Untersuchungen zur Rolle von Keratinozyten in peripheren Toleranzmechanismen und der Auslösung muriner Graft-versus-Host-Disease

外周耐受性是健康免疫系统防止组织破坏的关键特征，而外周耐受性的破坏是免疫介导的疾病（例如青少年糖尿病）中的关键事件。在预期的研究中，将使用转基因小鼠的体内模型，在K14启动子的控制下通过角质形成细胞表达不同水平的表面结合卵清蛋白（OVA），以分析皮肤中外周耐受的诱导和破坏机制。该项目将基于宿主实验室先前的工作，其中，在表达高水平表皮OVA的菌株中，静脉注射OVA特异性细胞毒性T细胞（OT-I）导致皮肤移植物抗宿主病，无论是否存在朗格汉斯细胞和真皮树突状细胞。鉴于这一发现，角质形成细胞（KC）在诱导和破坏耐受性中的作用将在KC表达表面-OVA、共刺激分子和细胞因子产生（由抗原呈递细胞提供的信号1-3）的水平上进行分析。从该项目中得出的数据和结论将有助于更深入地了解KC在诱导和消除耐受中的影响，并为体内干预研究提供基础。

Peripheral tolerance is a pivotal feature of the healthy immune system preventing tissue destruction, while breaking of peripheral tolerance is a key event in immune mediated diseases (e.g. juvenile diabetes). In the intended research, an in vivo model of transgenic mice, expressing different levels of surface bound Ovalbumin (OVA) by keratinocytes under the control of the K14-promotor, shall be used to analyse the mechanisms of induction and breaking of peripheral tolerance in the skin. The project will be based on previous work from the host laboratory, where i.v. injection of OVA-specific cytotoxic T cells (OT-I) led to cutaneous Graft-versus-Host-Disease in a strain expressing high levels of epidermal OVA, irrespective of the presence or absence of Langerhans cells and dermal dendritic cells. In light of this finding, the role of keratinocytes (KC) on the induction and breaking of tolerance will be analyzed at the level of KC expression of surface-OVA, costimulatory molecules and cytokine production (signals 1-3 provided by antigen presenting cells). The data and conclusions drawn from the project will contribute to a deeper understanding of the impact of KC in the induction and abrogation of tolerance and provide a basis for in vivo intervention studies.