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- Title
Blockade of Rat Chemokine Receptor CCR-1 by BX471 Reduces Acute Rejection and Is able to Reverse Chronic Allograft Nephropathy.
- Authors
Bedke, J.; Kiss, E.; Horuk, R.; Nelson, P. J.; Groene, H. J.
- Abstract
Objective: Chronic allograft nephropathy is a chronic inflammatory and fibrosing process. Recently it was shown that the blocking of CCR-1 might be useful in the therapy of kidney fibrosis. Methods: The effects of the CCR-1 antagonist BX471 (150 mg/kgBW/day) were studied in a Fischer 344 to Lewis renal transplantation model (n = 8 animals/group). In order to test whether BX471 can prevent acute rejection therapy was started on the day of transplantation and the animals sacrificed on day 10 and 21, respectively. To test the effects on chronic rejection, therapy was started on day 21 after transplantation, when chronic changes were already apparent in untreated animals, and the animals were sacrificed on day 42. Results: In all BX471 treated groups functional parameters (serum creatinine, proteinuria) were improved. Histological signs of acute rejection were slightly improved by day 10 and were significantly ameliorated by day 21: Acute glomerular rejection score: vehicle: 22.3 ± 0.75 vs. BX471: 7.3 ± 2.6 (p < 0.05); interstitial inlammation score: vehicle: 86.4 ± 10.6 vs. BX471: 57.0 ± 8.7 (p < 0.05). Signs of chronic rejection were significantly reduced by day 42: chronic tubulointerstitial damage score: Vehicle: 90% ± 3.0 vs. BX471: 12% ± 0.25 (p < 0.05). A significantly lower number of infiltrating cells (ED1, CD8) and proliferating (Ki67) mononuclear cells were observed in glomeruli and tubulointerstitium of all treated groups; mRNA expression (real-time RT-PCR) of hemoxygenase type 1, osteopontin and genes associated with fibrosis (PAI I; TGF-beta1) were downregulated in all treated groups. Conclusions: In experimental models of allograft rejection, CCR-1 blockade, led to a significant decrease of rejection phenomena. Acute rejection was inhibited and chronic allograft nephropathy was partially reserved. CCR-1 is an important signalling transducer in allograft rejection and could be a possible therapeutic option in transplantation medicine.
- Subjects
HOMOGRAFTS; KIDNEY diseases; KIDNEY transplantation; GRAFT rejection; MESSENGER RNA; GENE expression
- Publication
Kidney & Blood Pressure Research, 2004, Vol 27, Issue 5/6, p290
- ISSN
1420-4096
- Publication type
Article