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

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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.