Allogeneic haematopoietic stem cell transplantation (HSCT) is an important curative therapy for a large number of hematological diseases. Graft versus host disease (GVHD) remains the major complication of allogeneic HSCT, which occurs in 40-60% of transplant recipients and could be directly responsible for 25% of transplant related mortality and a significant proportion of transplant related morbidity. Established immunosuppressive treatments are of limited efficacy and have significant side effects. Extracorporeal Phototherapy (ECP) is an effective treatment for GvHD. Importantly, infection and relapse rates are not increased in the course of ECP treatment. Hence, ECP is an exciting model to study tolerance mechanisms. ECP actions include apoptosis, cytokine modulation and the induction of regulatory T cells but the underlying mechanisms have not been revealed yet. Antigen presenting cells like dendritic cells (DCs) are thought to be important in mediating ECP effects. The project aims at comprehensively analysing ECP effects with special focus on the modulation of dendritic cells by ECP induced apoptotic cells. A unique modified skin explant model simulating ECP treatment for GvHD will be used to analyse immunoregulatory characteristics of DCs and T cells modified by apoptotic cells. Proteins known to carry regulatory potential will be assessed and mRNA expression arrays will be used to identify novel molecules involved in tolerance. The project will furthermore explore if ECP induced apoptotic cells have unique properties by comparing different methods of apoptosis induction. The skin explant model will be used in an antigen-specific context to clarify whether ECP actions are T cell clone specific. The last part of the project will analyse DNA polymorphisms of molecules identified during the course of the project to predict reponses to ECP in patients. In summary, ECP will be used as a model to study tolerance and derive novel tolerogenic strategies.
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