Marked prolongation of cardiac allograft survival by dendritic cells genetically engineered with NF-kappa B oligodeoxyribonucleotide decoys and adenoviral vectors encoding CTLA4-Ig.
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-kappaB-dependent mechanisms, which can be blocked by double-stranded "decoy" oligodeoxyribonucleotides (ODNs) containing binding sites for NF-kappaB. Herein, we describe the combined use of NF-kappaB 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-kappaB 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.
Bonham
C Andrew
CA
Department of Surgery and Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Peng
Lansha
L
Liang
Xiaoyan
X
Chen
Zongyou
Z
Wang
Lianfu
L
Ma
Linlin
L
Hackstein
Holger
H
Robbins
Paul D
PD
Thomson
Angus W
AW
Fung
John J
JJ
Qian
Shiguang
S
Lu
Lina
L
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation*; D004338:Drug Combinations; D005786:Gene Expression Regulation / Q000187:drug effects; D005822:Genetic Vectors / Q000138:chemical synthesis / Q000494:pharmacology; D006082:Graft Enhancement, Immunologic / Q000379:methods*; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D049452:Green Fluorescent Proteins; D006131:Growth Inhibitors / Q000235:genetics / Q000494:pharmacology; D016027:Heart Transplantation / Q000276:immunology* / Q000379:methods; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics* / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides / Q000235:genetics* / Q000494:pharmacology; D015202:Protein Engineering / Q000379:methods; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014019:Tissue Donors; D019076:Transgenes / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D004338:Drug Combinations; D006131:Growth Inhibitors; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D008164:Luminescent Proteins; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D049452:Green Fluorescent Proteins; D000069594:Abatacept