Disparities at the major histocompatibility antigens (MHC) and associated minor antigens trigger harmful immune responses leading to graft rejection after transplantation. We showed that MHC-silenced cells and tissues are efficiently protected against rejection. In complex vascularized organs the endothelium is the major interface between donor and recipient. We therefore aimed at reducing the immunogenicity of the lung by silencing MHC expression on the endothelium. In porcine lungs short-hairpin RNAs targeting beta-2-microglobulin and class II-transactivator transcripts were delivered by lentiviral vectors during normothermic ex vivo perfusion to permanently silence Swine Leukocyte Antigen (SLA) I and II expression. The results demonstrated the feasibility to genetically engineer all lung regions achieving the targeted silencing effect of SLA I and II of 67% and 52%, respectively, without affecting cell viability or tissue integrity. This decrease of immunogenicity carries the potential to generate immunologically invisible organs to counteract the burden of rejection and immunosuppression.
- Figueiredo, C.
- Carvalho-Oliveira, M.
- Chen-Wacker, C.
- Jansson, K.
- Hoeffler, K.
- Yuzefovych, Y.
- Pogozhykh, O.
- Jin, Z.
- Kuehnel, M.
- Jonigk, D.
- Wiegmann, B.
- Sommer, W.
- Haverich, A.
- Warnecke, G.
- Blasczyk, R.
