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，而打破外周耐受性是免疫介导性疾病(如青少年糖尿病)的关键事件。在本研究中，将利用K14启动子控制的角质形成细胞表达不同水平的表面结合卵白蛋白(OVA)的转基因小鼠体内模型，分析皮肤外周耐受的诱导和打破的机制。该项目将以东道主实验室以前的工作为基础，在那里，I.V.无论是否存在朗格汉斯细胞和真皮树突状细胞，注射OVA特异性细胞毒性T细胞(OT-I)可导致高水平表达表皮OVA的菌株发生皮肤移植物抗宿主病。根据这一发现，角质形成细胞(KC)在诱导和打破耐受中的作用将从表面OVA的KC表达、共刺激分子和细胞因子产生(由抗原提呈细胞提供的信号1-3)水平进行分析。该项目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.