Abstract
Early damage to transplanted organs initiates excess inflammation that can cause ongoing injury, a leading cause for late graft loss. The endothelial glycocalyx modulates immune reactions and chemokine-mediated haptotaxis, potentially driving graft loss. In prior work, conditional deficiency of the glycocalyx-modifying enzyme N-deacetylase-N-sulfotransferase-1 (Ndst1f/f TekCre+) reduced aortic allograft inflammation. Here we investigated modification of heparan sulfate (HS) and chemokine interactions in whole-organ renal allografts. Conditional donor allograft Ndst1 deficiency (Ndst1−/−; C57Bl/6 background) was compared to systemic treatment with M-T7, a broad-spectrum chemokine-glycosaminoglycan (GAG) inhibitor. Early rejection was significantly reduced in Ndst1−/− kidneys engrafted into wildtype BALB/c mice (Ndst1+/+) and comparable to M-T7 treatment in C57Bl/6 allografts (P < 0.0081). M-T7 lost activity in Ndst1−/− allografts, while M-T7 point mutants with modified GAG-chemokine binding displayed a range of anti-rejection activity. CD3+ T cells (P < 0.0001), HS (P < 0.005) and CXC chemokine staining (P < 0.012), gene expression in NFκB and JAK/STAT pathways, and HS and CS disaccharide content were significantly altered with reduced rejection. Transplant of donor allografts with conditional Ndst1 deficiency exhibit significantly reduced acute rejection, comparable to systemic chemokine-GAG inhibition. Modified disaccharides in engrafted organs correlate with reduced rejection. Altered disaccharides in engrafted organs provide markers for rejection with potential to guide new therapeutic approaches in allograft rejection.
Highlights
Acute and chronic transplant rejection, with scarring and organ failure, prolong illness, increase mortality and increase the necessity for repeat transplant[1,2,3,4,5,6,7]
Our own work with aortic allografts, which is a model for chronic transplant vascular inflammation and fibrosis[20,21], we demonstrated reduced vasculopathy and inflammation at 4 weeks follow-up in Ndst1−/− donor aortas implanted in wild type (WT) BALB/c mice with normal Ndst[1] expression (Ndst1+/+)[19]
Histopathological markers for early rejection in grafts with Ndst[1] deficiency were compared to wildtype donor allografts, both treated with saline, at 10 days follow up (Fig. 1A,C,D–J)
Summary
Acute and chronic transplant rejection, with scarring and organ failure, prolong illness, increase mortality and increase the necessity for repeat transplant[1,2,3,4,5,6,7]. Both recurrent episodes of acute antibody-mediated immune rejection and persistent excess inflammation[1,2,3,4]. Both changes related to cellular rejection and antibody-mediated rejection have the potential to induce early damage to the graft with long-lasting effects. Chemokines have proven dual interactions with GAGs and with 7 transmembrane G protein coupled chemokine receptors on immune cells[15,16,17,18,19] This requisite GAG and receptor interaction presents one mechanism through which modified GAG composition may alter acute transplant injury and rejection. Chemokines activate cells via surface receptors, certain chemokines unexpectedly signal cell activation through cooperative receptor activation via direct GAG interaction, bypassing receptors[7]
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