1 Immunoengineering of the vascular endothelium to silence MHC expression during normothermic ex vivo lung perfusion

Figueiredo C1, Carvalho-Oliveira M2, Chen-Wacker C3, Jansson K4, Hoeffler K5, Yuzefovych Y6, Pogozhykh O7, Jin Z8, Kuehnel M9, Jonigk D10, Wiegmann B11, Sommer W12, Haverich A13, Warnecke G14, Blasczyk R15Hum Gene Ther. 2018 Sep 27. doi: 10.1089/hum.2018.117. [Epub ahead of print]

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.

PMID: 30261752 DOI: 10.1089/hum.2018.117