Kwun J, Hazinedaroglu S M, Schadde E, Kayaoglu H A, Fechner J, Hu H Z, Roenneburg D, Torrealba J, Shiao L, Hong X, Peng R, Szewczyk J W, Sullivan K A, DeMartino J, Knechtle S J
Division of Transplantation, Department of Surgery, University of Wisconsin-Madison, Madison, WI, USA.
Am J Transplant. 2008 Aug;8(8):1593-603. doi: 10.1111/j.1600-6143.2008.02250.x. Epub 2008 May 12.
Previous studies showed that absence of chemokine receptor Cxcr3 or its blockade prolong mouse cardiac allograft survival. We evaluated the effect of the CXCR3 receptor antagonist MRL-957 on cardiac allograft survival, and also examined the impact of anti-CXCR3 mAb in human CXCR3 knock-in mice. We found only a moderate increase in graft survival (10.5 and 16.6 days, p < 0.05) using either the antagonist or the antibody, respectively, compared to control (8.7 days). We re-evaluated cardiac allograft survival with two different lines of Cxcr3(-/-) mice. Interestingly, in our hands, neither of the independently derived Cxcr3(-/-) lines showed remarkable prolongation, with mean graft survival of 9.5 and 10.8 days, respectively. There was no difference in the number of infiltrating mononuclear cells, expansion of splenic T cells or IFN-gamma production of alloreactive T cells. Mechanistically, an increased other chemokine receptor fraction in the graft infiltrating CD8 T cells in Cxcr3(-/-) recipients compared to wild-type recipients suggested compensatory T-cell trafficking in the absence of Cxcr3. We conclude Cxcr3 may contribute to, but does not govern, leukocyte trafficking in this transplant model.
先前的研究表明，趋化因子受体Cxcr3缺失或其功能被阻断可延长小鼠心脏移植的存活时间。我们评估了CXCR3受体拮抗剂MRL-957对心脏移植存活时间的影响，并检测了抗CXCR3单克隆抗体对人CXCR3基因敲入小鼠的影响。我们发现，与对照组（8.7天）相比，使用拮抗剂或抗体时移植物存活时间仅适度增加（分别为10.5天和16.6天，p<0.05）。我们用两种不同品系的Cxcr3(-/-)小鼠重新评估了心脏移植的存活时间。有趣的是，在我们的实验中，两个独立获得的Cxcr3(-/-)品系均未显示出明显的延长，平均移植物存活时间分别为9.5天和10.8天。浸润的单核细胞数量、脾脏T细胞扩增或同种反应性T细胞产生的IFN-γ均无差异。从机制上讲，与野生型受体相比，Cxcr3(-/-)受体的移植物浸润CD8 T细胞中其他趋化因子受体比例增加，提示在缺乏Cxcr3的情况下存在代偿性T细胞迁移。我们得出结论，在这个移植模型中，Cxcr3可能有助于白细胞迁移，但并非其决定性因素。
