Regulation of Langerhans Cell Migration by Invariant Gamma Delta T Cells

恒定 Gamma Delta T 细胞对朗格汉斯细胞迁移的调节

• 批准号: 9136642
• 负责人: PETER Junghan KIM
• 金额: $ 15.27万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-27 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9136642
• 关键词: Affect; Autoimmune Diseases; Autoimmune Process; Biological Assay; Biopsy; Cell Communication; Cell Count; Cells; Cicatrix; Data; Defect; Dermatitis; Epidermis; Etiology; Face; Functional disorder; Future; Goals; Grant; High Prevalence; Homeostasis; Human; Immune; Immune System Diseases; Immune Tolerance; In Vitro; Inflammation; Insulin-Like Growth Factor I; Langerhans cell; Lead; Light; Lupus; Maintenance; Mediating; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; Operative Surgical Procedures; Organ; Pathogenesis; Pathway interactions; Patients; Phenotype; Population; Psoriasis; Publications; Punch Biopsy; Regulation; Research Proposals; Role; Sampling; Scleroderma; Skin; Specimen; Study models; Systemic Lupus Erythematosus; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Tissues; Up-Regulation; Work; Wound Healing; alpha-galactosylceramide; body system; cell motility; cytokine; design; disability; improved; in vivo; insight; lupus prone mice; migration; novel; novel therapeutics; prevent; psychosocial; research study; role model; tissue repair

DESCRIPTION (provided by applicant): Dermatitis is a common manifestation of lupus that can cause scarring and disfigurement. Lupus dermatitis is often difficult to treat and relatively little is known about its pathogenesis. The outer layer of the skin, the epidermis, contains two immune cells, the Langerhans cell (LC) and dendritic epidermal T cells (DETC). The relative simplicity of the skin makes it an ideal model for studying organ level immune tolerance. Recent studies have pointed to Langerhans cells as important regulators of skin tolerance. Our lab has recently shown that LC migration is impaired in mice prone to lupus dermatitis. DETCs are known to help promote wound healing but their overall function remains unclear. Exciting new data from our lab have shown a hereto- unknown function for the DETCs, that they regulate LC migration. Treatment with alpha-galactosylceramide (GalCer) improves dermatitis, increases DETC numbers in the epidermis, and restores LC migration in lupus prone mice. In this grant, we hypothesize that DETCs regulate the migration of LCs, and that LC-DETC interaction in the skin serves as a regulatory network that protects against skin inflammation. To test this hypothesis, we will: determine the role of DETC in LC migration, and investigate the mechanism or mechanisms by which DETCs regulate LC migration (Aim 1). In Aim 2, we will investigate the factors responsible for the LC migration defect seen in MRL mice. Guided by our preliminary findings that MRL-lpr mice also have a marked reduction in DETC numbers and that DETC-LC appear to interact with each other in vivo and in vitro, we hypothesize that impaired LC migration in lupus mice is due to reduced numbers of DETC in skin; increasing DETC numbers will enhance LC migration, and reduce skin inflammation. Future studies will start to transition our studies of DETCs and LC migration to human samples. Better understanding of the factors regulating LC migration may lead to novel therapies for the control of lupus dermatitis.

描述（由申请人提供）：皮炎是狼疮的常见表现，可导致疤痕和毁容。狼疮性皮炎通常很难治疗，其发病机制知之甚少。皮肤的外层（表皮）含有两种免疫细胞：朗格汉斯细胞（LC）和树突状表皮T细胞（DETC）。皮肤的相对简单性使其成为研究器官水平免疫耐受性的理想模型。最近的研究指出朗格汉斯细胞是皮肤耐受性的重要调节因子。我们的实验室最近表明，LC迁移受损的小鼠容易狼疮皮炎。已知DETC有助于促进伤口愈合，但其总体功能仍不清楚。来自我们实验室的令人兴奋的新数据已经显示了DETC的未知功能，即它们调节LC迁移。α-半乳糖神经酰胺（GalCer）治疗可改善皮炎，增加表皮中的DETC数量，并恢复狼疮易感小鼠的LC迁移。在这项研究中，我们假设DETC调节LC的迁移，皮肤中的LC-DETC相互作用作为一个调节网络，保护皮肤免受炎症。为了验证这一假设，我们将：确定DETC在LC迁移中的作用，并研究DETC调节LC迁移的机制（目的1）。在目标2中，我们将研究MRL小鼠中观察到的LC迁移缺陷的相关因素。根据我们的初步发现，MRL-lpr小鼠的DETC数量也显著减少，并且DETC-LC似乎在体内和体外相互作用，我们假设狼疮小鼠中LC迁移受损是由于皮肤中DETC数量减少;增加DETC数量将增强LC迁移，并减少皮肤炎症。未来的研究将开始将我们对DETC和LC迁移的研究转移到人体样本中。更好地了解调节LC迁移的因素可能会导致控制狼疮性皮炎的新疗法。