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Inhibition of chemokine-glycosaminoglycan interactions in donor tissue reduces mouse allograft vasculopathy and transplant rejection.

Dai E, Liu LY, Wang H, McIvor D, Sun YM, Macaulay C, King E, Munuswamy-Ramanujam G, Bartee MY, Williams J, Davids J, Charo I, McFadden G, Esko JD, Lucas AR - PLoS ONE (2010)

Bottom Line: Donor tissue GAG or CCR2 deficiency markedly reduced inflammation and vasculopathy, whereas recipient deficiencies did not.M-T1 and M3 inhibited WT (Ccr2(+/+) and Ndst1(+/+), p< or =0.006) allograft vasculopathy, but did not block vasculopathy in Ccr2(-/-) (p = 0.61).Interruption of chemokine-GAG interactions, even in the absence of chemokine-receptor blockade, is a highly effective approach to reduction of allograft rejection, reducing vascular inflammation and prolonging allograft survival.

View Article: PubMed Central - PubMed

Affiliation: Vascular Biology Research Group, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada.

ABSTRACT

Background: Binding of chemokines to glycosaminoglycans (GAGs) is classically described as initiating inflammatory cell migration and creating tissue chemokine gradients that direct local leukocyte chemotaxis into damaged or transplanted tissues. While chemokine-receptor binding has been extensively studied during allograft transplantation, effects of glycosaminoglycan (GAG) interactions with chemokines on transplant longevity are less well known. Here we examine the impact of interrupting chemokine-GAG interactions and chemokine-receptor interactions, both locally and systemically, on vascular disease in allografts.

Methodology/principal findings: Analysis of GAG or CC chemokine receptor 2 (CCR2) deficiency were coupled with the infusion of viral chemokine modulating proteins (CMPs) in mouse aortic allograft transplants (n = 239 mice). Inflammatory cell invasion and neointimal hyperplasia were significantly reduced in N-deacetylase-N-sulfotransferase-1 (Ndst1(f/f)TekCre(+)) heparan sulfate (GAG)-deficient (Ndst1(-/-), p<0.044) and CCR2-deficient (Ccr2(-/-), p<0.04) donor transplants. Donor tissue GAG or CCR2 deficiency markedly reduced inflammation and vasculopathy, whereas recipient deficiencies did not. Treatment with three CMPs was also investigated; Poxviral M-T1 blocks CC chemokine receptor binding, M-T7 blocks C, CC, and CXC GAG binding, and herpesviral M3 binds receptor and GAG binding for all classes. M-T7 reduced intimal hyperplasia in wild type (WT) (Ccr2(+/+), p< or =0.003 and Ccr2(-/-), p

Conclusions/significance: Interruption of chemokine-GAG interactions, even in the absence of chemokine-receptor blockade, is a highly effective approach to reduction of allograft rejection, reducing vascular inflammation and prolonging allograft survival. Although chemokines direct both local and systemic cell migration, interruption of inherent chemokine responses in the donor tissue unexpectedly had a greater therapeutic impact on allograft vasculopathy.

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Related in: MedlinePlus

Viral chemokine modulating proteins (CMPs) significantly reduce allograft neointimal hyperplasia with donor receptor and GAG dependent specificity.H & E stained cross sections. M-T1 (A) and M-T7 (C) at 0.6 µg, or greater, doses reduced plaque in Ccr2+/+ aortic transplants. M-T1 (B) did not inhibit intimal hyperplasia in Ccr2−/− donor allografts (B) whereas M-T7 did (D). Bar graphs illustrate significant reductions in intimal to medial thickness with M-T1 (E), M3 (F), and M-T7 treatment of Ccr2+/+ donor allografts, whereas M-T1 (E) and M3 (F) are inactive in Ccr2−/− donors. M-T7 did significantly reduce intimal hyperplasia in Ccr2−/− donor allografts (G). Reverse transplant to WT Ccr2+/+ mice did significantly reduce intimal area, but Ccr2−/− recipients show only a trend toward reduction with M-T7 treatment (H). Measurements reported as mean ± S.E. Arrows bracket intimal plaque. Arrowheads point to inflammatory cell invasion. Mag. 200X.
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pone-0010510-g002: Viral chemokine modulating proteins (CMPs) significantly reduce allograft neointimal hyperplasia with donor receptor and GAG dependent specificity.H & E stained cross sections. M-T1 (A) and M-T7 (C) at 0.6 µg, or greater, doses reduced plaque in Ccr2+/+ aortic transplants. M-T1 (B) did not inhibit intimal hyperplasia in Ccr2−/− donor allografts (B) whereas M-T7 did (D). Bar graphs illustrate significant reductions in intimal to medial thickness with M-T1 (E), M3 (F), and M-T7 treatment of Ccr2+/+ donor allografts, whereas M-T1 (E) and M3 (F) are inactive in Ccr2−/− donors. M-T7 did significantly reduce intimal hyperplasia in Ccr2−/− donor allografts (G). Reverse transplant to WT Ccr2+/+ mice did significantly reduce intimal area, but Ccr2−/− recipients show only a trend toward reduction with M-T7 treatment (H). Measurements reported as mean ± S.E. Arrows bracket intimal plaque. Arrowheads point to inflammatory cell invasion. Mag. 200X.

Mentions: To further examine the effects of selective blockade of chemokine-GAG interactions and chemokine-receptor interactions, we assessed the effects of three viral CMPs that target chemokine binding to either the receptor binding domain (M-T1), the GAG binding domain (M-T7), or both domains (M3). Cell invasion and intimal plaque growth were measured in the mouse aortic transplant model at 4 weeks follow up after treatment with each CMP (Fig. 2, Table 1, n = 239, including controls). To confirm the therapeutic targets for each CMP, effects were assessed after WT donor aortic transplant (Ccr2+/+ and Ndst1+/+) or after transplant of Ccr2−/− (Table 1, n = 165) or Ndst1−/− (n = 74) deficient donor aorta.


Inhibition of chemokine-glycosaminoglycan interactions in donor tissue reduces mouse allograft vasculopathy and transplant rejection.

Dai E, Liu LY, Wang H, McIvor D, Sun YM, Macaulay C, King E, Munuswamy-Ramanujam G, Bartee MY, Williams J, Davids J, Charo I, McFadden G, Esko JD, Lucas AR - PLoS ONE (2010)

Viral chemokine modulating proteins (CMPs) significantly reduce allograft neointimal hyperplasia with donor receptor and GAG dependent specificity.H & E stained cross sections. M-T1 (A) and M-T7 (C) at 0.6 µg, or greater, doses reduced plaque in Ccr2+/+ aortic transplants. M-T1 (B) did not inhibit intimal hyperplasia in Ccr2−/− donor allografts (B) whereas M-T7 did (D). Bar graphs illustrate significant reductions in intimal to medial thickness with M-T1 (E), M3 (F), and M-T7 treatment of Ccr2+/+ donor allografts, whereas M-T1 (E) and M3 (F) are inactive in Ccr2−/− donors. M-T7 did significantly reduce intimal hyperplasia in Ccr2−/− donor allografts (G). Reverse transplant to WT Ccr2+/+ mice did significantly reduce intimal area, but Ccr2−/− recipients show only a trend toward reduction with M-T7 treatment (H). Measurements reported as mean ± S.E. Arrows bracket intimal plaque. Arrowheads point to inflammatory cell invasion. Mag. 200X.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2865544&req=5

pone-0010510-g002: Viral chemokine modulating proteins (CMPs) significantly reduce allograft neointimal hyperplasia with donor receptor and GAG dependent specificity.H & E stained cross sections. M-T1 (A) and M-T7 (C) at 0.6 µg, or greater, doses reduced plaque in Ccr2+/+ aortic transplants. M-T1 (B) did not inhibit intimal hyperplasia in Ccr2−/− donor allografts (B) whereas M-T7 did (D). Bar graphs illustrate significant reductions in intimal to medial thickness with M-T1 (E), M3 (F), and M-T7 treatment of Ccr2+/+ donor allografts, whereas M-T1 (E) and M3 (F) are inactive in Ccr2−/− donors. M-T7 did significantly reduce intimal hyperplasia in Ccr2−/− donor allografts (G). Reverse transplant to WT Ccr2+/+ mice did significantly reduce intimal area, but Ccr2−/− recipients show only a trend toward reduction with M-T7 treatment (H). Measurements reported as mean ± S.E. Arrows bracket intimal plaque. Arrowheads point to inflammatory cell invasion. Mag. 200X.
Mentions: To further examine the effects of selective blockade of chemokine-GAG interactions and chemokine-receptor interactions, we assessed the effects of three viral CMPs that target chemokine binding to either the receptor binding domain (M-T1), the GAG binding domain (M-T7), or both domains (M3). Cell invasion and intimal plaque growth were measured in the mouse aortic transplant model at 4 weeks follow up after treatment with each CMP (Fig. 2, Table 1, n = 239, including controls). To confirm the therapeutic targets for each CMP, effects were assessed after WT donor aortic transplant (Ccr2+/+ and Ndst1+/+) or after transplant of Ccr2−/− (Table 1, n = 165) or Ndst1−/− (n = 74) deficient donor aorta.

Bottom Line: Donor tissue GAG or CCR2 deficiency markedly reduced inflammation and vasculopathy, whereas recipient deficiencies did not.M-T1 and M3 inhibited WT (Ccr2(+/+) and Ndst1(+/+), p< or =0.006) allograft vasculopathy, but did not block vasculopathy in Ccr2(-/-) (p = 0.61).Interruption of chemokine-GAG interactions, even in the absence of chemokine-receptor blockade, is a highly effective approach to reduction of allograft rejection, reducing vascular inflammation and prolonging allograft survival.

View Article: PubMed Central - PubMed

Affiliation: Vascular Biology Research Group, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada.

ABSTRACT

Background: Binding of chemokines to glycosaminoglycans (GAGs) is classically described as initiating inflammatory cell migration and creating tissue chemokine gradients that direct local leukocyte chemotaxis into damaged or transplanted tissues. While chemokine-receptor binding has been extensively studied during allograft transplantation, effects of glycosaminoglycan (GAG) interactions with chemokines on transplant longevity are less well known. Here we examine the impact of interrupting chemokine-GAG interactions and chemokine-receptor interactions, both locally and systemically, on vascular disease in allografts.

Methodology/principal findings: Analysis of GAG or CC chemokine receptor 2 (CCR2) deficiency were coupled with the infusion of viral chemokine modulating proteins (CMPs) in mouse aortic allograft transplants (n = 239 mice). Inflammatory cell invasion and neointimal hyperplasia were significantly reduced in N-deacetylase-N-sulfotransferase-1 (Ndst1(f/f)TekCre(+)) heparan sulfate (GAG)-deficient (Ndst1(-/-), p<0.044) and CCR2-deficient (Ccr2(-/-), p<0.04) donor transplants. Donor tissue GAG or CCR2 deficiency markedly reduced inflammation and vasculopathy, whereas recipient deficiencies did not. Treatment with three CMPs was also investigated; Poxviral M-T1 blocks CC chemokine receptor binding, M-T7 blocks C, CC, and CXC GAG binding, and herpesviral M3 binds receptor and GAG binding for all classes. M-T7 reduced intimal hyperplasia in wild type (WT) (Ccr2(+/+), p< or =0.003 and Ccr2(-/-), p

Conclusions/significance: Interruption of chemokine-GAG interactions, even in the absence of chemokine-receptor blockade, is a highly effective approach to reduction of allograft rejection, reducing vascular inflammation and prolonging allograft survival. Although chemokines direct both local and systemic cell migration, interruption of inherent chemokine responses in the donor tissue unexpectedly had a greater therapeutic impact on allograft vasculopathy.

Show MeSH
Related in: MedlinePlus