HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival
HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival
复制标题
HL A-G二聚体靶向颗粒酶B途径延长人移植肾存活
DOI：
10.1096/fj.201802017r
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发表时间：
2019-04-01
期刊：
影响因子：
4.8
通讯作者：
Horuzsko, Anatolij
中科院分区：
文献类型：
--
作者：
Ajith, Ashwin;Portik-Dobos, Vera;Horuzsko, Anatolij
人类白细胞抗原G（HLA-G），一个非经典的HLA Ib类分子参与维持母亲的耐受性半同种异体胎儿组织在怀孕期间，已成为一个潜在的治疗目标，以控制同种异体移植排斥反应。我们在这里证明，可溶性HLA-G二聚体的水平较高，在一组90例肾移植功能正常的患者相比，40例排斥（RJ）他们的移植。HLA-G二聚体水平不受人口统计学状况的影响。组织-器官移植排斥反应的潜在机制之一涉及颗粒酶和穿孔素的诱导，它们是由CD 8（+）细胞毒性T淋巴细胞表达的主要效应分子，并具有破坏同种异体移植物的功能。通过对T细胞介导的RJ和非排斥肾移植患者的细胞、白细胞Ig样受体B1（LILRB 1）转基因小鼠、人源化小鼠和基因工程HLA-G二聚体的细胞进行基因组学和分子及细胞分析，我们证明了HLA-G二聚体抑制人CD 8（+）T细胞活化和细胞毒性能力的新机制。这一机制涉及颗粒酶B表达的下调和LILRB 1的重要参与。因此，HLA-G二聚体有可能成为一种特异性和有效的治疗方法，用于预防同种异体移植排斥反应和延长移植物存活。
Human leukocyte antigen G (HLA-G), a nonclassic HLA class Ib molecule involved in the maintenance of maternal tolerance to semiallogeneic fetal tissues during pregnancy, has emerged as a potential therapeutic target to control allograft rejection. We demonstrate here that the level of soluble HLA-G dimer was higher in a group of 90 patients with a functioning renal allograft compared with 40 patients who rejected (RJ) their transplants. The HLA-G dimer level was not affected by demographic status. One of the potential mechanisms in tissue-organ allograft rejection involves the induction of granzymes and perforin, which are the main effector molecules expressed by CD8(+) cytotoxic T lymphocytes and function to destroy allogeneic transplants. Using genomics and molecular and cellular analyses of cells from T-cell-mediated RJ and nonrejected kidney transplant patients, cells from leukocyte Ig-like receptor B1 (LILRB1) transgenic mice, humanized mice, and genetically engineered HLA-G dimer, we demonstrated a novel mechanism by which HLA-G dimer inhibits activation and cytotoxic capabilities of human CD8(+) T cells. This mechanism implicated the down-regulation of Granzyme B expression and the essential involvement of LILRB1. Thus, HLA-G dimer has the potential to be a specific and effective therapy for prevention of allograft rejection and prolongation of graft survival.