Targeting the CXCR4-CXCL12 axis mobilizes autologous hematopoietic stem cells and prolongs islet allograft survival via programmed death ligand 1.
Targeting the CXCR4-CXCL12 axis mobilizes autologous hematopoietic stem cells and prolongs islet allograft survival via programmed death ligand 1.
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DOI：
10.4049/jimmunol.1000799
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发表时间：
2011-01-01
期刊：
影响因子：
--
通讯作者：
Abdi R
中科院分区：
文献类型：
--
作者：
Fiorina P;Jurewicz M;Vergani A;Petrelli A;Carvello M;D'Addio F;Godwin JG;Law K;Wu E;Tian Z;Thoma G;Kovarik J;La Rosa S;Capella C;Rodig S;Zerwes HG;Sayegh MH;Abdi R
CXCR 4的拮抗作用破坏了HSC上的CXCR 4受体与骨髓中基质细胞表达的CXCL 12之间的相互作用，随后导致造血干细胞（HSC）脱落至外周。由于其深刻的免疫调节作用，造血干细胞已成为一个有前途的治疗策略，自身免疫性疾病。我们试图研究动员的自体HSC的免疫调节作用，通过靶向CXCR 4-CXL 12轴，以促进胰岛细胞移植的植入。将来自BALB/c小鼠的胰岛移植到高血糖C57 BL/6小鼠的肾包膜下，用CXCR 4拮抗剂治疗受体导致HSC动员和胰岛移植物存活延长。在抗CXCR 4治疗中加入雷帕霉素进一步促进了HSC动员和胰岛移植物存活，诱导了强大的和可转移的宿主低反应性，而给予ACK 2（抗CD 117）mAb则阻止了CXCR 4拮抗剂介导的HSC释放并恢复了移植物排斥反应。动员的HSC显示表达高水平的负共刺激分子PD-L1，并且从WT小鼠提取的HSC（而不是从PD-L1 KO提取的HSC）抑制体外同种免疫应答。此外，PD-L1 KO小鼠中的HSC动员未能延长胰岛移植物存活。因此，靶向CXCR 4-CXCL 12轴可以动员自体HSC，并通过PD-L1介导的机制促进胰岛同种异体移植物的长期存活。
Antagonism of CXCR4 disrupts the interaction between the CXCR4 receptor on HSCs and the CXCL12 expressed by stromal cells in the bone marrow, which subsequently results in the shedding of hematopoietic stem cells (HSCs) to the periphery. Due to their profound immunomodulatory effects, HSCs have emerged as a promising therapeutic strategy for autoimmune disorders. We sought to investigate the immunomodulatory role of mobilized autologous HSCs, via target of the CXCR4-CXL12 axis, to promote engraftment of islet cell transplantation. Islets from BALB/c mice were transplanted beneath the kidney capsule of hyperglycemic C57BL/6 mice, and treatment of recipients with CXCR4 antagonist resulted in mobilization of HSCs and in prolongation of islet graft survival. Addition of Rapamycin to anti-CXCR4 therapy further promoted HSC mobilization and islet allograft survival, inducing a robust and transferable host hyporesponsiveness, while administration of an ACK2 (anti-CD117) mAb halted CXCR4 antagonist-mediated HSC release and restored allograft rejection. Mobilized HSCs were shown to express high levels of the negative co-stimulatory molecule PD-L1, and HSCs extracted from WT mice, but not from PD-L1 KO, suppressed the in vitro alloimmune response. Moreover, HSC mobilization in PD-L1 KO mice failed to prolong islet allograft survival. Targeting the CXCR4-CXCL12 axis thus mobilizes autologous HSCs and promotes long-term survival of islet allografts via a PD-L1-mediated mechanism.
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影响因子：
2.4
作者：
Flomenberg, N;DiPersio, J;Calandra, G
通讯作者：
Calandra, G
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影响因子：
7.7
作者：
Fiorina, Paolo;Jurewicz, Mollie;Abdi, Reza
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影响因子：
7.7
作者：
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Sayegh, MH
影响因子：
20.3
作者：
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