The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality
The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality
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DOI：
10.1182/blood.v99.10.3493
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发表时间：
2002-05-15
期刊：
影响因子：
20.3
通讯作者：
Blazar, BR
中科院分区：
文献类型：
--
作者：
Taylor, PA;Lees, CJ;Blazar, BR
免疫调节性CD4(+)CD25(+)细胞在诱导和维持自身耐受和预防自身免疫中起着至关重要的作用。最近，CD25(+)细胞被证明是通过共刺激阻断体外诱导同种异体抗原耐受和抑制同种异体皮肤移植排斥反应所必需的。这里提供的数据表明，CD4(+)CD25(+)细胞在移植物抗宿主病(GVHD)的产生中发挥着重要作用。移植前去除供者T细胞接种中的CN(+)CD25(+)细胞或受体体内CD25缺失的细胞会导致多个品系组合中由CD4(+)或整个T细胞介导的GVHD增加，而与全身照射条件无关。当输注新鲜纯化的供者CD4(+)CD25(+)细胞时，与整个CD4(+)细胞同等数量的输注可适度抑制GVHD。由于CD4(+)CD25(+)细胞仅占全部CD4(+)细胞总数的5%~10%，因此大量新鲜供者的CD4(+)CD25(+)细胞的应用在临床上可能是不可行的。然而，我们发现通过体外激活和扩增可以获得大量的CD4(+)CD25(+)细胞。培养的CD4(+)CD25(+)细胞与CD4(+)T细胞或CD25缺失的全T细胞同等数量地注射，可显著抑制快速致死性nGVHD。据我们所知，这项研究是第一次证明激活的、培养的CD4(+)CD25(+)细胞可以在相关的体内动物疾病模型中提供实质性的保护。这些数据对临床骨髓和实体器官移植具有重要的指导意义。CD4(+)CD25(+)细胞值得考虑作为一种令人兴奋的新的细胞治疗方式，以抑制不良的自体和同种异体反应。(C)2002年，由美国血液病学会公布。
Immune regulatory CD4(+)CD25(+) cells play a vital role In the Induction and maintenance of self-tolerance and the prevention of autoimmunity. Recently, CD4 CD25(+) cells have been shown to be required for the ex vivo induction of tolerance to alloantigen via costimulatory blockade and to inhibit allogeneic skin graft rejection. Data presented here demonstrate that CD4(+)CD25(+) cells play an important role in graft-versus-host disease (GVHD) generation. Depletion of CN(+)CD25(+) cells from the donor T-cell inoculum or In vivo CD25-depletlon of the recipient before transplantation resulted in Increased GVHD mediated by CD4(+) or whole T cells in several strain combinations irrespective of the total body irradiation conditioning regime. The infusion of freshly purified donor CD4(+)CD25(+) cells modestly inhibited GVHD when administered in equal numbers with whole CD4(+) cells. Because CD4(+)CD25(+) cells only account for 5% to 10% of the total CD4(+) population, the administration of high numbers of fresh donor CD4(+)CD25(+) cells may not be clinically practical. However, we found that large numbers of CD4(+)CD25(+) cells can be obtained by ex vivo activation and expansion. Cultured CD4(+)CD25(+) cells, administered in equal numbers with CD4(+) T cells or CD25-depleted whole T cells, resulted in significant inhibition of rapidly lethal nGVHD. To our knowledge, this study is the first to demonstrate that activated, cultured CD4(+)CD25(+) cells can offer substantial protection in a relevant in vivo animal model of disease. These data have important ramifications for clinical bone marrow and solid organ transplantation. CD4(+)CD25(+) cells warrant consideration as an exciting new modality of cellular therapy for the inhibition of undesirable autologous and allogeneic responses. (C) 2002 by The American Society of Hematology.