Inhibition of chemokine-glycosaminoglycan interactions in donor tissue reduces mouse allograft vasculopathy and transplant rejection.
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.
Dai
Erbin
E
Vascular Biology Research Group, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada.
Liu
Li-Ying
LY
Wang
Hao
H
McIvor
Dana
D
Sun
Yun Ming
YM
Macaulay
Colin
C
King
Elaine
E
Munuswamy-Ramanujam
Ganesh
G
Bartee
Mee Yong
MY
Williams
Jennifer
J
Davids
Jennifer
J
Charo
Israel
I
McFadden
Grant
G
Esko
Jeffrey D
JD
Lucas
Alexandra R
AR
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
C515335:Ccr2 protein, mouse; D018925:Chemokines; D006025:Glycosaminoglycans; D054390:Receptors, CCR2; D014764:Viral Proteins; D015238:Sulfotransferases; C021350:heparitin sulfotransferase
Virology. 1996 Jan 1;215(1):17-30
8553583
Nat Immunol. 2001 Feb;2(2):116-22
11175803
J Biol Chem. 1995 Feb 17;270(7):3031-8
7852384
Surg Today. 2004;34(8):668-72
15290396
J Immunol. 2009 Oct 1;183(7):4273-83
19734211
J Immunol. 2002 Jul 1;169(1):522-30
12077284
J Clin Invest. 2000 Jan;105(1):35-44
10619859
Transplantation. 1997 Jun 27;63(12):1807-12
9210509
Transplantation. 2003 Jul 15;76(1):249-52
12865819
J Biol Chem. 2006 Mar 24;281(12):8041-50
16407226
J Immunol. 2002 Aug 1;169(3):1556-60
12133984
J Exp Med. 2000 Nov 20;192(10):1515-20
11085753
Nat Immunol. 2005 Sep;6(9):902-10
16056228
Annu Rev Biochem. 2005;74:385-410
15952892
Curr Opin Lipidol. 2001 Apr;12(2):175-80
11264989
J Clin Invest. 2000 Jun;105(11):1613-21
10841520
Atherosclerosis. 1995 Dec;118 Suppl:S57-67
8821466
Transplantation. 2002 May 15;73(9):1392-7
12023615
J Vasc Surg. 2009 Jul;50(1):152-60
19563963
J Immunol. 2001 Sep 1;167(5):2979-84
11509648
Circulation. 2008 Apr 1;117(13):1649-57
18347211
J Heart Lung Transplant. 2002 Oct;21(10):1090-100
12398874
Transplant Proc. 1993 Feb;25(1 Pt 1):382
8438344
Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9008-13
11470923
J Clin Invest. 2002 Apr;109(7):905-14
11927617
Arterioscler Thromb Vasc Biol. 2009 Nov;29(11):1794-801
19734197
Am J Transplant. 2006 Oct;6(10):2292-306
16889607
Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6086-90
8327487
Transplantation. 1996 May 15;61(9):1300-5
8629287
Trends Pharmacol Sci. 2003 Mar;24(3):126-30
12628357
J Vasc Res. 2008;45(6):538-46
18463419
Nat Immunol. 2008 Sep;9(9):970-80
18711434
PLoS One. 2009 Sep 17;4(9):e7066
19759904
Immunity. 2001 Apr;14(4):387-97
11336684
J Immunol. 2004 Nov 1;173(9):5776-85
15494530
Immunology. 2009 Mar;126(3):394-404
18800989
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1885-90
12571364
J Immunol. 2004 Jan 15;172(2):767-75
14707046
Arterioscler Thromb Vasc Biol. 2007 Jun;27(6):1259-68
17395854
Transplantation. 2004 Jun 15;77(11):1652-60
15201663
Int Immunopharmacol. 2005 Oct;5(11):1622-32
16039552
Transplantation. 2005 Mar 27;79(6):672-9
15785373
Science. 1992 Nov 20;258(5086):1369-72
1455233
Virology. 1998 Oct 10;250(1):173-84
9770431
J Immunol. 2004 Oct 15;173(8):4765-74
15470015
J Biol Chem. 2001 Apr 6;276(14):10620-6
11116158
J Virol. 1997 Jun;71(6):4356-63
9151824