Beneficial effects of CCR1 blockade on the progression of chronic renal allograft damage.
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-beta1, biglycan) was downregulated at day 21; reduced collagen deposition was observed, parallel to a significant lower number of alpha-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.
Bedke
J
J
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Kiss
E
E
Schaefer
L
L
Behnes
C-L
CL
Bonrouhi
M
M
Gretz
N
N
Horuk
R
R
Diedrichs-Moehring
M
M
Wildner
G
G
Nelson
P J
PJ
Gröne
H J
HJ
D000818:Animals; D058578:Biglycan; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D006084:Graft Rejection / Q000188:drug therapy* / Q000473:pathology; D006085:Graft Survival; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000473:pathology; D016030:Kidney Transplantation; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D023421:Models, Animal; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D011509:Proteoglycans / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects
C546886:Bgn protein, rat; D058578:Biglycan; C515302:Ccr1 protein, rat; D016326:Extracellular Matrix Proteins; D010671:Phenylurea Compounds; D010880:Piperidines; D011509:Proteoglycans; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; C411885:BX 471