Multitransgenic donor animals and new immunosuppressive strategies in preclinical experimental xenotransplantation models

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The generation of pigs transgenic for hCD59, hDAF/siaGT, hTRAIL, HLA-E, human thrombomodulin and human heme-oxygenase 1 offers the possibility to investigate new strategies to overcome delayed xenograft rejection in vivo. The effect of further modifications of the donor organs (CTLA4-Ig, vIL-10) will be investigated in a mouse model using rAAV as a vector. rAAV mediated gene transfer into porcine hearts will then be investigated in an allogeneic heart transplantation model. Using an appropriate ex-vivo perfusion set-up, multitransgenic and/or knock-out porcine organs generated in projects II and III will be investigated as to their therapeutic effectiveness. In addition, the working-heart model allows to perform a systematic screen for new targets to overcome acute vascular rejection by expression profiling at different time-points after exposure to human blood. During orthotopic transplantation of transgenic or multitransgenic pig hearts into primates the effects of both rejection and ischemia-reperfusion-injury on microcirculatory changes will be visualized and quantified in vivo using Orthogonal Polarization Spectral Imaging (OPSI). Novel immunomodulatory strategies will be investigated using a combination of cyclophosphamide (attenuated induction therapy), immunoadsorption (GAS914), anti HLA-DR antibodies and tacrolimus/ sirolimus.