Miura M, Morita K, Kobayashi H, Hamilton T A, Burdick M D, Strieter R M, Fairchild R L
Urological Institute and Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
J Immunol. 2001 Sep 15;167(6):3494-504. doi: 10.4049/jimmunol.167.6.3494.
The use of chemokine antagonism as a strategy to inhibit leukocyte trafficking into inflammatory sites requires identification of the dominant chemokines mediating recruitment. The chemokine(s) directing T cells into cardiac allografts during acute rejection remain(s) unidentified. The role of the CXC chemokines IFN-gamma inducible protein 10 (IP-10) and monokine induced by IFN-gamma (Mig) in acute rejection of A/J (H-2(a)) cardiac grafts by C57BL/6 (H-2(b)) recipients was tested. Intra-allograft expression of Mig was observed at day 2 posttransplant and increased to the time of rejection at day 7 posttransplant. IP-10 mRNA and protein production were 2.5- to 8-fold lower than Mig. Whereas allografts were rejected at day 7-9 in control recipients, treatment with rabbit antiserum to Mig, but not to IP-10, prolonged allograft survival up to day 19 posttransplant. At day 7 posttransplant, allografts from Mig antiserum-treated recipients had marked reduction in T cell infiltration. At the time of rejection in Mig antiserum-treated recipients (i.e., days 17-19), intra-allograft expression of macrophage-inflammatory protein-1alpha, -1beta, and their ligand CCR5 was high, whereas expression of CXCR3, the Mig receptor, was virtually absent. Mig was produced by the allograft endothelium as well as by recipient allograft-infiltrating macrophages and neutrophils, indicating the synergistic interactions between innate and adaptive immune compartments during acute rejection. Collectively, these results indicate that Mig is a dominant recruiting factor for alloantigen-primed T cells into cardiac allografts during acute rejection. Although Mig antagonism delays acute heart allograft rejection, the results also suggest that the alloimmune response circumvents Mig antagonism through alternative mechanisms.
使用趋化因子拮抗作用作为抑制白细胞迁移至炎症部位的策略，需要确定介导募集的主要趋化因子。在急性排斥反应期间，将T细胞导向心脏同种异体移植物的趋化因子仍未明确。我们测试了CXC趋化因子γ干扰素诱导蛋白10（IP-10）和γ干扰素诱导的单核因子（Mig）在C57BL/6（H-2(b)）受体对A/J（H-2(a)）心脏移植物急性排斥反应中的作用。在移植后第2天观察到移植物内Mig的表达，至移植后第7天排斥反应发生时其表达增加。IP-10的mRNA和蛋白产量比Mig低2.5至8倍。在对照受体中，同种异体移植物在第7 - 9天被排斥，而用兔抗Mig抗血清而非抗IP-10抗血清治疗可将同种异体移植物存活期延长至移植后第19天。在移植后第7天，来自Mig抗血清治疗受体的同种异体移植物中T细胞浸润明显减少。在Mig抗血清治疗受体发生排斥反应时（即第17 - 19天），移植物内巨噬细胞炎性蛋白-1α、-1β及其配体CCR5的表达较高，而Mig受体CXCR3的表达几乎缺失。Mig由同种异体移植物内皮细胞以及受体同种异体移植物浸润的巨噬细胞和中性粒细胞产生，表明在急性排斥反应期间固有免疫和适应性免疫区室之间存在协同相互作用。总体而言，这些结果表明Mig是急性排斥反应期间同种抗原致敏T细胞进入心脏同种异体移植物的主要募集因子。虽然Mig拮抗作用可延迟急性心脏同种异体移植排斥反应，但结果也表明同种免疫反应通过其他机制规避了Mig拮抗作用。
