CCR5 Blockade in Combination with Cyclosporine Increased Cardiac Graft Survival and Generated Alternatively Activated Macrophages in Primates
CCR5 Blockade in Combination with Cyclosporine Increased Cardiac Graft Survival and Generated Alternatively Activated Macrophages in Primates
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CCR5 阻断与环孢素联合使用可增加灵长类动物心脏移植物的存活率并产生替代性激活的巨噬细胞
DOI：
10.4049/jimmunol.1002143
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发表时间：
2011-03-15
影响因子：
4.4
通讯作者：
Xia, Jiahong
中科院分区：
文献类型：
--
作者：
Li, Jun;Chen, Gang;Xia, Jiahong
Maraviroc（MVC）是一种在巨噬细胞和活化T细胞上表达的CCR 5的特异性拮抗剂，可调节炎症，并可用于HIV感染患者。在这项研究中，我们使用非人灵长类动物来研究MVC单独或与环孢素（CsA）联合使用延长心脏移植物存活的效果和机制。在已建立的恒河猴心脏移植模型中，用MVC加CsA治疗的受体心脏移植物存活时间显著延长（>240天，p < 0.001）。与其他组相比，MVC/CsA组的这些体内结果与延迟的同种抗体反应和CCR 5+、CD 4+、CD 8+和CD 68+细胞的移植物浸润显著减少相关（p < 0.05）。此外，MVC/CsA组移植物中交替激活的巨噬细胞（AAMs）数量增加，过氧化物酶体增殖物激活受体γ（PPARγ）表达增加。阻断PPARγ后，移植物存活时间延长（中位存活时间为45 d），AAM表达上调。总之，MVC/CsA保护灵长类动物的心脏同种异体移植物，这种作用与通过激活PPARγ核受体产生AAM有关。
Maraviroc (MVC), a specific antagonist of CCR5 expressed on macrophages and activated T cells, may modulate inflammation and may be useful in patients with HIV infection. In this study we used nonhuman primates to examine the effect and mechanism of MVC alone or in combination with cyclosporine (CsA) to prolong cardiac allograft survivals. In an established rhesus monkey cardiac allograft model, recipients treated with MVC plus CsA showed significantly prolonged survival of heart allografts (>240 d, p < 0.001). These in vivo results in the MVC/CsA group correlated with delayed alloantibody response and markedly decreased graft infiltration by CCR5+, CD4+, CD8+, and CD68+ cells (p < 0.05), as compared with other groups. Furthermore, grafts from the MVC/CsA group had elevated numbers of alternatively activated macrophages (AAMs) and the expression of peroxisome proliferator-activated receptor γ (PPARγ). Blockade of PPARγ abrogated the prolonged allograft survival (median survival time, 45 d) and the upregulated AAMs in MVC/CsA-treated recipients. In conclusion, MVC/CsA protects cardiac allograft in primates and this effect is associated with generating AAMs through activation of the PPARγ nuclear receptor.