Long-term survival of limb allografts induced by pharmacologically conditioned, donor alloantigen-pulsed dendritic cells without maintenance immunosuppression
Long-term survival of limb allografts induced by pharmacologically conditioned, donor alloantigen-pulsed dendritic cells without maintenance immunosuppression
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DOI：
10.1097/tp.0b013e31815e870e
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发表时间：
2008-01-27
期刊：
影响因子：
6.2
通讯作者：
Feili-Hariri, Maryam
中科院分区：
文献类型：
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作者：
Ikeguchi, Ryosuke;Sacks, Justin M.;Feili-Hariri, Maryam
背景资料。我们最近发现，移植后应用同种异体抗原(Ag)冲击的未成熟树突状细胞(DC)可以提高同种异体肢体移植的存活率。由于移植物无限期存活，我们通过药物(雷帕霉素；RAPA)进一步修饰DC，并确定它们对移植物存活的影响，而不进行持续的免疫抑制治疗。我们比较了供体抗原冲击的RAPA条件下的大鼠骨髓DC(Rapa DC)和对照DC(CTR DC)在接受抗淋巴细胞血清(ALS)治疗的受者术后短期给予环孢素A(CsA)治疗后抑制肢体移植后同种异体反应性T细胞反应的能力。两种DC的主要组织相容性复合体(MHC)II、CD40和CD54的表达水平相似，而RAPA DC的CD86表达水平较低。在Toll样受体激活后，两个群体都产生了最低限度的IL-12p70，但Rapa DC分泌了较低水平的IL-6和IL-10。DC在混合白细胞反应中刺激T细胞增殖的能力很低。供体抗原冲击DC不改变其表型或功能。有趣的是，在接受围手术期肌萎缩侧索硬化症和21天环孢素A治疗的大鼠移植后，给予供体抗原冲击的RAPA DC显著延缓了移植物排斥反应，并促进了移植物的长期存活(125天)。异种抗原致敏的RAPA DC在体外诱导T细胞低反应性，促进分泌IL-10的CD4(+)T细胞的产生。在复合组织移植后输注供体抗原脉冲的、RAPA调节的DC可以在完全MHC不匹配和没有持续免疫抑制治疗的情况下防止包括皮肤在内的移植物的排斥反应。
Background. We showed recently that limb allograft survival could be enhanced by administration of alloantigen (Ag)-pulsed immature dendritic cells (DC) after transplantation. Since indefinite graft survival was not achieved, we have further modified the DC by pharmacologic (rapamycin; Rapa) conditioning and ascertained their influence on graft survival, without continued immunosuppressive therapy.Methods. We compared the ability of donor Ag-pulsed, Rapa-conditioned rat myeloid DC (Rapa DC) and control DC (CTR DC) to inhibit alloreactive T-cell responses after limb transplantation in antilymphocyte serum (ALS)-treated recipients given a short postoperative course of cyclosporine (CsA).Results. Both DC populations expressed similar levels of major histocompatibility complex (MHC) II, CD40 and CD54, but Rapa DC expressed lower CD86. After toll-like receptor activation, both populations produced minimal interleukin (IL)-12p70, but Rapa DC secreted lower levels of IL-6 and IL-10. The capacity of DCs to stimulate T-cell proliferation in mixed leukocyte reactions was very low. Pulsing of the DC with donor Ag did not alter their phenotype or function. Interestingly, posttransplant administration of donor Ag-pulsed Rapa DC to rats given perioperative ALS and 21 days CsA significantly delayed graft rejection and promoted long-term (> 125 days) graft survival. AlloAg-pulsed Rapa DC induced T-cell hyporesponsiveness and promoted the generation of IL-10-secreting CD4(+) T cells upon ex vivo challenge.Conclusions. Infusion of donor Ag-pulsed, Rapa-conditioned DC after composite tissue transplantation can prevent rejection of the grafts, including skin, across a full MHC mismatch and in the absence of continued immunosuppressive therapy.