Abstract
BackgroundBinding 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 FindingsAnalysis 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≤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≤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≤0.001).Conclusions/SignificanceInterruption 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.
Highlights
Chemokines interact with both glycosaminoglycans (GAG) and cell surface receptors
We examine the effects of chemokine-GAG interactions on inflammatory cell responses, vasculopathy development, and graft survival in mouse aortic and renal transplant models, with comparison to chemokine-receptor interactions
To test whether M-T7 inhibitory action is mediated through blockade of chemokine to heparan sulfate GAG binding, we examined wild type (WT) (C57Bl/6 background, Ndst1+/+) donor to WT Balb/c recipient aortic allograft transplants and Ndst12/2 donor to WT Balb/c recipient mouse aortic allograft transplants, with and without treatment with M-T7 (Table 1, n = 74)
Summary
Chemokines interact with both glycosaminoglycans (GAG) and cell surface receptors. Both interactions accelerate and localize inflammatory cell responses in damaged or transplanted tissues, but how the interaction of chemokines with tissue polysaccharides, GAGs, regulate pathologic inflammatory responses is only partially understood [1,2,3,4]. Binding to tissue and cell surface GAGs is thought to present the chemokine N-terminus to inflammatory cell surfaces where the cognate seventransmembrane G-protein coupled chemokine receptors initiate the signaling responses that drive leukocyte taxis. These interactions directionally guide cells toward increasing concentrations of chemokines and act as a primary defense to remove pathogens or to begin repair responses after trauma, transplant, or injury [1,2,3,4,5]. We examine the impact of interrupting chemokine-GAG interactions and chemokine-receptor interactions, both locally and systemically, on vascular disease in allografts
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