雷帕霉素在诱导耐受性树突状细胞中的应用。

Use of rapamycin in the induction of tolerogenic dendritic cells.

作者信息

Fischer Ryan, Turnquist Heth R, Taner Timuçin, Thomson Angus W

机构信息

Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

出版信息

Handb Exp Pharmacol. 2009(188):215-32. doi: 10.1007/978-3-540-71029-5_10.

DOI:10.1007/978-3-540-71029-5_10

PMID:19031028

Abstract

Rapamycin (RAPA), a macrocyclic triene antibiotic pro-drug, is a clinically-utilized 'tolerance-sparing' immunosuppressant that inhibits the activity of T, B, and NK cells. Furthermore, maturation-resistance and tolerogenic properties of dendritic cells (DC) can be supported and preserved by conditioning with RAPA. Propagation of murine bone marrow (BM)-derived myeloid DC (mDC) in clinically relevant concentrations of RAPA (RAPA-DC) generates phenotypically immature DC with low levels of MHC and significantly reduced co-stimulatory molecules (especially CD86), even when exposed to inflammatory stimuli. RAPA-DC are weak stimulators of T cells and induce hyporesponsiveness and apoptosis in allo-reactive T cells. An interesting observation has been that RAPA-DC retain the ability to stimulate and enrich the regulatory T cells (Treg). Presumably as a result of these properties, alloantigen (alloAg)-pulsed recipient-derived DC are effective in subverting anti-allograft immune responses in rodent transplant models, making them an attractive subject for further investigation of their tolerance-promoting potential.

摘要

雷帕霉素（RAPA）是一种大环三烯抗生素前体药物，是一种临床应用的“耐受性保留”免疫抑制剂，可抑制T细胞、B细胞和NK细胞的活性。此外，通过用RAPA处理，可以支持和保留树突状细胞（DC）的成熟抗性和耐受性特性。在临床相关浓度的RAPA（RAPA-DC）中培养小鼠骨髓（BM）来源的髓样DC（mDC），即使暴露于炎症刺激下，也会产生表型不成熟的DC，其MHC水平低，共刺激分子（尤其是CD86）显著减少。RAPA-DC是T细胞的弱刺激剂，可诱导同种反应性T细胞低反应性和凋亡。一个有趣的观察结果是，RAPA-DC保留了刺激和富集调节性T细胞（Treg）的能力。推测由于这些特性，同种抗原（alloAg）脉冲的受体来源DC在啮齿动物移植模型中有效颠覆抗同种异体移植免疫反应，使其成为进一步研究其促进耐受性潜力的有吸引力的对象。