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Viral macrophage inflammatory protein-II improves acute rejection in allogeneic rat kidney transplants.

Bedke J, Stojanovic T, Kiss E, Behnes CL, Proudfoot AE, Gröne HJ - World J Urol (2010)

Bottom Line: Heterotopic rat kidney transplantation was performed in the Fischer 344 to Lewis transplantation model and animals were treated with vMIP-II (2 x 15 microg or 100 microg/day) for 7 days.Functional microcirculation of peritubular capillaries was significantly improved in vivo, and the firm adherence of leukocytes was significantly reduced by vMIP-II treatment.The administration of the broad-spectrum antagonist vMIP-II improved acute renal allograft damage, mainly by a reduction in leukocyte recruitment with a subsequently improved renal cortical microcirculation in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Eberhard Karls University Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany. bedke@live.com

ABSTRACT

Purpose: During rejection, leukocytes are recruited from the peripheral circulation into the graft leading to the damage of endothelial cells, capillary perfusion failure and graft loss. Chemokines play a pivotal role in the recruitment of leukocytes to the endothelium. Viral macrophage inflammatory protein-II (vMIP-II), a human herpes virus-8 DNA-encoded protein, is a broad-spectrum chemokine antagonist. The aim of the study was to prove the beneficial activity of vMIP-II treatment on acute rat kidney allograft damage.

Methods: Heterotopic rat kidney transplantation was performed in the Fischer 344 to Lewis transplantation model and animals were treated with vMIP-II (2 x 15 microg or 100 microg/day) for 7 days. Rejection-induced damage was analyzed by histology, and microcirculatory changes within the graft were analyzed by in vivo microscopy.

Results: Viral macrophage inflammatory protein-II significantly improved acute glomerular damage and tubulointerstitial inflammation and lowered the extent of vascular and tubulointerstitial damage of the treated allografts. Functional microcirculation of peritubular capillaries was significantly improved in vivo, and the firm adherence of leukocytes was significantly reduced by vMIP-II treatment.

Conclusions: The administration of the broad-spectrum antagonist vMIP-II improved acute renal allograft damage, mainly by a reduction in leukocyte recruitment with a subsequently improved renal cortical microcirculation in vivo.

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a Influence of vMIP-II treatment on acute rejection-induced histologic changes: 7 days after transplantation, a reduction in acute rejection with lower glomerular damage, vascular rejection, tubulointerstitial inflammation and tubulointerstitial damage was observed in both dosages. The damage was significantly improved for the high dose treatment group as compared to control for glomerular damage and tubulointerstitial inflammation. Vascular rejection and tubulointerstitial damage were improved as compared to untreated controls, although not significantly. A dose-dependant effect on the reduction of acute rejection-induced changes was noted for the glomerular damage, the tubulointerstitial inflammation and the tubulointerstitial damage (n.s. not significant, p < 0.05). b Untreated allografts show a high rate of adherent and transmigrated leukocytes at the vessel wall as a sign of acute vascular rejection in a preglomerular artery. c In contrast, vMIP-II treatment reduced signs of vascular rejection (endothelialitis), magnification ×400
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Fig1: a Influence of vMIP-II treatment on acute rejection-induced histologic changes: 7 days after transplantation, a reduction in acute rejection with lower glomerular damage, vascular rejection, tubulointerstitial inflammation and tubulointerstitial damage was observed in both dosages. The damage was significantly improved for the high dose treatment group as compared to control for glomerular damage and tubulointerstitial inflammation. Vascular rejection and tubulointerstitial damage were improved as compared to untreated controls, although not significantly. A dose-dependant effect on the reduction of acute rejection-induced changes was noted for the glomerular damage, the tubulointerstitial inflammation and the tubulointerstitial damage (n.s. not significant, p < 0.05). b Untreated allografts show a high rate of adherent and transmigrated leukocytes at the vessel wall as a sign of acute vascular rejection in a preglomerular artery. c In contrast, vMIP-II treatment reduced signs of vascular rejection (endothelialitis), magnification ×400

Mentions: In the untreated renal allografts, signs of tubulointerstitial rejection (interstitial infiltration and tubulitis), as well as a glomerular mononuclear cell infiltrate (transplant glomerulitis) and a vascular damage due to the subendothelial infiltration of mononuclear cells (endothelialitis, transmural arteritis) were observed by day 7. Two concentrations of vMIP-II (2 × 15 and 100 µg) were studied in the model. Both dosages of vMIP-II reduced glomerular injury (control vs. LD-vMIP-II vs. HD-vMIP-II; 33.0 ± 8.0 vs. 14.1 ± 2.1 vs. 8.8 ± 3.0), tubulointerstitial inflammation (115.0 ± 21.5 vs. 67.0 ± 16.2 vs. 35.0 ± 4.1) and tubular damage (11.0 ± 3.8 vs. 8.5 ± 2.7 vs. 4.4 ± 3.0) (Fig. 1a). Vascular cell infiltration was slightly improved (control vs. LD-vMIP-II vs. HD-vMIP-II; 45.23 ± 7.5 vs. 35.9 ± 2.9 vs. 33.1 ± 6.0) (Fig. 1a–c). The high dose (100 µg) had the most prominent effect with a significant reduction in tubulointerstitial inflammation (control vs. HD-vMIP-II, p < 0.05) and glomerular injury (control vs. HD-vMIP-II, p < 0.05) (Fig. 1a). The comparison between the high- and the low-dose treatment group did not show a significant difference between the groups, although a possible dose-dependant effect was observed for the glomerular damage, tubulointerstitial inflammation and tubulointerstitial damage. Light microscopy showed no obvious effect of vMIP-II on the endogenous contralateral kidney (data not shown).Fig. 1


Viral macrophage inflammatory protein-II improves acute rejection in allogeneic rat kidney transplants.

Bedke J, Stojanovic T, Kiss E, Behnes CL, Proudfoot AE, Gröne HJ - World J Urol (2010)

a Influence of vMIP-II treatment on acute rejection-induced histologic changes: 7 days after transplantation, a reduction in acute rejection with lower glomerular damage, vascular rejection, tubulointerstitial inflammation and tubulointerstitial damage was observed in both dosages. The damage was significantly improved for the high dose treatment group as compared to control for glomerular damage and tubulointerstitial inflammation. Vascular rejection and tubulointerstitial damage were improved as compared to untreated controls, although not significantly. A dose-dependant effect on the reduction of acute rejection-induced changes was noted for the glomerular damage, the tubulointerstitial inflammation and the tubulointerstitial damage (n.s. not significant, p < 0.05). b Untreated allografts show a high rate of adherent and transmigrated leukocytes at the vessel wall as a sign of acute vascular rejection in a preglomerular artery. c In contrast, vMIP-II treatment reduced signs of vascular rejection (endothelialitis), magnification ×400
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Related In: Results  -  Collection

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Fig1: a Influence of vMIP-II treatment on acute rejection-induced histologic changes: 7 days after transplantation, a reduction in acute rejection with lower glomerular damage, vascular rejection, tubulointerstitial inflammation and tubulointerstitial damage was observed in both dosages. The damage was significantly improved for the high dose treatment group as compared to control for glomerular damage and tubulointerstitial inflammation. Vascular rejection and tubulointerstitial damage were improved as compared to untreated controls, although not significantly. A dose-dependant effect on the reduction of acute rejection-induced changes was noted for the glomerular damage, the tubulointerstitial inflammation and the tubulointerstitial damage (n.s. not significant, p < 0.05). b Untreated allografts show a high rate of adherent and transmigrated leukocytes at the vessel wall as a sign of acute vascular rejection in a preglomerular artery. c In contrast, vMIP-II treatment reduced signs of vascular rejection (endothelialitis), magnification ×400
Mentions: In the untreated renal allografts, signs of tubulointerstitial rejection (interstitial infiltration and tubulitis), as well as a glomerular mononuclear cell infiltrate (transplant glomerulitis) and a vascular damage due to the subendothelial infiltration of mononuclear cells (endothelialitis, transmural arteritis) were observed by day 7. Two concentrations of vMIP-II (2 × 15 and 100 µg) were studied in the model. Both dosages of vMIP-II reduced glomerular injury (control vs. LD-vMIP-II vs. HD-vMIP-II; 33.0 ± 8.0 vs. 14.1 ± 2.1 vs. 8.8 ± 3.0), tubulointerstitial inflammation (115.0 ± 21.5 vs. 67.0 ± 16.2 vs. 35.0 ± 4.1) and tubular damage (11.0 ± 3.8 vs. 8.5 ± 2.7 vs. 4.4 ± 3.0) (Fig. 1a). Vascular cell infiltration was slightly improved (control vs. LD-vMIP-II vs. HD-vMIP-II; 45.23 ± 7.5 vs. 35.9 ± 2.9 vs. 33.1 ± 6.0) (Fig. 1a–c). The high dose (100 µg) had the most prominent effect with a significant reduction in tubulointerstitial inflammation (control vs. HD-vMIP-II, p < 0.05) and glomerular injury (control vs. HD-vMIP-II, p < 0.05) (Fig. 1a). The comparison between the high- and the low-dose treatment group did not show a significant difference between the groups, although a possible dose-dependant effect was observed for the glomerular damage, tubulointerstitial inflammation and tubulointerstitial damage. Light microscopy showed no obvious effect of vMIP-II on the endogenous contralateral kidney (data not shown).Fig. 1

Bottom Line: Heterotopic rat kidney transplantation was performed in the Fischer 344 to Lewis transplantation model and animals were treated with vMIP-II (2 x 15 microg or 100 microg/day) for 7 days.Functional microcirculation of peritubular capillaries was significantly improved in vivo, and the firm adherence of leukocytes was significantly reduced by vMIP-II treatment.The administration of the broad-spectrum antagonist vMIP-II improved acute renal allograft damage, mainly by a reduction in leukocyte recruitment with a subsequently improved renal cortical microcirculation in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Eberhard Karls University Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany. bedke@live.com

ABSTRACT

Purpose: During rejection, leukocytes are recruited from the peripheral circulation into the graft leading to the damage of endothelial cells, capillary perfusion failure and graft loss. Chemokines play a pivotal role in the recruitment of leukocytes to the endothelium. Viral macrophage inflammatory protein-II (vMIP-II), a human herpes virus-8 DNA-encoded protein, is a broad-spectrum chemokine antagonist. The aim of the study was to prove the beneficial activity of vMIP-II treatment on acute rat kidney allograft damage.

Methods: Heterotopic rat kidney transplantation was performed in the Fischer 344 to Lewis transplantation model and animals were treated with vMIP-II (2 x 15 microg or 100 microg/day) for 7 days. Rejection-induced damage was analyzed by histology, and microcirculatory changes within the graft were analyzed by in vivo microscopy.

Results: Viral macrophage inflammatory protein-II significantly improved acute glomerular damage and tubulointerstitial inflammation and lowered the extent of vascular and tubulointerstitial damage of the treated allografts. Functional microcirculation of peritubular capillaries was significantly improved in vivo, and the firm adherence of leukocytes was significantly reduced by vMIP-II treatment.

Conclusions: The administration of the broad-spectrum antagonist vMIP-II improved acute renal allograft damage, mainly by a reduction in leukocyte recruitment with a subsequently improved renal cortical microcirculation in vivo.

Show MeSH
Related in: MedlinePlus