title: Blocking of CCR5 and CXCR3 suppresses the infiltration of macrophages in acute renal allograft rejection.
abstract: BACKGROUND
  The chemokine receptors CCR5 and CXCR3 are expressed by T cells and macrophages. We examined effects of a CCR5/CXCR3 antagonist (TAK), with a particular focus on the role of macrophages, in a rat kidney transplant model.
  
  
  METHODS
  Dark Agouti rat kidneys were transplanted into Lewis rats. The recipients were treated daily with a 10 mg/kg TAK on posttransplant days 0 to 14 and/or 2 mg/kg of cyclosporine A (CsA) on days 0 to 5. Graft survival, histological changes, and the expression of chemokines and chemokine receptors on T cells and macrophages were studied.
  
  
  RESULTS
  Treatment with TAK alone suppressed CD4+T cell infiltration and slightly prolonged graft survival. The expressions of both CCR5 and CXCR3, and activated macrophage-associated cytokines and chemokines, were significantly increased on macrophages that had been separated from rejecting kidneys, compared with those from spleens. However, these upregulations were decreased in macrophages from kidneys that had been treated with TAK. Immunohistochemistry also showed that macrophages infiltrating tubules of rejecting kidney expressed both receptors. In the CsA alone group, macrophages were the dominant infiltrating cells, and all allografts were rejected within 10 days. A combined therapy involving CsA and TAK resulted in decreased macrophage infiltration, and graft survival was substantially prolonged. The levels of activated macrophage-associated cytokines and chemokines were also decreased.
  
  
  CONCLUSIONS
  The dual blocking of CCR5/CXCR3 can be useful in decreasing rejection, with or without CsA. This mechanism acts, not only to block T-cell recruitment to a kidney graft but to suppress the infiltration of macrophages as well.
authors: Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors: Yoichi
authors: Y
authors: Kakuta
authors: Masayoshi
authors: M
authors: Okumi
authors: Shuji
authors: S
authors: Miyagawa
authors: Koichi
authors: K
authors: Tsutahara
authors: Toyofumi
authors: T
authors: Abe
authors: Koji
authors: K
authors: Yazawa
authors: Katsuyoshi
authors: K
authors: Matsunami
authors: Hideaki
authors: H
authors: Otsuka
authors: Shiro
authors: S
authors: Takahara
authors: Norio
authors: N
authors: Nonomura
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D065100:CCR5 Receptor Antagonists; D002465:Cell Movement / Q000502:physiology*; D018925:Chemokines / Q000378:metabolism; D016572:Cyclosporine / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D006084:Graft Rejection / Q000473:pathology* / Q000503:physiopathology* / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000502:physiology*; D008297:Male; D023421:Models, Animal; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D019713:Receptors, CCR5 / Q000187:drug effects / Q000502:physiology; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D014184:Transplantation, Homologous
chemical_list: D000577:Amides; D065100:CCR5 Receptor Antagonists; D018925:Chemokines; C515189:Cxcr3 protein, rat; D016207:Cytokines; D007166:Immunosuppressive Agents; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D016572:Cyclosporine; C119369:TAK 779