2001
DOI: 10.4049/jimmunol.166.7.4773
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Specific Immunotherapy by Genetically Engineered APCs: The “Guided Missile” Strategy

Abstract: We tested the hypothesis that APCs genetically engineered to present an Ag and to express Fas ligand (FasL) simultaneously can target and eliminate Ag-specific T cells. Transgenic T cells specific for influenza hemagglutinin (HA) were used as targets. We prepared recombinant vaccinia virus vectors (VVV) to transfer the gene constructs individually or simultaneously into APCs. We prevented unwanted viral replication by attenuating the VVVs with psoralen-UV light treatment. For presentation of the HA Ag, APCs we… Show more

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Cited by 20 publications
(20 citation statements)
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References 37 publications
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“…The resistance of mDC toward Fas-mediated apoptosis has been attributed to the increased expression of anti-apoptotic molecules during DC maturation, and increased levels of c-FLIP and Bcl-x L have been detected in mDC compared with iDC (35,38). To prevent Fas-mediated self-destruction, it has been proposed that APC should be transduced with an apoptosis inhibitor in combination with FasL, and protection from Fas-mediated apoptosis could be achieved in murine APC by coexpression of a truncated Fas-associated death domain protein together with FasL using a recombinant vaccinia virus (20). However, our results demonstrate that coexpression of an apoptosis inhibitor is not required if mDC were used for generation of FasL-expressing human killer APC.…”
Section: Discussioncontrasting
confidence: 47%
See 1 more Smart Citation
“…The resistance of mDC toward Fas-mediated apoptosis has been attributed to the increased expression of anti-apoptotic molecules during DC maturation, and increased levels of c-FLIP and Bcl-x L have been detected in mDC compared with iDC (35,38). To prevent Fas-mediated self-destruction, it has been proposed that APC should be transduced with an apoptosis inhibitor in combination with FasL, and protection from Fas-mediated apoptosis could be achieved in murine APC by coexpression of a truncated Fas-associated death domain protein together with FasL using a recombinant vaccinia virus (20). However, our results demonstrate that coexpression of an apoptosis inhibitor is not required if mDC were used for generation of FasL-expressing human killer APC.…”
Section: Discussioncontrasting
confidence: 47%
“…However, all these studies were performed using murine DC, B cells, macrophages, or cell lines as APC (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)39). Therefore, for future clinical application, it had to be determined whether human DC can be efficiently transduced with FasL and whether these cells would be capable of eliminating Fas ϩ target cells.…”
Section: Discussionmentioning
confidence: 99%
“…20 CII-loaded B cells were proven to exert potent suppressive effects on clinical arthritis independently of IL-4 production. On the other hand, beneficial effects using macrophages required both antigen presentation and genetic modifications, suggesting that, once they had migrated to the affected joints, these manipulated APC acted via specific interactions with T cells and local delivery of the anti-inflammatory cytokine.…”
Section: Figure 4 In Vivo Migration Of Macrophages Into the Joints Ofmentioning
confidence: 99%
“…19 Most recent strategies pointed to immunosuppressive capacities of Gene Therapy antigen-presenting cells (APC) engineered to express regulatory proteins. 20 For example, APC expressing high levels of Fas ligand down-modulated pathological signs in a murine model of chronic inflammatory disease. 21 In the current study, we hypothesized that the antigenprocessing capacity and migratory properties of various APC may represent an appropriate endogenous system for site-specific delivery of therapeutic transgene proteins during autoimmune diseases.…”
Section: Introductionmentioning
confidence: 99%
“…Our studies presented herein using the AKR.H-2 b mouse strain, which exhibits spontaneous endogenous viral Ag expression triggering antiviral CTL nonresponsiveness, thus serve to emphasize the veto cell mechanism as a natural, physiologic virus escape mechanism. However, as has been recently suggested (35), FasL-expressing, specific epitope-presenting APCs could also be prospectively constructed to target and kill corresponding autoreactive T cells to potentially ameliorate autoimmune diseases.…”
Section: Final Commentsmentioning
confidence: 99%