Efficacy of interleukin 10 gene hydrofection in pig liver vascular isolated ‘in vivo’ by surgical procedure with interest in liver transplantation


Autoři: Luis Sendra aff001;  María José Herrero aff001;  Eva María Montalvá aff003;  Inmaculada Noguera aff005;  Francisco Orbis aff004;  Ana Díaz aff005;  Rafael Fernández-Delgado aff006;  Rafael López-Andújar aff003;  Salvador F. Aliño aff001
Působiště autorů: Pharmacogenetics Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain aff001;  Gene Therapy Unit, Department of Pharmacology, Universitat de Valencia, Valencia, Spain aff002;  Unit of Experimental Hepatology and Liver Transplantation, Instituto de Investigación Sanitaria La Fe, Valencia, Spain aff003;  HPB Surgery and Transplant Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain aff004;  SCSIE, Central Services of Experimental Support, Universitat de Valencia, Valencia, Spain aff005;  Pediatrics Unit, Department of Pediatrics, Obstetrics and Gynecology, Universitat de Valencia, Valencia, Spain aff006;  Clinical Pharmacology Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain aff007
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224568

Souhrn

Aim

Liver transplantation is the only curative strategy for final stage liver diseases. Despite the great advances achieved during the last 20 years, the recipient immune response after transplantation is not entirely controlled. This results in high rates of acute cell rejection and, approximately, 10% of early mortality. Therapeutic treatment could be improved by efficiently transfecting genes that encode natural immunosuppressant proteins, employing safe procedures that could be transferred to clinical setting. In this sense, interleukin 10 plays a central role in immune tolerance response by acting at different levels.

Methods

hIL10 gene was hydrofected by retrograde hydrodynamic injection in pig liver with complete vascular exclusion mediated by an ‘in vivo’ surgical procedure. Levels of IL10 DNA, RNA and protein were determined within liver tissue 1 and 10 days after the injection and, more frequently, also the interleukin-10 protein in peripheral blood.

Results

The procedure was safe for the animals and neither hemodynamic parameters nor liver function determinations showed relevant alterations. The hIL10 hydrofection in watertight liver mediated efficient gene transfer and this was transcribed and translated to protein, achieving up to 110 pg/ml of IL10 in peripheral blood. This value is close to that considered able to reduce the activity of TNFα by half (IL10 IC50 for TNFα = 124 pg/ml).

Conclusions

Results of this work suggest that IL10 liver hydrofection with vascular exclusion in vivo is a safe and transferable procedure that mediates plasma protein levels with potential clinical interest in immune modulation after transplantation.

Klíčová slova:

Cytokines – Gene delivery – Liver – Liver transplantation – Surgical and invasive medical procedures – Swine – Vascular surgery – Gene transfer


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2019 Číslo 11