title: Dendritic cells transduced with viral interleukin 10 or Fas ligand: no evidence for induction of allotolerance in vivo.
abstract: Dendritic cells (DC) are the most potent presenters of alloantigens and therefore are responsible for the induction of allograft rejection. Genetic modifications of DC allowing the expression of a tolerogenic molecule may render them immunosuppressive. We transduced bone marrow-derived DC with recombinant MFG retrovirus encoding either viral interleukin (vIL)-10 or Fas ligand (FasL) to induce transplantation tolerance. Up to 10 ng/ml of bioactive vIL-10 was produced by DC after transfer of the corresponding gene. Although the inhibitory properties of vIL-10-transduced DC were revealed in vitro in a mixed lymphocyte culture, no clear down-regulation of the allogeneic response was observed in vivo after single or multiple injections of those DC overexpressing vIL-10. When we transduced wild-type bone marrow-derived DC with recombinant MFG retrovirus encoding murine FasL, cells quickly died, probably because of suicidal or fratricidal Fas-dependent death. Indeed, only DC from Fas-deficient lpr mice survived to FasL gene transfer. Those FasL-transduced lpr DC exhibited a strong cytotoxic activity against Fas-positive targets in vitro. DC overexpressing FasL did not behave as immunosuppressive DC in vivo. The subcutaneous injection of FasL+ lpr DC in MHC class II-disparate mice hyperactivated the allospecific proliferation of T cells in the draining lymph nodes compared with mice treated with control-transduced DC. These results argue against the development of FasL+ DC or vIL-10-secreting DC as immunosuppressive tools in vivo. The alternative pathways of T-cell activation triggered by these genetically modified DC need to be investigated.
authors.affiliation: 2 Laboratory of Physiology, Medical School of Vrije Universiteit Brussel.
authors.forename: Sofia
authors.initials: S
authors.lastname: Buonocore
authors.forename: Sonja
authors.initials: S
authors.lastname: Van Meirvenne
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Demoor
authors.forename: Frédéric
authors.initials: F
authors.lastname: Paulart
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
authors.forename: Michel
authors.initials: M
authors.lastname: Goldman
authors.forename: Véronique
authors.initials: V
authors.lastname: Flamand
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology / Q000502:physiology*; D053222:Fas Ligand Protein; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics*; D014161:Transduction, Genetic; D023001:Transplantation Tolerance
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016753:Interleukin-10