Immunoregulatory properties of rapamycin-conditioned monocyte-derived dendritic cells and their role in transplantation.
Immunoregulatory properties of rapamycin-conditioned monocyte-derived dendritic cells and their role in transplantation.
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DOI：
10.1186/2047-1440-1-16
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发表时间：
2012-09-28
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影响因子：
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通讯作者：
Thomson AW
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作者：
Macedo C;Turquist H;Metes D;Thomson AW
为了尽量减少移植和自身免疫性疾病中免疫抑制（IS）药物的慢性施用，已经开发了各种基于细胞的耐受性治疗，包括使用调节性或耐受性树突状细胞（tolDC）。这些基于dc的疗法旨在利用这些专业抗原提呈细胞固有的免疫调节潜力。在这篇简短的综述中，我们描述了雷帕霉素条件DC （rapamycin-conditioned DC）的耐受性和目前的局限性。RAPA-DC是在单核细胞来源的DC繁殖过程中，免疫抑制大环内酯类雷帕霉素抑制整合激酶哺乳动物雷帕霉素靶蛋白（mTOR）而产生的。与tolDC的特点一致，小鼠RAPA-DC对促炎刺激诱导的表型成熟表现出抗性；表现出迁移到次级淋巴组织的能力（对抗原向T细胞的“交叉呈递”很重要），并丰富自然发生的CD4+调节性T细胞。在啮齿类动物模型中，在器官移植之前，用供体抗原脉冲递送受体衍生的RAPA-DC可以无限期延长同种异体心脏移植的存活时间，特别是在与短期IS联合使用时。这些令人鼓舞的数据支持正在进行的开发用于临床试验的RAPA-DC的努力。然而，与小鼠RAPA-DC相比，人类RAPA-DC已被证明仅部分抵抗由促炎细胞因子触发的成熟，并且在其对效应t细胞扩增和功能的影响方面表现出异质性。总的来说，证据表明需要进行更深入的研究，以更好地了解mTOR控制人类DC功能的机制。这些研究可能会促进RAPA-DC单独治疗或与保留/增强其耐受性的药物一起作为临床免疫调节载体的发展。
In efforts to minimize the chronic administration of immunosuppression (IS) drugs in transplantation and autoimmune disease, various cell-based tolerogenic therapies, including the use of regulatory or tolerogenic dendritic cells (tolDC) have been developed. These DC-based therapies aim to harness the inherent immunoregulatory potential of these professional antigen-presenting cells. In this short review, we describe both the demonstrated tolerogenic properties, and current limitations of rapamycin-conditioned DC (RAPA-DC). RAPA-DC are generated through inhibition of the integrative kinase mammalian target of rapamycin (mTOR) by the immunosuppressive macrolide rapamycin during propagation of monocyte-derived DC. Consistent with the characteristics of tolDC, murine RAPA-DC display resistance to phenotypic maturation induced by pro-inflammatory stimuli; exhibit the ability to migrate to secondary lymphoid tissue (important for ‘cross-presentation’ of antigen to T cells), and enrich for naturally-occurring CD4+ regulatory T cells. In rodent models, delivery of recipient-derived RAPA-DC pulsed with donor antigen prior to organ transplantation can prolong allogeneic heart-graft survival indefinitely, especially when combined with a short course of IS. These encouraging data support ongoing efforts to develop RAPA-DC for clinical testing. When compared to murine RAPA-DC however, human RAPA-DC have proven only partially resistant to maturation triggered by pro-inflammatory cytokines, and display heterogeneity in their impact on effector T-cell expansion and function. In total, the evidence suggests the need for more in-depth studies to better understand the mechanisms by which mTOR controls human DC function. These studies may facilitate the development of RAPA-DC therapy alone or together with agents that preserve/enhance their tolerogenic properties as clinical immunoregulatory vectors.