A New Approach to the Blocking of Alloreactive T Cell-Mediated Graft-versus-Host Disease by In Vivo Administration of Anti-CXCR3 Neutralizing Antibody
A New Approach to the Blocking of Alloreactive T Cell-Mediated Graft-versus-Host Disease by In Vivo Administration of Anti-CXCR3 Neutralizing Antibody
复制标题
通过体内施用抗 CXCR3 中和抗体阻断同种异体反应性 T 细胞介导的移植物抗宿主病的新方法
DOI：
10.4049/jimmunol.181.11.7581
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发表时间：
2008-12-01
影响因子：
4.4
通讯作者：
Zhang, Yanyun
中科院分区：
文献类型：
--
作者：
He, Shan;Cao, Qi;Zhang, Yanyun
趋化因子和趋化因子受体在引导同种异体反应性供体T细胞迁移到移植物抗宿主病（GVHD）靶器官中起关键作用。然而，通过针对趋化因子受体的拮抗剂Ab阻断GVHD仍然是一个难以实现的目标。使用人类GVHD小鼠模型，我们证明了体内给予抗CXCR 3抗体21天（长期），但不能持续7天（短期），抑制同种异体反应性CD 8（+）T细胞介导的GVHD。在移植物抗宿主反应期间，输注的供体CD 8（+）T细胞产生两种GVHD的有效诱导剂亚群：CXCR 3（+）CD 8（+）和CXCR 3（-）CD 8（+）T细胞。与CXCR（3+）CD 8（+）T细胞相比，CXCR 3（-）CD 8（+）T细胞产生较少的颗粒酶B、Fas配体、IFN-γ和TNF-α。有趣的是，用树突状细胞或IL-2刺激诱导CXCR 3（+）CD 8（+）和CXCR 3（-）CD 8（+）T细胞之间的动态转化。短期抗CXCR 3抗体治疗仅抑制CXCR 3（+）CD 8（+）T细胞介导的GVHD，但不抑制由CXCR 3（-）CD 8（+）T细胞诱导的疾病。抗CXCR 3 Ab的延长体内施用显著减少同种异体反应性CD 8 + T细胞向GVHD靶器官中的浸润，并抑制由CXCR 3（+）CD 8（+）或CXCR 3（-）CD 8（+）T细胞介导的GVHD。因此，我们已经建立了一种新的和有效的方法，有可能引起新的临床方法，用于预防和治疗异基因造血干细胞移植后GVHD。免疫学杂志，2008，181：7581-7592.
Chemokines and chemokine receptors play critical roles in directing the migration of alloreactive donor T cells into graft-vs-host disease (GVHD) target organs. However, blockade of GVHD by antagonist Ab against chemokine receptors remains an elusive goal. Using a mouse model of human GVHD, we demonstrate that in vivo administration of anti-CXCR3 Ab for 21 days (long-term), but not for 7 days (short-term), inhibits alloreactive CD8(+) T cell-mediated GVHD. During a graft-vs-host reaction, infused donor CD8(+)T cells generate two subsets of potent inducers of GVHD: CXCR3(+)CD8(+) and CXCR3(-)CD8(+) T cells. Compared with CXCR(3+)CD8(+) T cells, CXCR3(-)CD8(+) T cells produce less granzyme B, Fas ligand, IFN-gamma, and TNF-alpha. Interestingly, stimulation with either dendritic cells or IL-2 induces a dynamic conversion between CXCR3(+)CD8(+) and CXCR3(-)CD8(+) T cells. Short-term anti-CXCR3 Ab treatment inhibits only CXCR3(+)CD8(+) T cell-mediated GVHD, but not the disease induced by CXCR3(-)CD8(+) T cells. Prolonged in vivo administration of anti-CXCR3 Ab significantly reduces the infiltration of alloreactive CD8+ T cells into GVHD target organs and inhibits GVHD mediated by either CXCR3(+)CD8(+) or CXCR3(-)CD8(+) T cells. Thus, we have established a novel and effective approach with the potential to give rise to new clinical methods for preventing and treating GVHD after allogeneic hematopoietic stem cell transplantation. The Journal of Immunology, 2008, 181: 7581-7592.