ITUN INSERM 1064, CHU Hôtel-Dieu Nantes, France.
Front Immunol. 2012 Aug 9;3:218. doi: 10.3389/fimmu.2012.00218. eCollection 2012.
The use of immunosuppressive (IS) drugs to treat transplant recipients has markedly reduced the incidence of acute rejection and early graft loss. However, such treatments have numerous adverse side effects and fail to prevent chronic allograft dysfunction. In this context, therapies based on the adoptive transfer of regulatory cells are promising strategies to induce indefinite transplant survival. The use of tolerogenic dendritic cells (DC) has shown great potential, as preliminary experiments in rodents have demonstrated that administration of tolerogenic DC prolongs graft survival. Recipient DC, Donor DC, or Donor Ag-pulsed recipient DC have been used in preclinical studies and administration of these cells with suboptimal immunosuppression increases their tolerogenic potential. We have demonstrated that autologous unpulsed tolerogenic DC injected in the presence of suboptimal immunosuppression are able to induce Ag-specific allograft tolerance. We derived similar tolerogenic DC in different animal models (mice and non-human primates) and confirmed their protective abilities in vitro and in vivo. The mechanisms involved in the tolerance induced by autologous tolerogenic DC were also investigated. With the aim of using autologous DC in kidney transplant patients, we have developed and characterized tolerogenic monocyte-derived DC in humans. In this review, we will discuss the preclinical studies and describe our recent results from the generation and characterization of tolerogenic monocyte-derived DC in humans for a clinical application. We will also discuss the limits and difficulties in translating preclinical experiments to theclinic.
使用免疫抑制 (IS) 药物治疗移植受者可显著降低急性排斥反应和早期移植物丢失的发生率。然而，这些治疗方法有许多不良反应，并且不能预防慢性移植物功能障碍。在这种情况下，基于过继转移调节细胞的治疗是诱导无限期移植存活的有前途的策略。使用耐受性树突状细胞 (DC) 显示出巨大的潜力，因为啮齿动物的初步实验表明，给予耐受性 DC 可延长移植物存活时间。在临床前研究中使用了受者 DC、供者 DC 或供者 Ag 脉冲受者 DC，并且用亚最佳免疫抑制药物给予这些细胞可增加其耐受性潜能。我们已经证明，在亚最佳免疫抑制存在下注射的自体未脉冲耐受性 DC 能够诱导 Ag 特异性同种异体移植物耐受。我们在不同的动物模型（小鼠和非人类灵长类动物）中得到了类似的耐受性 DC，并在体外和体内证实了它们的保护能力。还研究了自体耐受性 DC 诱导的耐受所涉及的机制。为了在肾移植患者中使用自体 DC，我们已经在人类中开发并表征了耐受性单核细胞衍生的 DC。在这篇综述中，我们将讨论临床前研究，并描述我们最近在人类中生成和表征用于临床应用的耐受性单核细胞衍生 DC 的结果。我们还将讨论将临床前实验转化为临床的局限性和困难。
