Schröder Carsten, Pierson Richard N, Nguyen Bao-Ngoc H, Kawka Douglas W, Peterson Laurence B, Wu Guosheng, Zhang Tianshu, Springer Martin S, Siciliano Sal J, Iliff Susan, Ayala Julia M, Lu Min, Mudgett John S, Lyons Kathy, Mills Sander G, Miller Geraldine G, Singer Irwin I, Azimzadeh Agnes M, DeMartino Julie A
Division of Cardiac Surgery, Department of Surgery, University of Maryland and Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA.
J Immunol. 2007 Aug 15;179(4):2289-99. doi: 10.4049/jimmunol.179.4.2289.
Pharmacologic antagonism of CCR5, a chemokine receptor expressed on macrophages and activated T cells, is an effective antiviral therapy in patients with macrophage-tropic HIV infection, but its efficacy in modulating inflammation and immunity is only just beginning to be investigated. In this regard, the recruitment of CCR5-bearing cells into clinical allografts is a hallmark of acute rejection and may anticipate chronic rejection, whereas conventionally immunosuppressed renal transplant patients homozygous for a nonfunctional Delta32 CCR5 receptor rarely exhibit late graft loss. Therefore, we explored the effects of a potent, highly selective CCR5 antagonist, Merck's compound 167 (CMPD 167), in an established cynomolgus monkey cardiac allograft model. Although perioperative stress responses (fever, diminished activity) and the recruitment of CCR5-bearing leukocytes into the graft were markedly attenuated, anti-CCR5 monotherapy only marginally prolonged allograft survival. In contrast, relative to cyclosporine A monotherapy, CMPD 167 with cyclosporine A delayed alloantibody production, suppressed cardiac allograft vasculopathy, and tended to further prolong graft survival. CCR5 therefore represents an attractive therapeutic target for attenuating postsurgical stress responses and favorably modulating pathogenic alloimmunity in primates, including man.
CCR5是一种在巨噬细胞和活化T细胞上表达的趋化因子受体，对其进行药理拮抗是治疗巨噬细胞嗜性HIV感染患者的一种有效抗病毒疗法，但其在调节炎症和免疫方面的功效才刚刚开始得到研究。在这方面，携带CCR5的细胞向临床同种异体移植物中的募集是急性排斥反应的一个标志，并且可能预示着慢性排斥反应，而对于无功能的Delta32 CCR5受体纯合的传统免疫抑制肾移植患者很少出现晚期移植物丢失。因此，我们在已建立的食蟹猴心脏同种异体移植模型中探索了一种强效、高度选择性的CCR5拮抗剂，默克公司的化合物167（CMPD 167）的作用。虽然围手术期应激反应（发热、活动减少）以及携带CCR5的白细胞向移植物中的募集明显减弱，但抗CCR5单一疗法仅略微延长了同种异体移植物的存活时间。相比之下，相对于环孢素A单一疗法，CMPD 167与环孢素A联合使用可延迟同种异体抗体的产生，抑制心脏同种异体移植物血管病变，并倾向于进一步延长移植物存活时间。因此，CCR5是减轻术后应激反应并有利地调节包括人类在内的灵长类动物致病性同种免疫的一个有吸引力的治疗靶点。
