title: Inhibition of chemokine-glycosaminoglycan interactions in donor tissue reduces mouse allograft vasculopathy and transplant rejection.
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.
  
  
  RESULTS
  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</=0.027) aortic allografts, but not in Ndst1(-/-) aortic allografts (p = 0.933). 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). M-T7 treatment alone, even without immunosuppressive drugs, also significantly prolonged survival of renal allograft transplants (p< or =0.001).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Vascular Biology Research Group, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Erbin
authors.initials: E
authors.lastname: Dai
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Liu
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Dana
authors.initials: D
authors.lastname: McIvor
authors.forename: Yun Ming
authors.initials: YM
authors.lastname: Sun
authors.forename: Colin
authors.initials: C
authors.lastname: Macaulay
authors.forename: Elaine
authors.initials: E
authors.lastname: King
authors.forename: Ganesh
authors.initials: G
authors.lastname: Munuswamy-Ramanujam
authors.forename: Mee Yong
authors.initials: MY
authors.lastname: Bartee
authors.forename: Jennifer
authors.initials: J
authors.lastname: Williams
authors.forename: Jennifer
authors.initials: J
authors.lastname: Davids
authors.forename: Israel
authors.initials: I
authors.lastname: Charo
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Lucas
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology / Q000637:transplantation; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D006025:Glycosaminoglycans / Q000378:metabolism*; D006084:Graft Rejection / Q000150:complications / Q000201:enzymology / Q000276:immunology*; D006965:Hyperplasia; D007249:Inflammation / Q000150:complications / Q000473:pathology; D016030:Kidney Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D054390:Receptors, CCR2 / Q000172:deficiency / Q000378:metabolism; D015238:Sulfotransferases / Q000172:deficiency / Q000378:metabolism; D016019:Survival Analysis; D014019:Tissue Donors; D014184:Transplantation, Homologous; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D014652:Vascular Diseases / Q000150:complications / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D014764:Viral Proteins / Q000494:pharmacology
chemical_list: C515335:Ccr2 protein, mouse; D018925:Chemokines; D006025:Glycosaminoglycans; D054390:Receptors, CCR2; D014764:Viral Proteins; D015238:Sulfotransferases; C021350:heparitin sulfotransferase
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