Feasibility of CTLA4Ig gene delivery and expression in vivo using retrovirally transduced myeloid dendritic cells that induce alloantigen-specific T cell anergy in vitro

Takayama, Takuya; Morelli, Adrián E.; Robbins, Paul D.; Tahara, Hideaki; Thomson, Angus W.

doi:10.1038/sj.gt.3301244

Cited by 47 publications

(24 citation statements)

References 50 publications

(75 reference statements)

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“…34,35 Alternatively, immune responses have been suppressed in an antigen-specific manner by CD95L-transfected 'killer' DC and by CTLA4-Ig-transfected 'tolerogenic' DC. 16,36 Time-consuming and costly ex vivo DC manipulation processes remain a major technical hurdle preventing these potentially useful approaches from clinical application. Our technology of gene gun-mediated, LCtargeted gene expression system may move this field toward practical medicine.…”

Section: Discussionmentioning

confidence: 99%

Development of a Langerhans cell-targeted gene therapy format using a dendritic cell-specific promoter

et al. 2001

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Section: Discussionmentioning

confidence: 99%

Development of a Langerhans cell-targeted gene therapy format using a dendritic cell-specific promoter

et al. 2001

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“…Moreover, DCs rendered tolerogenic in vitro by blocking surface CM as a result of CTLA4-Ig gene delivery appear to promote immune deviation (38). To address the influence of rAd CTLA4-Ig/NF-B ODN DCs on host Th cytokine expression, cardiac allografts were obtained from mice given the transduced DCs or control DCs 7 days before heart transplantation.…”

Section: Ad Ctla4-ig/nf-b Odn Dcs Suppress Th1 and Th2 Cytokine Gene mentioning

confidence: 99%

Marked Prolongation of Cardiac Allograft Survival by Dendritic Cells Genetically Engineered with NF-κB Oligodeoxyribonucleotide Decoys and Adenoviral Vectors Encoding CTLA4-Ig

Bonham

Peng

Liang

et al. 2002

The Journal of Immunology

123

100

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Bone marrow-derived dendritic cells (DCs) can be genetically engineered using adenoviral (Ad) vectors to express immunosuppressive molecules that promote T cell unresponsiveness. The success of these DCs for therapy of allograft rejection has been limited in part by the potential of the adenovirus to promote DC maturation and the inherent ability of the DC to undergo maturation following in vivo administration. DC maturation occurs via NF-κB-dependent mechanisms, which can be blocked by double-stranded “decoy” oligodeoxyribonucleotides (ODNs) containing binding sites for NF-κB. Herein, we describe the combined use of NF-κB ODNs and rAd vectors encoding CTLA4-Ig (Ad CTLA4-Ig) to generate stably immature murine myeloid DCs that secrete the potent costimulation blocking agent. These Ad CTLA4-Ig-transduced ODN DCs exhibit markedly impaired allostimulatory ability and promote apoptosis of activated T cells. Furthermore, administration of Ad CTLA4-Ig ODN-treated donor DCs (C57BL10; B10(H-2b)) before transplant significantly prolongs MHC-mismatched (C3HHeJ; C3H(H-2k)) vascularized heart allograft survival, with long-term (>100 days) donor-specific graft survival in 40% of recipients. The mechanism(s) responsible for DC tolerogenicity, which may involve activation-induced apoptosis of alloreactive T cells, do not lead to skewing of intragraft Th cytokine responses. Use of NF-κB antisense decoys in conjunction with rAd encoding a potent costimulation blocking agent offers promise for therapy of allograft rejection or autoimmune disease with minimization of systemic immunosuppression.

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“…In contrast, novel strategies were developed to enhance the capacity of DC to induce immunological tolerance. These strategies include pretreatment of DC with IL-10 (4), UV irradiation (5), use of DC in an immature state (6), or transduction of DC with immunoregulatory molecules such as IL-10 (7), TGF-␤ (8), and CTLA-4 (9).…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

Mature But Not Immature Fas Ligand (CD95L)-Transduced Human Monocyte-Derived Dendritic Cells Are Protected from Fas-Mediated Apoptosis and Can Be Used as Killer APC

Hoves

Krause²,

Halbritter³

et al. 2003

The Journal of Immunology

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Several in vitro and animal studies have been performed to modulate the interaction of APCs and T cells by Fas (CD95/Apo-1) signaling to delete activated T cells in an Ag-specific manner. However, due to the difficulties in vector generation and low transduction frequencies, similar studies with primary human APC are still lacking. To evaluate whether Fas ligand (FasL/CD95L) expressing killer APC could be generated from primary human APC, monocyte-derived dendritic cells (DC) were transduced using the inducible Cre/Loxp adenovirus vector system. Combined transduction of DC by AdLoxpFasL and AxCANCre, but not single transduction with these vectors, resulted in dose- and time-dependent expression of FasL in >70% of mature DC (mDC), whereas <20% of immature DC (iDC) expressed FasL. In addition, transduction by AdLoxpFasL and AxCANCre induced apoptosis in >80% of iDC, whereas FasL-expressing mDC were protected from FasL/Fas (CD95/Apo-1)-mediated apoptosis despite coexpression of Fas. FasL-expressing mDC eliminated Fas+ Jurkat T cells as well as activated primary T cells by apoptosis, whereas nonactivated primary T cells were not deleted. Induction of apoptosis in Fas+ target cells required expression of FasL in DC and cell-to-cell contact between effector and target cell, and was not dependent on soluble FasL. Induction of apoptosis in Fas+ target cells required expression of FasL in DC, cell-to-cell contact between effector and target cell, and was not dependent on soluble FasL. The present results demonstrate that FasL-expressing killer APC can be generated from human monocyte-derived mDC using adenoviral gene transfer. Our results support the strategy to use killer APCs as immunomodulatory cells for the treatment of autoimmune disease and allograft rejection.

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Feasibility of CTLA4Ig gene delivery and expression in vivo using retrovirally transduced myeloid dendritic cells that induce alloantigen-specific T cell anergy in vitro

Cited by 47 publications

References 50 publications

Development of a Langerhans cell-targeted gene therapy format using a dendritic cell-specific promoter

Development of a Langerhans cell-targeted gene therapy format using a dendritic cell-specific promoter

Marked Prolongation of Cardiac Allograft Survival by Dendritic Cells Genetically Engineered with NF-κB Oligodeoxyribonucleotide Decoys and Adenoviral Vectors Encoding CTLA4-Ig

Mature But Not Immature Fas Ligand (CD95L)-Transduced Human Monocyte-Derived Dendritic Cells Are Protected from Fas-Mediated Apoptosis and Can Be Used as Killer APC

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