Donor Antigen-Loaded IKK2dn Gene-Modified Dendritic Cells Prolong Allograft Survival
Donor Antigen-Loaded IKK2dn Gene-Modified Dendritic Cells Prolong Allograft Survival
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DOI：
10.1111/j.1365-3083.2010.02384.x
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发表时间：
2010-05-01
影响因子：
3.7
通讯作者：
Shi, G.
中科院分区：
文献类型：
--
作者：
Ouyang, J.;Fan, C.;Shi, G.
树突状细胞(DC)是调节免疫应答的关键因素，其成熟状态决定了其诱导免疫应答或耐受的能力。以往的研究表明，用腺病毒转染腺病毒载体阻断骨髓来源的树突状细胞(BMDC)中的IKK2，可以抑制核因子-kappaB的激活，损害DC的成熟。在此，我们用腺病毒载体(AdV-IKK2dn-DC)将IKK2dn导入受体大鼠(Lewis)BMDC，发现在同种异体抗原刺激下，AdV-IKK2dn-DC降低了B7-2和B7-1的表达。与未感染的DC相比，它们诱导同种异体T细胞增殖的能力显著降低。AdV-IKK2dn-DC刺激的同种异体T细胞分泌IL-10水平较高，而分泌干扰素-γ水平较低。此外，我们还发现，以抗原特异性方式致敏BN(Brown挪威大鼠)脾细胞裂解物的AdV-IKK2dn-DC显著延长了移植肾的存活时间。这些结果表明，负载BN抗原的AdV-IKK2dn-DC能够抑制抗同种异体免疫反应，诱导移植免疫耐受，为负载供体抗原的受体DC诱导免疫耐受提供了实验基础。我们的发现可能为已故供者肾移植提供一种更可行的策略。
Dendritic cells (DC) are key factors in regulating immune responses, and they induce immune response or tolerance depends on its maturation states. Previous studies demonstrated that blocking IKK2 in bone marrow-derived dendritic cells (BMDC) by adenoviral transfection with a kinase-defective dominant negative form of IKK2 (IKK2dn) could inhibit NF-kappa B activation and impair DC maturation. Here, we transfected IKK2dn into recipient rat (Lewis) BMDC by adenovirus vector (Adv-IKK2dn-DC) and found that Adv-IKK2dn-DC had reduced B7-2 and B7-1 expression under alloantigen stimulation. Their ability to induce allogeneic T-cell proliferation was markedly reduced in comparison with uninfected DC. A higher IL-10 secretion and a lower IFN-gamma secretion were detected in Adv-IKK2dn-DC-stimulated allogenic T cells. Furthermore, we showed that Adv-IKK2dn-DC pulsed with BN (Brown Norway rats) splenocyte lysates markedly prolonged the survival of renal allografts in an antigen-specific manner. These findings suggested that Adv-IKK2dn-DC loaded with BN antigen could suppress anti-alloimmune response and induce tolerance to allografts, which provided an experimental base for immune tolerance induction by recipient DC loaded with donor antigens. Our finding may provide a more feasible strategy for deceased-donor renal transplantation.