Publication

Genetic Engineering of the Kidney to Permanently Silence MHC Transcripts During ex vivo Organ Perfusion

Yuzefovych, Y., Valdivia, E., Rong, S., Hack, F., Rother, T., Schmitz, J., Braesen, J. H., Wedekind, D., Moers, C., Wenzel, N., Gueler, F., Blasczyk, R. & Figueiredo, C., 19-Feb-2020, In : Frontiers in Immunology. 11, 12 p., 265.

Research output: Contribution to journalArticleAcademicpeer-review

  • Yuliia Yuzefovych
  • Emilio Valdivia
  • Song Rong
  • Franziska Hack
  • Tamina Rother
  • Jessica Schmitz
  • Jan Hinrich Braesen
  • Dirk Wedekind
  • Cyril Moers
  • Nadine Wenzel
  • Faikah Gueler
  • Rainer Blasczyk
  • Constanca Figueiredo

Organ gene therapy represents a promising tool to correct diseases or improve graft survival after transplantation. Polymorphic variation of the major histocompatibility complex (MHC) antigens remains a major obstacle to long-term graft survival after transplantation. Previously, we demonstrated that MHC-silenced cells are protected against allogeneic immune responses. We also showed the feasibility to silence MHC in the lung. Here, we aimed at the genetic engineering of the kidney toward permanent silencing of MHC antigens in a rat model. We constructed a sub-normothermic ex vivo perfusion system to deliver lentiviral vectors encoding shRNAs targeting β2-microglobulin and the class II transactivator to the kidney. In addition, the vector contained the sequence for a secreted nanoluciferase. After kidney transplantation (ktx), we detected bioluminescence in the plasma and urine of recipients of an engineered kidney during the 6 weeks of post-transplant monitoring, indicating a stable transgene expression. Remarkably, transcript levels of β2-microglobulin and the class II transactivator were decreased by 70% in kidneys expressing specific shRNAs. Kidney genetic modification did not cause additional cell death compared to control kidneys after machine perfusion. Nevertheless, cytokine secretion signatures were altered during perfusion with lentiviral vectors as revealed by an increase in the secretion of IL-10, MIP-1α, MIP-2, IP-10, and EGF and a decrease in the levels of IL-12, IL-17, MCP-1, and IFN-γ. Biodistribution assays indicate that the localization of the vector was restricted to the graft. This study shows the potential to generate immunologically invisible kidneys showing great promise to support graft survival after transplantation and may contribute to reduce the burden of immunosuppression.

Original languageEnglish
Article number265
Number of pages12
JournalFrontiers in Immunology
Volume11
Publication statusPublished - 19-Feb-2020

    Keywords

  • transplantation, kidney, organ engineering, HLA, gene therapy, lentiviral vector, organ perfusion, NORMOTHERMIC PERFUSION, RENAL-TRANSPLANTATION, MACHINE PERFUSION, LUNG, THERAPY, EXPRESSION, PREVENTION, REJECTION, PROTECTS, SURVIVAL

Download statistics

No data available

ID: 133328505