Yun James J, Whiting David, Fischbein Michael P, Banerji Anamika, Irie Yoshihito, Stein Daniel, Fishbein Michael C, Proudfoot Amanda E I, Laks Hillel, Berliner Judith A, Ardehali Abbas
Department of Surgery, Division of Cardiothoracic Surgery, University of California at Los Angeles, Los Angeles, Calif, USA.
Circulation. 2004 Feb 24;109(7):932-7. doi: 10.1161/01.CIR.0000112595.65972.8A. Epub 2004 Feb 2.
Chemokine-chemokine receptor interaction and the subsequent recruitment of T-lymphocytes to the graft are early events in the development of chronic rejection of transplanted hearts or cardiac allograft vasculopathy (CAV). In this study, we sought to determine whether blockade of chemokine receptors CCR1 and CCR5 with Met-RANTES affects the development of CAV in a murine model.
B6.CH-2(bm12) strain donor hearts were transplanted heterotopically into wild-type C57BL/6 mice (myosin heavy chain II mismatch). Recipients were treated daily with either Met-RANTES or vehicle starting on postoperative day 4 and were euthanized on postoperative days 24 and 56. We found that Met-RANTES significantly reduced intimal thickening in this model of chronic rejection and that Met-RANTES markedly decreased the infiltration of CD4 and CD8 T lymphocytes and MOMA-2+ monocytes/macrophages into transplanted hearts. Met-RANTES also suppressed the ex vivo and in vitro proliferative responses of recipient splenocytes to donor antigens. Finally, Met-RANTES treatment was associated with a marked reduction in RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels in the donor hearts.
Antagonism of the chemokine receptors CCR1 and CCR5 with Met-RANTES attenuates CAV development in vivo by reducing mononuclear cell recruitment to the transplanted heart, proliferative responses to donor antigens, and intragraft RANTES/CCL5 and monocyte chemoattractant protein-1 gene transcript levels. These findings suggest that chemokine receptors CCR1 and CCR5 play significant roles in the development of chronic rejection and may serve as potential therapeutic targets.
趋化因子 - 趋化因子受体相互作用以及随后T淋巴细胞向移植物的募集是移植心脏慢性排斥反应或心脏同种异体移植血管病变（CAV）发展过程中的早期事件。在本研究中，我们试图确定用Met-RANTES阻断趋化因子受体CCR1和CCR5是否会影响小鼠模型中CAV的发展。
将B6.CH-2(bm12)品系供体心脏异位移植到野生型C57BL/6小鼠体内（肌球蛋白重链II不匹配）。从术后第4天开始，接受者每天接受Met-RANTES或赋形剂治疗，并在术后第24天和第56天实施安乐死。我们发现，在这个慢性排斥反应模型中，Met-RANTES显著减少了内膜增厚，并且Met-RANTES明显减少了CD4和CD8 T淋巴细胞以及MOMA-2 +单核细胞/巨噬细胞向移植心脏的浸润。Met-RANTES还抑制了受体脾细胞对供体抗原的体外和体内增殖反应。最后，Met-RANTES治疗与供体心脏中RANTES/CCL5和单核细胞趋化蛋白-1基因转录水平的显著降低有关。
用Met-RANTES拮抗趋化因子受体CCR1和CCR5可通过减少单核细胞向移植心脏的募集、对供体抗原的增殖反应以及移植物内RANTES/CCL5和单核细胞趋化蛋白-1基因转录水平来减轻体内CAV的发展。这些发现表明趋化因子受体CCR1和CCR5在慢性排斥反应的发展中起重要作用，并可能成为潜在的治疗靶点。
