title: CCR5 blockade in combination with cyclosporine increased cardiac graft survival and generated alternatively activated macrophages in primates.
abstract: 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.
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Ping
authors.initials: P
authors.lastname: Ye
authors.forename: Sihua
authors.initials: S
authors.lastname: Wang
authors.forename: Kailun
authors.initials: K
authors.lastname: Zhang
authors.forename: Wenhao
authors.initials: W
authors.lastname: Chen
authors.forename: Stanislaw M
authors.initials: SM
authors.lastname: Stepkowski
authors.forename: Junhua
authors.initials: J
authors.lastname: Li
authors.forename: Shan
authors.initials: S
authors.lastname: Zhong
authors.forename: Jiahong
authors.initials: J
authors.lastname: Xia
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000276:immunology; D065100:CCR5 Receptor Antagonists; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003510:Cyclohexanes / Q000627:therapeutic use*; D016572:Cyclosporine / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008253:Macaca mulatta; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D000077592:Maraviroc; D047495:PPAR gamma / Q000096:biosynthesis / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D019713:Receptors, CCR5 / Q000502:physiology; D014230:Triazoles / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D047495:PPAR gamma; D019713:Receptors, CCR5; D014230:Triazoles; D016572:Cyclosporine; D000077592:Maraviroc