Marked prolongation of cardiac allograft survival by dendritic cells genetically engineered with NF-κB oligodeoxyribonucleotide decoys and adenoviral vectors encoding CTLA4-Ig
Marked prolongation of cardiac allograft survival by dendritic cells genetically engineered with NF-κB oligodeoxyribonucleotide decoys and adenoviral vectors encoding CTLA4-Ig
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DOI：
10.4049/jimmunol.169.6.3382
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发表时间：
2002-09-15
影响因子：
4.4
通讯作者：
Lu, L
中科院分区：
文献类型：
--
作者：
Bonham, CA;Peng, LS;Lu, L
可以使用腺病毒 (Ad) 载体对骨髓来源的树突状细胞 (DC) 进行基因改造，以表达促进 T 细胞无反应的免疫抑制分子。这些 DC 用于治疗同种异体移植排斥的成功部分受到腺病毒促进 DC 成熟的潜力以及 DC 在体内施用后经历成熟的固有能力的限制。 DC 成熟通过 NF-kappaB 依赖性机制发生，该机制可以被含有 NF-kappaB 结合位点的双链“诱饵”寡脱氧核糖核苷酸 (ODN) 阻断。在此，我们描述了联合使用 NF-kappaB ODN 和编码 CTLA4-Ig (Ad CTLA4-Ig) 的 rAd 载体来生成稳定的未成熟小鼠骨髓 DC，其分泌有效的共刺激阻断剂。这些 Ad CTLA4-Ig 转导的 ODN DC 表现出明显受损的同种刺激能力并促进活化 T 细胞的凋亡。此外，移植前给予 Ad CTLA4-Ig ODN 处理的供体 DC（C57BL10；B10(H-2(b))）可显着延长 MHC 错配（C3HHeJ；C3H(H-2(k))）血管化心脏同种异体移植物的存活率，40% 的受体具有长期（>100 天）供体特异性移植物存活率。负责 DC 耐受原性的机制可能涉及同种异体反应性 T 细胞的激活诱导凋亡，但不会导致移植物内 Th 细胞因子反应的偏差。将 NF-κB 反义诱饵与编码有效共刺激阻断剂的 rAd 结合使用，有望治疗同种异体移植排斥或自身免疫性疾病，同时最大限度地减少全身免疫抑制。
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-2(b))) before transplant significantly prolongs MHC-mismatched (C3HHeJ; C3H(H-2(k))) 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.