Effects of IL‐10‐ and FasL‐overexpressing dendritic cells on liver transplantation tolerance in a heterotopic liver transplantation rat model

Abstract

Acute rejection is the major determinant for the long-term survival of donor liver after liver transplantation (LT). The aim of this study was to examine the therapeutic potential of interleukin (IL)-10-FasL-overexpressing immature dendritic cells (imDCs) to induce local immunosuppression in liver grafts. imDCs derived from donors were transduced by lentiviral vectors expressing human IL-10 and/or Fas ligand (FasL) gene(s), and the expression of surface molecules and the ability to induce T-cell proliferation were measured. imDCs were intraperitoneally injected into recipient rats as a model of LT to examine the rejection grade [Banff rejection activity index (RAI)], liver functions [Alanine aminotransferase, Aspartate aminotransferase (AST) and total bilirubin (TBIL)] and post-transplant survival. IL-10 and FasL co-transduction of imDCs induced a greater reduction in CD80, CD86 and major histocompatibility complex class II (MHC II) expression, as well as T-cell proliferation, but increased levels of IL-10 and FasL in culture supernatants compared with mono-transduced or untransduced imDCs (P < 0.05). The infusion of co-transduced imDCs in LT recipients reduced RAI scores, decreased plasma AST and TBIL, and prolonged survival compared with mono-transduced or untransduced imDC-treated liver allografts. These findings demonstrated that the transfusion of IL-10-FasL/imDCs enhanced immune tolerance and prolonged the survival of liver allografts after LT. The immunomodulatory activity of IL-10-and FasL-modified imDCs might be a new therapeutic approach to prevent organ rejection in clinical transplantation.

High Mobility Group Box 1 Contributes to the Acute Rejection of Liver Allografts by Activating Dendritic Cells

“…The liver tissues were fixed in 4% paraformaldehyde and then embedded in paraffin. Midsagittal serial sections (4-μm thick) were cut and stained with H&E. The rejection activity index (RAI) of grafted livers was quantified with reference to the histopathology of the portal area, damage of the bile duct, and venous endothelial inflammation as described previously ( 22 ). To identify the infiltrating inflammatory cells, immunohistochemical analysis was performed.…”

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

“…The increased level of Fas-L could induce T cell apoptosis ( 84 ). Immature DC transduced by lentiviral vectors expressing human IL-10 and FasL genes could significantly reduce the expression of costimulatory molecules and T cell proliferation and extend the survival period of rat liver allografts ( 94 ). Tol-DC have a unique subset: CD11b high Ia low Tol-DC.…”

“…The injection of IL-10-pulsed DC enriches graft infiltrating regulatory CD8 + T cells and tolerogenic myeloid cells with suppression-associated phenotypes ( 80 ). DC cotransfected Fas-L and IL-10 have more capacity to inhibit T cell activation and prolong the survival period of allografts than Fas-L alone ( 94 ).…”

Gastrodin Ameliorates Acute Rejection via IRE1α/TRAF2/NF-κB in Rats Receiving Liver Allografts

“…After rinsing with running water for seconds, sections were dehydrated with different concentrations of ethanol and xylene and sealed with neutral gum, and pathological changes were observed under the optical microscope. The Rejection Activity Index (RAI) scores (up to 9) are as follows: RAI<3 is classified as nondeterministic acute rejection, RAI = 3∼5 is classified as mild rejection, RAI = 5∼7 is classified as moderate rejection, and RAI = 7∼9 is classified as severe rejection reaction [21].…”