Multipotent adult progenitor cells can suppress graft-versus-host disease via prostaglandin E2 synthesis and only if localized to sites of allopriming
Multipotent adult progenitor cells can suppress graft-versus-host disease via prostaglandin E2 synthesis and only if localized to sites of allopriming
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DOI：
10.1182/blood-2009-03-213850
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发表时间：
2009-07-16
期刊：
影响因子：
20.3
通讯作者：
Blazar, Bruce R.
中科院分区：
文献类型：
--
作者：
Highfill, Steven L.;Kelly, Ryan M.;Blazar, Bruce R.
多能成体祖细胞（MAPCs）是一种能够产生多种组织细胞的非造血干细胞。因此，MAPCs有望在移植后修复组织损伤。在体外，MAPCs以剂量依赖、细胞接触无关和t调节细胞无关的方式有效抑制同种异体t细胞的活化和增殖。抑制主要通过MAPCs中前列腺素E-2的合成发生，导致促炎细胞因子的产生减少。当系统给予MAPCs时，MAPCs不能定位同种异体启动位点，也不能抑制移植物抗宿主病（GVHD）。为了确保MAPCs与供体T细胞共定位，骨髓移植时将MAPCs直接注射到脾脏中。MAPCs通过体内前列腺素E-2合成限制供体t细胞增殖和gvhd诱导的损伤。此外，MAPCs改变了脾脏T细胞和抗原呈递细胞中从阳性和抑制性共刺激途径表达的平衡。这些发现首次描述了MAPC诱导的t细胞同种异体反应抑制的免疫抑制能力和机制，并阐明了MAPC共定位到初始供体t细胞活化位点才能抑制GVHD。这些数据对临床使用同种异体MAPCs和其他免疫调节非造血干细胞预防GVHD具有重要意义。(血。2009;114:693 - 701)
Multipotent adult progenitor cells (MAPCs) are nonhematopoietic stem cells capable of giving rise to a broad range of tissue cells. As such, MAPCs hold promise for tissue injury repair after transplant. In vitro, MAPCs potently suppressed allogeneic T-cell activation and proliferation in a dose-dependent, cell contact-independent, and T-regulatory cell-independent manner. Suppression occurred primarily through prostaglandin E-2 synthesis in MAPCs, which resulted in decreased proinflammatory cytokine production. When given systemically, MAPCs did not home to sites of allopriming and did not suppress graft-versus-host disease (GVHD). To ensure that MAPCs would colocalize with donor T cells, MAPCs were injected directly into the spleen at bone marrow transplantation. MAPCs limited donor T-cell proliferation and GVHD-induced injury via prostaglandin E-2 synthesis in vivo. Moreover, MAPCs altered the balance away from positive and toward inhibitory costimulatory pathway expression in splenic T cells and antigen-presenting cells. These findings are the first to describe the immunosuppressive capacity and mechanism of MAPC-induced suppression of T-cell alloresponses and illustrate the requirement for MAPC colocalization to sites of initial donor T-cell activation for GVHD inhibition. Such data have implications for the use of allogeneic MAPCs and possibly other immunomodulatory nonhematopoietic stem cells for preventing GVHD in the clinic. (Blood. 2009;114:693-701)