Bo Tang, Chenchen Qin, Huihui Liu, Shengchao Miao, Chao Xue, Zhenhua Wang, Yang Zhang, Yujun Dong, Wei Liu, Hanyun Ren
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引用次数: 0
摘要
背景:淋巴细胞通过趋化因子受体(如 CCR5 和 CXCR3)的迁移在 aGVHD 的发病机制中起着至关重要的作用。我们之前的研究表明,添加 CCR5 或 CXCR3 拮抗剂只能轻微缓解 aGVHD 的发展。鉴于携带 CXCR3 和 CXCR5 的 T 淋巴细胞的特异性,我们研究了联合阻断 CXCR5 和 CXCR3 是否能进一步减轻小鼠 aGVHD:方法:我们建立了小鼠 aGVHD 模型,以评估 CCR5 或/和 CXCR3 阻断对 aGVHD 发病的疗效。通过免疫染色细胞的定量计算淋巴细胞的分布。通过评估 T 细胞的增殖、活力和分化,评估对 T 细胞的免疫调节作用:结果:我们利用小鼠异体 HSCT 模型证明,阻断 CCR5 和 CXCR3 可有效缓解 aGVHD 的发生。对这种预防作用的免疫机制的进一步研究表明,更多的 T 细胞被阻滞在继发性淋巴器官(SLO)中,这可能会导致 T 细胞向 GVHD 靶器官的浸润减少。我们的研究还表明,滞留在SLO中的T细胞抑制了Th1和Tc1的活化,抑制了Th1和Tc1的极化,并诱导了Treg细胞的产生:这些数据表明,同时阻断 CCR5 和 CXCR3 可通过调节供体源性 T 细胞的分布和功能来减轻小鼠 aGVHD,这可能适用于临床环境中的 aGVHD 预防。
Blockade of CCR5 and CXCR3 attenuates murine acute graft-versus-host disease through modulating donor-derived T-cell distribution and function.
Lymphocyte trafficking via chemokine receptors such as C-C chemokine receptor 5 (CCR5) and CXCR3 plays a critical role in the pathogenesis of acute graft-versus-host disease (aGVHD). Our previous studies showed that the addition of CCR5 or CXCR3 antagonists could only slightly alleviate the development of aGVHD. Given the specificity of T lymphocytes bearing CXCR3 and CCR5, we investigated whether combined CCR5 and CXCR3 blockade could further attenuate murine aGVHD. A mouse model of aGVHD was established to assess the efficacy of CCR5 and/or CXCR3 blockade on the development of aGVHD. The distribution of lymphocytes was calculated by quantification of immunostaining cells. The immunomodulatory effect on T cells was assessed by evaluating T-cell proliferation, viability, and differentiation. Using the murine allogeneic hematopoietic stem cell transplantation model, we demonstrated that blockade of both CCR5 and CXCR3 could efficiently alleviate the development of aGVHD. Further investigation on the immune mechanisms for this prophylactic effect showed that more T cells were detained into secondary lymphoid organs (SLOs), which may lead to reduced infiltration of T cells into GVHD target organs. Our study also showed that T cells detained in SLOs dampened the activation, suppressed the polarization toward T helper type 1 (Th1) and T cytotoxic type 1 (Tc1) cells, and induced the production of Treg cells. These data suggest that concurrent blockade of CCR5 and CXCR3 attenuates murine aGVHD through modulating donor-derived T-cell distribution and function, and this might be applicable for aGVHD prophylaxis in clinical settings.
期刊介绍:
International Immunology is an online only (from Jan 2018) journal that publishes basic research and clinical studies from all areas of immunology and includes research conducted in laboratories throughout the world.