Administration of dendritic cells transduced with antisense oligodeoxyribonucleotides targeting CD80 or CD86 prolongs allograft survival
Administration of dendritic cells transduced with antisense oligodeoxyribonucleotides targeting CD80 or CD86 prolongs allograft survival
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DOI：
10.1097/01.tp.0000076470.35404.49
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发表时间：
2003-08-27
期刊：
影响因子：
6.2
通讯作者：
Qian, SG
中科院分区：
文献类型：
--
作者：
Liang, XY;Lu, LN;Qian, SG
背景抗原呈递细胞上共刺激分子的表达在决定T细胞免疫应答中是至关重要的。我们研究了设计用于靶向CD 80或CD 86 mRNA的高亲和力反义寡脱氧核苷酸（ODNs）转导对树突状细胞（DCs）表型和功能的影响。用粒细胞巨噬细胞集落刺激因子和白细胞介素（IL）-4诱导C57 BL/10（B10; H2（B））骨髓细胞增殖DC，并分别用抗CD 80或抗CD 86反义寡核苷酸（碱基错配寡核苷酸作为对照）转导。流式细胞术检测反义ODN对细胞表型的影响。通过体外混合白细胞反应和细胞毒活性检测DC的同种异体刺激功能，并观察其对同种异体移植物存活的影响。ODNs被DC有效地掺入，这通过脂质体的存在而增强。靶向CD 80或CD 86 mRNA的反义寡核苷酸特异性地抑制DC中CD 80或CD 86的表达，并抑制其诱导C3 H（H2（k））脾T细胞增殖反应和供体特异性细胞毒性T淋巴细胞活性的能力。这与IL-2减少，但IL-4产生增加和T细胞凋亡增加有关。与对照组相比，C3 H受体注射抗CD 80或CD 86反义ODN可明显延长心脏移植物的存活时间。针对CD 80或CD 86 mRNA的反义ODN转导是一种可行且有效的修饰DC的方法，通过诱导T细胞低反应性和凋亡使其成为耐受原性的DC。这可能会导致新的移植治疗策略的发展。
Background. The expression of costimulatory molecules on antigen-presenting cells is crucial in determining T-cell immune responses. We examined the effects of transduction with high-affinity antisense oligodeoxyribonucleotides (ODNs) designed to target the mRNA of CD80 or CD86 on the phenotype and function of dendritic cells (DCs).Materials and Methods. DCs were propagated from C57BL/10 (B10; H2(b)) bone marrow cells in granulocyte macrophage-colony stimulating factor and interleukin (IL)-4, and transduced with anti-CD80 or anti-CD86 antisense ODNs (base-mismatched ODNs as controls). The effect of antisense ODN on phenotype was examined by flow cytometry. The allostimulatory function of DCs was assessed by mixed leukocyte reaction and cytotoxic activity in vitro, and the influence on allograft survival was assessed in vivo.Results. ODNs were effectively incorporated by DCs, which were enhanced by the presence of lipofectamine. Antisense ODNs targeting CD80 or CD86 mRNA specifically suppressed the expression of CD80 or CD86 in DCs and inhibited their capacity to elicit the proliferative responses, donor-specific cytotoxic T-lymphocyte activity in C3H (H2(k)) spleen T cells. This was associated with decreased IL-2, but elevated IL-4 production, and an increase in T-cell apoptosis. In contrast with the administration of control DCs into C3H recipients that exacerbated rejection of B10 cardiac allografts, injection of DCs transduced with anti-CD80 or CD86 antisense ODN significantly prolonged the survival of heart allografts.Conclusion. Transduction with antisense ODN targeting CD80 or CD86mRNA is a feasible and effective approach to modify DCs that renders them tolerogenic by inducing T-cell hyporesponsiveness and apoptosis. This may lead to the development of new therapeutic strategies in transplantation.