Rapamycin-conditioned, alloantigen-pulsed myeloid dendritic cells present donor MHC class I/peptide via the semi-direct pathway and inhibit survival of antigen-specific CD8(+) T cells in vitro and in vivo.
Rapamycin-conditioned, alloantigen-pulsed myeloid dendritic cells present donor MHC class I/peptide via the semi-direct pathway and inhibit survival of antigen-specific CD8(+) T cells in vitro and in vivo.
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DOI：
10.1016/j.trim.2011.05.001
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发表时间：
2011-07
影响因子：
1.5
通讯作者：
Thomson AW
中科院分区：
文献类型：
--
作者：
Fischer RT;Turnquist HR;Wang Z;Beer-Stolz D;Thomson AW
树突状细胞（DC）是骨髓来源的抗原（Ag）呈递细胞，由于其调节先天性和适应性免疫的能力，其作为治疗靶点和潜在的细胞疫苗的“专业”感兴趣。利用DC固有的致耐受性是一种有希望的和未完全探索的预防同种异体移植排斥反应的方法。以前，我们和其他人已经报道了药理学修饰的DC抵抗成熟抑制CD 4 + T细胞应答和延长同种异体移植物存活的能力。在这里，我们评估了小鼠骨髓DC的能力与免疫抑制前体药物雷帕霉素（RAPA）的条件下，获得和直接提出同种抗原同基因的CD 8 + T细胞。RAPA-条件DC（RAPA-DC）与同种异体脾细胞裂解物脉冲获得和表达供体MHC I类，并在体外增强直接反应性供体Ag特异性CD 8 + T细胞的凋亡。此外，在它们的过继转移后，它们降低了这些T细胞在体内的存活率。RAPA-DC抑制同种异体抗原特异性CD 8 + T细胞存活的能力提供了一种潜在的机制，通过该机制，宿主来源的DC可以充当T细胞同种异体反应性的负调节剂并支持供体特异性无反应性。用同种抗原脉冲的RAPA-DC进行连续性细胞治疗可能提供抑制同种免疫的有效方法，减少对全身免疫抑制的依赖。
Dendritic cells (DC) are “professional” bone marrow-derived antigen (Ag)-presenting cells of interest both as therapeutic targets and potential cellular vaccines due to their ability to regulate innate and adaptive immunity. Harnessing the inherent tolerogenicity of DC is a promising and incompletely explored approach to the prevention of allograft rejection. Previously, we and others have reported the ability of pharmacologically-modified DC that resist maturation to inhibit CD4+ T cell responses and prolong allograft survival. Here we evaluated the ability of murine myeloid DC conditioned with the immunosuppressive pro-drug rapamycin (RAPA) to acquire and directly present alloAg to syngeneic CD8+ T cells. RAPA-conditioned DC (RAPA-DC) pulsed with allogeneic splenocyte lysate acquired and expressed donor MHC class I and enhanced the apoptotic death of directly-reactive donor Ag-specific CD8+ T cells in vitro. Moreover, following their adoptive transfer, they reduced the survival of these T cells in vivo. The ability of RAPA-DC to inhibit the survival of alloAg-specific CD8+ T cells provides a potential mechanism by which host-derived DC may act as negative regulators of T cell alloreactivity and support donor-specific unresponsiveness. Adoptive cell therapy with alloAg-pulsed RAPA-DC may offer an effective approach to suppression of alloimmunity, with reduced dependence on systemic immunosuppression.