Generation of immunologically invisible organs through ex vivo MHC silencing to prevent rejection in a miniature swine lung transplantation model

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Currently, lung diseases occupy the rank 4 of the leading cause of death worldwide with an increasing prevalence and incidence. Lung transplantation is a highly successful therapy for patients with end-stage pulmonary disease, which is, however, hampered by frequent and early development of chronic rejection and high rate of opportunistic infections. Disparities between donor and recipient at the loci of the human leukocyte antigen (HLA) remain the main cause for immune rejection events and the need for strong immunosuppression. Previously, we have shown the feasibility to permanently suppress HLA expression in different cell and tissue types using RNA interference technology. Recently, we have shown in rat and mouse models that MHC-silenced cells are able to escape a humoral and cellular allogeneic immune rejection. The low MHC levels achieved using specific shRNAs allowed to prevent antibody-mediated, T- and NK-cell cytotoxicity. Hence, this project aims to reduce the immunogenicity of the lung by silencing MHC expression to improve graft survival after allogeneic transplantation. As the endothelium of a vascularized solid organ triggers and serves as the main target to the allogeneic immune response, we will focus on the downregulation of MHC class I and II expression on the lung endothelium during ex vivo lung perfusion (EVLP). A lentiviral vector will be used for the delivery of MHC-specific shRNA into the lung endothelial cells. Here, the protocol to achieve the permanent genetic engineering of the lung endothelium using the EVLP platform will be optimized. An established miniature swine lung transplantation model will be used to evaluate whether silencing SLA expression on the organ endothelium supports lung survival after allogeneic transplantation, by preventing acute and chronic rejection, even in the absence of immunosuppression. This interdisciplinary proposal has the potential to open a new horizon in the field of lung transplantation and a might be easily expanded to other solid organs.