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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

M-T7 CMP loses inhibitory activity in Ndst1−/− donor allografts.Bar graphs of intimal/medial thickness ratios measured in aortic transplant cross-sections at 4 weeks follow up post transplant. M-T7 reduced plaque in WT (C57Bl/6, Ndst1+/+) donor (P<0.032), but not in Ndst1−/− donor (P = 0.933) to Balb/c recipient allografts (A). In the reverse transplant of Balb/c to WT (C57Bl/6, Ndst1+/+) M-T7 again reduced plaque (P<0.050), but not in Balb/c to Ndst1−/− transplants (P = 0.588). M-T1 treatment reduced plaque in Ndst1−/− donor aortic transplanted mice at 4 weeks follow up (C), but this trend is non significant (P = 0.222). Measurements reported as mean ± S.E.
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pone-0010510-g003: M-T7 CMP loses inhibitory activity in Ndst1−/− donor allografts.Bar graphs of intimal/medial thickness ratios measured in aortic transplant cross-sections at 4 weeks follow up post transplant. M-T7 reduced plaque in WT (C57Bl/6, Ndst1+/+) donor (P<0.032), but not in Ndst1−/− donor (P = 0.933) to Balb/c recipient allografts (A). In the reverse transplant of Balb/c to WT (C57Bl/6, Ndst1+/+) M-T7 again reduced plaque (P<0.050), but not in Balb/c to Ndst1−/− transplants (P = 0.588). M-T1 treatment reduced plaque in Ndst1−/− donor aortic transplanted mice at 4 weeks follow up (C), but this trend is non significant (P = 0.222). Measurements reported as mean ± S.E.

Mentions: The preceding studies indicated that M-T7 retained inhibitory, anti-inflammatory activity in Ccr2−/− aortic allograft transplants, indicating that M-T7 anti-inflammatory activity is not dependent upon Ccr2. To test whether M-T7 inhibitory action is mediated through blockade of chemokine to heparan sulfate GAG binding, we examined WT (C57Bl/6 background, Ndst1+/+) donor to WT Balb/c recipient aortic allograft transplants and Ndst1−/− donor to WT Balb/c recipient mouse aortic allograft transplants, with and without treatment with M-T7 (Table 1, n = 74). M-T7 significantly reduced intimal/medial thickness in the WT C57Bl/6 (Table 1, n = 12, p<0.032)(Fig. 3A) transplants, but did not further reduce plaque in the Ndst1−/− mouse donor allografts (Table 1, n = 12, Fig. 3A, p = 0.933, ANOVA p = 0.072).


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)

M-T7 CMP loses inhibitory activity in Ndst1−/− donor allografts.Bar graphs of intimal/medial thickness ratios measured in aortic transplant cross-sections at 4 weeks follow up post transplant. M-T7 reduced plaque in WT (C57Bl/6, Ndst1+/+) donor (P<0.032), but not in Ndst1−/− donor (P = 0.933) to Balb/c recipient allografts (A). In the reverse transplant of Balb/c to WT (C57Bl/6, Ndst1+/+) M-T7 again reduced plaque (P<0.050), but not in Balb/c to Ndst1−/− transplants (P = 0.588). M-T1 treatment reduced plaque in Ndst1−/− donor aortic transplanted mice at 4 weeks follow up (C), but this trend is non significant (P = 0.222). Measurements reported as mean ± S.E.
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Related In: Results  -  Collection

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pone-0010510-g003: M-T7 CMP loses inhibitory activity in Ndst1−/− donor allografts.Bar graphs of intimal/medial thickness ratios measured in aortic transplant cross-sections at 4 weeks follow up post transplant. M-T7 reduced plaque in WT (C57Bl/6, Ndst1+/+) donor (P<0.032), but not in Ndst1−/− donor (P = 0.933) to Balb/c recipient allografts (A). In the reverse transplant of Balb/c to WT (C57Bl/6, Ndst1+/+) M-T7 again reduced plaque (P<0.050), but not in Balb/c to Ndst1−/− transplants (P = 0.588). M-T1 treatment reduced plaque in Ndst1−/− donor aortic transplanted mice at 4 weeks follow up (C), but this trend is non significant (P = 0.222). Measurements reported as mean ± S.E.
Mentions: The preceding studies indicated that M-T7 retained inhibitory, anti-inflammatory activity in Ccr2−/− aortic allograft transplants, indicating that M-T7 anti-inflammatory activity is not dependent upon Ccr2. To test whether M-T7 inhibitory action is mediated through blockade of chemokine to heparan sulfate GAG binding, we examined WT (C57Bl/6 background, Ndst1+/+) donor to WT Balb/c recipient aortic allograft transplants and Ndst1−/− donor to WT Balb/c recipient mouse aortic allograft transplants, with and without treatment with M-T7 (Table 1, n = 74). M-T7 significantly reduced intimal/medial thickness in the WT C57Bl/6 (Table 1, n = 12, p<0.032)(Fig. 3A) transplants, but did not further reduce plaque in the Ndst1−/− mouse donor allografts (Table 1, n = 12, Fig. 3A, p = 0.933, ANOVA p = 0.072).

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