Regulation of Cutaneous Accessory Cell Activity in Healt

健康时皮肤辅助细胞活性的调节

• 批准号: 7331357
• 负责人: MARK UDEY
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7331357
• 关键词: Regulation; Cutaneous; Accessory; Cell; Activity

Studies of the C-type lectin termed Langerin (CD207), a protein whose expression is restricted to epidermal Langerhans cells and (in mice) CD8 alpha-expressing dendritic cells, have been concluded. Our results indicate that Langerin binds selectively to several extracellular matrix molecules, including the alpha chain of type I procollagen and cell-associated fibronectin. These results implicate Langerin in interactions beween Langerhans cells and extracellular matrix; interactions that may be important for Langerhans cell development or trafficking.Our interest in the phagocyte- and tumor cell-derived protein MFG-E8 continues. In accordance with our prediction and consistent with its alpha-v beta-3 integrin- and phosphatidyl serine binding activity, others have demonstrated that MFG-E8 can mediate the uptake of apoptotic cells by macrophages. We have generated several MFG-E8 mouse mutants to determine if MFG-E8 has a non-redundant role in apoptotic cell uptake in vivo and, further, to determine if MFG-E8 is involved in cross presentation of antigens that are not expressed by antigen presenting cells. Because MFG-E8 is homologous to del1, a protein expressed by endothelial cells in embryos and in tumors, we are also defining the role that MFG-E8 may play in angiogeneis and tumorigenesis. Results, to date, indicate that tumor cells produce MFG-E8 and that MFG-E8 promotes tumorigenesis in both orthotopic and transgenic models of cancer in mice (melanoma, non-melanoma skin cancer and pancreatic beta-cell cancer). In addition, ongoing experiments suggest that MFG-E8 may be a relevant therapeutic target in cancer.The final project area in the laboratory involves testing the feasibility of using T cell receptor proteins expressed by clonal T cell malignancies as tumor antigens in vaccines. DNA-based (genetic vaccination) strategies are being emphasized because of concerns regarding the practicality of patient-specific therapies. A reproducible model involving subcutaneous growth of T cell lymphomas in mice has been established in the laboratory. cDNAs encoding T cell receptor alpha and beta chains from this murine T cell lymphoma have been cloned and sequenced, and several candidate vaccines have been generated. We have determined that several candidate vaccines have activity. In the course of these studies, we identified a novel adjuvant strategy that dramatically increases the efficacy of TCR-based vaccines. Because we anticipate that this adjuvant strategy will be generally applicable and well tolerated, incorporation into human vaccine trials may be feasible.

对称为 Langerin (CD207) 的 C 型凝集素的研究已经得出结论，该蛋白的表达仅限于表皮 Langerhans 细胞和（在小鼠中）表达 CD8 α 的树突状细胞。我们的结果表明，Langerin 选择性地结合几种细胞外基质分子，包括 I 型原胶原的 α 链和细胞相关的纤连蛋白。这些结果表明 Langerin 参与朗格汉斯细胞和细胞外基质之间的相互作用。这些相互作用对于朗格汉斯细胞的发育或运输可能很重要。我们对吞噬细胞和肿瘤细胞衍生蛋白 MFG-E8 的兴趣仍在继续。根据我们的预测并与其 α-v beta-3 整合素和磷脂酰丝氨酸结合活性一致，其他人已经证明 MFG-E8 可以介导巨噬细胞对凋亡细胞的摄取。我们已经产生了几种 MFG-E8 小鼠突变体，以确定 MFG-E8 在体内凋亡细胞摄取中是否具有非冗余作用，并进一步确定 MFG-E8 是否参与不由抗原表达的抗原的交叉呈递呈现细胞。由于 MFG-E8 与 del1（一种由胚胎和肿瘤中的内皮细胞表达的蛋白质）同源，因此我们还定义了 MFG-E8 在血管生成和肿瘤发生中可能发挥的作用。迄今为止的结果表明，肿瘤细胞产生 MFG-E8，并且 MFG-E8 在小鼠癌症的原位和转基因模型（黑色素瘤、非黑色素瘤皮肤癌和胰腺 β 细胞癌）中促进肿瘤发生。此外，正在进行的实验表明MFG-E8可能是癌症的相关治疗靶点。实验室的最后一个项目领域包括测试使用克隆性T细胞恶性肿瘤表达的T细胞受体蛋白作为疫苗中的肿瘤抗原的可行性。由于对患者特异性疗法的实用性的担忧，基于 DNA（基因疫苗接种）的策略受到重视。实验室已建立了小鼠 T 细胞淋巴瘤皮下生长的可重复模型。编码来自这种鼠 T 细胞淋巴瘤的 T 细胞受体 α 和 β 链的 cDNA 已经被克隆和测序，并且已经产生了几种候选疫苗。我们已经确定几种候选疫苗具有活性。在这些研究过程中，我们确定了一种新的佐剂策略，可以显着提高基于 TCR 的疫苗的功效。因为我们预计这种佐剂策略将普遍适用且耐受性良好，因此纳入人体疫苗试验可能是可行的。