Donor-derived, tolerogenic dendritic cells suppress immune rejection in the indirect allosensitization-dominant setting of corneal transplantation
Donor-derived, tolerogenic dendritic cells suppress immune rejection in the indirect allosensitization-dominant setting of corneal transplantation
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DOI：
10.1189/jlb.1011500
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发表时间：
2012-04-01
影响因子：
5.5
通讯作者：
Dana, Reza
中科院分区：
文献类型：
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作者：
Hattori, Takaaki;Saban, Daniel R.;Dana, Reza
人们的兴趣主要集中在使用体外操纵的DC来最佳地诱导移植耐受和促进同种异体移植物的存活。据了解，供体来源的致耐受树突状细胞抑制同种异体致敏的直接途径，但这种树突状细胞是否也能类似地抑制间接途径仍不清楚。因此，我们使用小鼠角膜移植模型来解决这个问题，因为这些同种异体移植是以间接途径占优势的方式被排斥的。有趣的是，接受供者骨髓来源的DCregs的受者，通过GM-CSF、IL-10和转化生长因子-β1培养产生的DCregs，显著延长了角膜移植物的存活时间。相应地，根据ELISPOT的测定，这些受者表现出了间接同种异体致敏T细胞频率的有效降低。相对于MDCs或IDC的DCregs检测显示，对MHC-II和共刺激分子的上调具有抵抗力，并且刺激MLRs的能力受损。在体内，在角膜移植受者中应用DCreg导致抑制CD4(+)干扰素-伽马(+)T细胞频率和相关的Treg小室中Foxp3表达的增加。我们的结论是，供者来源的、具有耐受性的DC显著抑制了间接途径，从而确定了这些细胞在移植中的一种新的调节机制。J.Leukoc。比奥尔。2012年：91：621-627。
Significant interest has been focused on the use of ex vivo-manipulated DCs to optimally induce transplant tolerance and promote allograft survival. Although it is understood that donor-derived, tolerogenic DCs suppress the direct pathway of allosensitization, whether such DCs can similarly suppress the indirect pathway remains unclear. We therefore used the murine model of corneal transplantation to address this, as these allografts are rejected in an indirect pathway-dominant manner. Interestingly, recipients administered with donor bone marrow-derived DCregs, generated via culturing with GM-CSF, IL-10, and TGF-beta 1, significantly prolonged survival of corneal allografts. Correspondingly, these recipients demonstrated a potent reduction in the frequency of indirectly allosensitized T cells, as determined by ELISPOT. Examination of DCregs relative to mDCs or iDCs showed a resistance to up-regulation of MHC-II and costimulatory molecules, as well as an impaired capacity to stimulate MLRs. In vivo, DCreg administration in corneal-allografted recipients led to inhibition of CD4(+)IFN-gamma(+) T cell frequencies and an associated increase in Foxp3 expression in the Treg compartment. We conclude that donor-derived, tolerogenic DCs significantly suppress the indirect pathway, thereby identifying a novel regulatory mechanism for these cells in transplantation. J. Leukoc. Biol. 91: 621-627; 2012.