reduced neuropathology/demyelination, reduced microglial activation/proliferation and reduced production of inflammatory cytokines. Most intriguingly, the role of class II MHC is unaffected by the absence of T cells in RAGb mice, but dependent on an intact class II MHC cytoplasmic tail. This caused us to propose that class II may serve an in vivo role in signal transduction, distinct from its conventional biologic role in antigen presenting. The Aims are: 1.Analyze a transgenic mouse strain, H-2M for its response to cuprizone treatment. If conventional antigen processing is not important, then the deletion of H-2M should not affect cuprizone-induced demyelination. 2.Analyze how class II MHC and T cells affect the remyelination process. Recent studies in our laboratory have demonstrated that inflammatory cytokines are necessary for optimal remyelination. The presence of MHC class II causes enhanced cytokine expression, therefore it is timely to determine the role of MHC during remyelination, and if lymphocytes are involved in this process. 3. Determine novel mediators of class II MHC-mediated signaling. We will determine if recently discovered mediators of class II signaling, cell activation and proliferation are affected in microglia/macrophages. 4. Identify genes that are activated upon class II MHC engagement. in a microglial-macrophage line by Affy metrix screening, and assess the status of these genes in the cuprizone model.

描述（由申请人提供）：MHC II 类分子表达于中枢神经系统（CNS）在许多神经系统疾病和脱髓鞘疾病。在大多数此类疾病中，T 细胞通常受影响的中枢神经系统中不存在。阐述 II 类 MHC 在 CNS 中的重要性疾病，我们已经表征了两种脱髓鞘模型，表现出类别小胶质细胞上 II MHC 超表达。这些疾病的特点模型显示 II 类 MHC 的缺失导致明显的症状减轻症状、神经病理学/脱髓鞘减少、小胶质细胞减少激活/增殖并减少炎症细胞因子的产生。最多有趣的是，II 类 MHC 的作用不受 T 细胞缺失的影响在 RAGb 小鼠中，但依赖于完整的 II 类 MHC 细胞质尾。这使我们提出 II 类可能在信号中发挥体内作用转导，不同于其在抗原中的传统生物学作用呈现。目标是： 1.分析转基因小鼠品系H-2M对铜宗的反应治疗。如果常规抗原处理不重要，那么 H-2M 的缺失不应影响铜宗诱导的脱髓鞘。 2.分析II类MHC和T细胞如何影响髓鞘再生过程。最近的我们实验室的研究表明，炎症细胞因子最佳髓鞘再生所必需的。 MHC II 类原因的存在细胞因子表达增强，因此及时确定其作用髓鞘再生期间的 MHC，以及淋巴细胞是否参与该过程。 3. 确定 II 类 MHC 介导的信号传导的新介质。我们将确定是否最近发现了 II 类信号传导介质、细胞小胶质细胞/巨噬细胞的激活和增殖受到影响。 4. 鉴定在 II 类 MHC 参与时被激活的基因。在一个通过Affy metrix筛选小胶质细胞-巨噬细胞系，并评估其状态铜宗模型中的这些基因。