Beneficial effects of CCR1 blockade on the progression of chronic allograft nephropathy

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1 Beneficial effects of CCR1 blockade on the progression of chronic allograft nephropathy J. Bedke 1,2, E. Kiss 2, L. Schaefer 3, M. Bonrouhi 2, N. Gretz 4, H.-J. Gröne 2 1 Klinik für Urologie, Universität Heidelberg 2 Abteilung für Zelluläre und Molekulare Pathologie, DKFZ, Heidelberg 3 Institut für Pharmakologie, Universität Frankfurt 4 Zentrum für Medizinische Forschung, Klinikum Mannheim

2 Background Chronic renal allograft (CAN) damage is characterized by persistent activity of interstitial monocytes / macrophages, T-cells and myofibroblasts with subsequent accumulation and deposition of matrix proteins Chemokines and their receptors are linked to the development of CAN The β-chemokine receptor CCR1: expressed on macrophages and T-cells Ligands: CCL3 (MIP-1α), CCL4 (MIP-1β) and RANTES (CCL5) BX 471 is a selective non-peptide antagonist of CCR1, with no crossreactivity to CCR5 Small leucin rich proteoglycan (SLRP): Biglycan: collagen fibril formation and stability pro-inflammatory (TLR2), Il-8 Bedke et al (Am J Transplant): Beneficial effects of CCR1 Blockade on the Progression of Chronic Renal Allograft Damage

3 Background Hypothesis: Chemokines / chemokine receptors exert a major influence on chronic damage in renal allografts by reducing the infiltration of mononuclear cells into the graft and by direct inhibition of matrix synthesis Aim: To analyze the effect of chronic blockade of CCR1 by BX 471 on chronic renal allograft damage

4 Study design Rat allogeneic renal transplantation, F-344 Lewis model, one endogenous kidney Day Tx Group I Group II Treatment: 3 x daily BX mg/kg b.w. or vehicle, s.c.

5 Chronic renal allograft damage Vehicle 42d BX471 42d Tubulointerstitial rejection and transplant glomerulitis of renal allografts at day 42 after transplantation without and with BX 471 treatment (21-42day)

6 Chronic renal allograft damage Glomerulosclerosis Chronic Tubulointerstitial Injury glomerular damage score ** n.s. * tubulointerstitial injury score ** n.s. ** 0 Vehicle BX471 Vehicle BX Vehicle BX471 Vehicle BX d 21-42d 0-21d 21-42d

7 Effect of CCR1 blockade on collagen I Vehicle 42d BX471 42d Collagen I staining of renal allografts at day 42 after transplantation without and with BX 471 treatment (21-42day)

8 Effect of CCR1 blockade on myofibroblast expression Vehicle 42d BX471 42d α-sma SMA staining of renal allografts at day 42 after transplantation without and with BX 471 treatment (21-42day)

9 Effect of BX 471 on myofibroblasts and collagen deposition α-sma Sirius red cells/hpf ** ** ** ** % 50 ** ** n.s. * Vehicle BX471 Vehicle BX471 0 Vehicle BX471 Vehicle BX ** Collagen I n.s. ** 300 Collagen III ** * n.s. score * score * 0 Vehicle BX471 Vehicle BX471 0 Vehicle BX471 Vehicle BX d 21-42d 0-21d 21-42d

10 CCL5 induced biglycan expression in rat macrophages A B (A) Western blot for BGN core protein in macrophage culture supernatants after a 24-h stimulation with CCL5 stimulation ( ng/ml). (B) RT-PCR for BGN expression normalized to GAPDH in macrophages stimulated with CCL5 ( ng/ml) for 4 24 h.

11 Effect of CCR1 blockade on CCL5-induced biglycan expression in rat macrophages RT-PCR for BGN expression normalized to GAPDH in macrophages stimulated for 24 h with CCL5 with and without inhibition of CCR1 by BX 471 (300 nm)

12 Summary The CCR1 antagonist BX 471 can prevent the development of chronic damage in renal allografts This effect is achieved partly by a reduction of infiltration of leukocytes into the graft, partly by an inhibition of the fibrogenic potential of macrophages

13 Conclusion BX 471 CCR1 inhibition my be used for the prevention and treatment of chronic renal allograft damage The β-chemokine receptor CCR1 has a direct proinflammatory and fibrogeneic action in chronic inflammation It remains to be seen, whether this is also true for other chemokines / chemokine receptors Bedke et al. Am J Transplant 2007, 3:

14 Effect of CCR1 blockade on collagen III Vehicle 42d BX471 42d Collagen III staining of renal allografts at day 42 after transplantation without and with BX 471 treatment (21-42day)

15 Renal allograft response cell infiltration CD8+ T-Cells Tubulointerstitium ED1+ Monocytes/Macrophages Tubulointerstitium 150 * *** 100 ** ** cells/hpf cells/hpf Vehicle BX471 Vehicle BX471 Vehicle BX471 0 Vehicle BX471 Vehicle BX471 Vehicle BX d 0-21d 21-42d 0-10d 0-21d 21-42d Effect of BX 471 treatment on ED1+ monocyte/macrophage infiltration

16 Functional parameters Serum Creatinine 3 * 2 mg/dl 1 0 Vehicle BX471 Vehicle BX471 Vehicle BX d 0-21d 21-42d

17 Acute inflammatory allograft response Interstitial Rejection Transplant Glomerulitis tubulointerstitial inflammation score * *** glomerular injury score ** 0 Vehicle BX471 Vehicle BX471 Vehicle BX471 0 Vehicle BX471 Vehicle BX471 Vehicle BX d 0-21d 21-42d 0-10d 0-21d 21-42d

18 Effect of BX 471 on biglycan expression in rat macrophages in vivo of transplanted kidneys Vehicle BX 471 Biglycan mrna expression by in situ hybridization in untreated and BX471 treated allografts at day 21 after transplantation (200x)

19 Molecular structure of BX 471 BX 471 a CCR1 antagonist: : R-N-[5R [5-chloro-2-[2-[4-[(4-fluorophenyl)methyl] fluorophenyl)methyl]- 2-methyl-1-piperazinyl] piperazinyl]-2-oxoethoxy]phenyl]urea hydrochloric acid salt (Liang M et al. JBC 2000)

20 Chronic renal allograft damage Vehicle 21d BX471 21d Preglomerular artery of renal allografts at day 21 after transplantation without and with BX 471 treatment (0-21day)

21 Allograft response of fibrosis-associated genes PAI-1 TGF-β1 Mean Fluorescence Mean Fluorescence 0.02 ** ** Vehicle BX471 Vehicle BX Vehicle BX471 Vehicle BX d 21-42d Real-time RT-PCR 0-21d 21-42d

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