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

Frontiers in Immunology
Yuliia YuzefovychConstanca Figueiredo

Abstract

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...Continue Reading

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Citations

Apr 24, 2020·Molecular Diagnosis & Therapy·Jeffrey D Rubin, Michael A Barry
Sep 25, 2020·Transplant International : Official Journal of the European Society for Organ Transplantation·Sarah A HosgoodMichael L Nicholson
Apr 21, 2021·Transplantation Reviews·Kristin CarlsonDavid P Al-Adra
Apr 27, 2021·Frontiers in Immunology·Charlotte FlahouNaoshi Sugimoto
Jun 30, 2021·Scientific Reports·Shahar CohenEviatar Nesher
Jun 13, 2021·Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society·Kristin N CarlsonDavid P Al-Adra

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Methods Mentioned

BETA
genetic modification
enzyme-linked immunosorbent assay
urine collection
Assay
PCR
electrophoresis

Software Mentioned

GraphPad Prism
StepOnePlus
BioRad Image Lab
StepOnePlus Real - Time PCR System
GraphPad
Xponent

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