He Shan, Cao Qi, Qiu Yuhua, Mi Jianqing, Zhang Jingwu Z, Jin Min, Ge Hailiang, Emerson Stephen G, Zhang Yi, Zhang Yanyun
Institute of Health Sciences and Shanghai Institute of Immunology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Immunol. 2008 Dec 1;181(11):7581-92. doi: 10.4049/jimmunol.181.11.7581.
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 CXCR3(+)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.
趋化因子和趋化因子受体在引导同种异体反应性供体T细胞迁移至移植物抗宿主病（GVHD）靶器官的过程中发挥着关键作用。然而，使用趋化因子受体拮抗剂抗体来阻断GVHD仍是一个难以实现的目标。利用人类GVHD小鼠模型，我们证明，体内给予抗CXCR3抗体21天（长期）而非7天（短期），可抑制同种异体反应性CD8(+) T细胞介导的GVHD。在移植物抗宿主反应过程中，输注的供体CD8(+) T细胞产生GVHD的两个强效诱导子集：CXCR3(+)CD8(+)和CXCR3(-)CD8(+) T细胞。与CXCR3(+)CD8(+) T细胞相比，CXCR3(-)CD8(+) T细胞产生的颗粒酶B、Fas配体、IFN-γ和TNF-α较少。有趣的是，用树突状细胞或IL-2刺激会诱导CXCR3(+)CD8(+)和CXCR3(-)CD8(+) T细胞之间的动态转化。短期抗CXCR3抗体治疗仅抑制CXCR3(+)CD8(+) T细胞介导的GVHD，而不抑制CXCR3(-)CD8(+) T细胞诱导的疾病。体内长期给予抗CXCR3抗体可显著减少同种异体反应性CD8(+) T细胞向GVHD靶器官的浸润，并抑制由CXCR3(+)CD8(+)或CXCR3(-)CD8(+) T细胞介导的GVHD。因此，我们建立了一种新的有效方法，有可能产生预防和治疗异基因造血干细胞移植后GVHD的新临床方法。
