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Blocking of CCR5 and CXCR3 suppresses the infiltration of macrophages in acute renal allograft rejection.
- Source :
-
Transplantation [Transplantation] 2012 Jan 15; Vol. 93 (1), pp. 24-31. - Publication Year :
- 2012
-
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.<br />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.<br />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.<br />Conclusion: 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.
- Subjects :
- Amides pharmacology
Animals
Chemokines metabolism
Cyclosporine therapeutic use
Cytokines metabolism
Graft Rejection prevention & control
Graft Survival drug effects
Immunosuppressive Agents therapeutic use
Kidney Transplantation immunology
Male
Models, Animal
Quaternary Ammonium Compounds pharmacology
Rats
Rats, Inbred Lew
Rats, Inbred Strains
Receptors, CCR5 drug effects
Receptors, CCR5 physiology
Receptors, CXCR3 drug effects
Receptors, CXCR3 physiology
Transplantation, Homologous
CCR5 Receptor Antagonists
Cell Movement physiology
Graft Rejection pathology
Graft Rejection physiopathology
Kidney Transplantation pathology
Macrophages physiology
Receptors, CXCR3 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1534-6080
- Volume :
- 93
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Transplantation
- Publication Type :
- Academic Journal
- Accession number :
- 22124337
- Full Text :
- https://doi.org/10.1097/TP.0b013e31823aa585