DEC-205 AND AUTOIMMUNITY

DEC-205 和自身免疫

基本信息

批准号：
6268243
负责人：
Michel C Nussenzweig
金额：
$ 8.22万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-06-01 至 1999-05-31
项目状态：
已结题

项目摘要

Self-reactive T lymphocytes are normally deleted centrally or silenced in the periphery. However, anti-self reactivity is a characteristic pathologic feature of a number of autoimmune disorders. Elegant studies with transgenic mice, and purified cells in tissue culture have demonstrated that deletion of auto-reactive T cells in the thymus is likely to be triggered by thymic medullary dendritic cells. By contrast, the thymic epithelium appears to be predominantly involved in positive selection. But despite the central role of dendritic cells and thymic epithelial cells in the establishment and maintenance of self tolerance, and the requirement that these two cell types process a variety of different self and foreign antigens, neither cell type has been shown to express specific receptors for antigen capture. We have recently cloned a 205Kd candidate receptor for antigen capture expressed by dendritic cells and thymic epithelial cells (DEC-205). The new receptor is a membrane anchored protein which has ten separate Ca++ dependent carbohydrate recognition domains suggesting that it will recognize specific carbohydrate structures. Using anti-receptor antibodies as probes, we have shown that antigens bound to DEC-205 were efficiently processed and presented to T cells. However, the natural ligands of DEC- 205 remain to be defined. The long range goal of the proposed research is to elucidate the molecular requirements for ligand binding by DEC-205, and to understand the role of this new receptor in induction and preservation of tolerance. The working hypothesis is that DEC-25 binds to carbohydrate structures, and that antigens bearing these carbohydrates will be captured by DEC-205 for processing and presentation. The first part of the proposed project will be to establish the ligand binding specificity of DEC-205. For this purpose we will produce recombinant DEC-205, and perform binding studies as has been done for related receptors. In the second part of the project we will explore the effects of a DEC-205 mutation on T cell development and the immune responses in vivo. Finally the sequence of the human counterpart of mouse DEC-205 will be determined and molecular probes produced from the cDNA will be investigated as markers for human dendritic cells in normal subjects, and in patients with autoimmune diseases. These studies have significant implications for understanding how auto-antigens can produce tolerance, and together with other components of the proposed program will identify new pathways for the induction of tolerance.

自身反应性T淋巴细胞通常被集中删除或沉默外围。然而，抗自反应性是一个特征许多自身免疫性疾病的病理特征。优雅的学习转基因小鼠和组织培养中的纯化细胞证明胸腺中自身反应性 T 细胞的缺失可能由胸腺髓质树突状细胞触发。相比之下，胸腺上皮似乎主要参与阳性选择。但尽管树突状细胞和胸腺发挥着核心作用上皮细胞建立和维持自我耐受性，以及这两种细胞类型处理各种变化的要求不同的自身和外来抗原，两种细胞类型都没有被证明表达抗原捕获的特异性受体。我们最近克隆了树突表达的205Kd抗原捕获候选受体细胞和胸腺上皮细胞（DEC-205）。新的受体是膜锚定蛋白具有 10 个独立的 Ca++ 依赖性碳水化合物识别域表明它会识别特定的碳水化合物结构。使用抗受体抗体作为探针，我们已经证明抗原与 DEC-205 的结合是有效的处理并呈递给 T 细胞。然而，DEC-的天然配体 205 仍有待定义。拟议研究的长期目标是阐明 DEC-205 配体结合的分子要求，以及了解这种新受体在诱导和保存中的作用的宽容。工作假设是 DEC-25 与碳水化合物结合结构，并且携带这些碳水化合物的抗原将被捕获由 DEC-205 进行处理和呈现。第一部分拟议的项目将是建立配体结合特异性十二月 205。为此，我们将生产重组 DEC-205，并且像对相关受体所做的那样进行结合研究。在在该项目的第二部分，我们将探讨 DEC-205 的效果 T细胞发育和体内免疫反应的突变。最后小鼠 DEC-205 的人类对应物的序列将被确定由 cDNA 产生的分子探针将被研究为正常受试者和患有此病的患者中人类树突状细胞的标记物自身免疫性疾病。这些研究具有重大意义了解自身抗原如何产生耐受性，并与拟议方案的其他组成部分将确定新的途径耐受的诱导。