Beneficial Effects of CCR1 Blockade on the Progression of Chronic Renal Allograft Damage

• Published in: American journal of transplantation Vol. 7; no. 3; pp. 527 - 537
• Main Authors: Bedke, J., Kiss, E., Schaefer, L., Behnes, C.‐L., Bonrouhi, M., Gretz, N., Horuk, R., Diedrichs‐Moehring, M., Wildner, G., Nelson, P. J., Gröne, H.J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-03-2007; Blackwell
• Subjects: Animals; Biglycan; Biological and medical sciences; BX 471; CCR1; chemokines; chronic allograft nephropathy; Disease Progression; Extracellular Matrix Proteins - antagonists & inhibitors; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Fibrosis; Graft Rejection - drug therapy; Graft Rejection - pathology; Graft Survival; Kidney Failure, Chronic - drug therapy; Kidney Failure, Chronic - pathology; Kidney Transplantation; Lymphocyte Activation - drug effects; Macrophages - drug effects; Macrophages - immunology; Medical sciences; Models, Animal; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Phenylurea Compounds - pharmacology; Phenylurea Compounds - therapeutic use; Piperidines - pharmacology; Piperidines - therapeutic use; Proteoglycans - antagonists & inhibitors; Proteoglycans - genetics; Proteoglycans - metabolism; Rats; Receptors, CCR1; Receptors, Chemokine - antagonists & inhibitors; Renal failure; RNA, Messenger - analysis; RNA, Messenger - metabolism; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; T-Lymphocytes - drug effects; Proteoglycan; Prognosis; BX 471; chronic allograft nephropathy; Homograft; Transplantation; Chemokine receptor; CC chemokine; Homotransplantation; Surgery; Graft; Evolution; Damage; Kidney disease; CCR1; Urinary system disease; Biglycan; chemokines; CCR1 chemokine receptor; Rejection; Chronic; Nephropathy; Treatment; Renal failure; Lesion
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2006.01654.x

The biology of chemokines and their receptors have been linked to the development of chronic allograft damage. Effects of CCR1 antagonist BX 471 were studied in a Fischer to Lewis renal transplantation model at days 10, 21 and 42 after transplantation. BX 471 treatment did not effectively reduce signs of acute rejection at day 10 but significantly improved allograft function and morphology at day 21 posttransplantation. When therapy was initiated on day 21 after transplantation, glomerulosclerosis and tubulointerstitial fibrosis were significantly inhibited by day 42 posttransplantation. Parallel decrease in infiltrating and proliferating mononuclear cells (ED1, CD8 and Ki67) was observed in treated allografts. Expression of acute phase reactive and proinflammatory genes (HO‐1, osteopontin) and molecules associated with fibrosis (PAI‐1, TGF‐β1, biglycan) was downregulated at day 21; reduced collagen deposition was observed, parallel to a significant lower number of α‐SMA+ interstitial myofibroblasts. In situ hybridization demonstrated that biglycan expression was reduced following CCR1 blockade in interstitium of treated allografts. CCR1 antagonism was found to inhibit CCL5‐induced secretion of biglycan by macrophages in vitro. CCR1 blockade significantly inhibited development and progression of chronic allograft damage. CCR1 antagonists may represent a therapeutic option for chronic inflammation and fibrosis in renal grafts.
Blockade of the chemokine receptor CCR1 leads to a significant reduction of glomerulosclerosis and allograft fibrosis in rat renal allografts associated with a decrease of leukocyte infiltration of the graft and a direct inhibition of matrix synthesis.