Abstract 16198: Modifying Heparan Suflate Glycoasminoglycan Content and Chemokine Binding in Transplanted Donor Organs Improves Vascular Inflammation and Rejection
Background: Transplant allograft vasculopathy (TAV) is the leading cause for late transplant organ loss. TAV is induced by activation and invasion of inflammatory monocytes and T cells in response to chemokine binding to glycosaminolycans (GAGs) in the endothelial glycocalyx. We investigated the effect of inhibiting heparin sulfate (HS-GAG) / chemokine interactions on rejection in a renal transplant model with (a) heparin sulfate HS-GAG deficient (Ndst1-/-) donor mice and (b) a virus-derived chemokine modulating protein M-T7, that is blocks C, CC and CXC interaction with GAGs.
Methods: BALB/c renal allograft recipients receiving either Ndst1-/- (C57BL/6 background) or C57Bl/6 wild type (WT) donor kidneys (n = 48 each) were treated for 10 days with either Saline, M-T7 or one of three M-T7 point mutations (100 ng/gm) with differing inhibitory actions for HS-GAG / chemokine interaction. No other immunosuppressants were added.
Results: Ndst1-/- kidneys had 10X reduced HS content and markedly reduced sulfation compared to WT kidneys. Overall acute rejection and vasculitis scores were significantly reduced in Ndst1-/- donor kidneys (P < 0.0001). In WT donors, M-T7 significantly reduced rejection and vasculitis (P < 0.0001), but interestingly, lost activity in Ndst1-/- allografts. CD3+ cells were significantly reduced (P < 0.0001) in Ndst1-/- donor grafts and with M-T7 treatment in WT transplants and TH17+ cells were significantly reduced in spleen cell isolates. M-T7 point mutation E209I retained activity in both Ndst1-/- and WT donors while but R171E was active only in WT. The third mutant F137D was inactive. PCR array analysis detected significant decreases in IL-4, NOS2 and CC chemokine 20, in Ndst1-/- donor transplants or in WT transplants with M-T7 or M-T7 mutant treatments with significant reductions in TAV.
Conclusions: A critical role played by HS-GAG / chemokine interactions in the DONOR allograft transplant is demonstrated by these studies. Significant decreases in acute rejection and inflammatory vasculitis are seen in Ndst1-/- donors with saline treatment and after treatment of C57Bl/6 WT donor grafts with M-T7. HS-GAG composition of donor organs has a potential decisive effect on transplant viability.
Author Disclosures: S. Ambadapadi: None. H. Chen: None. M. Bartee: None. D. Zheng: None. S. Morshed: None. D. Wakefield: None. W. Clapp: None. A. Lucas: Ownership Interest; Modest; Viron Therapeutics, Inc.. Consultant/Advisory Board; Modest; Viron Therapeutics, Inc..
- © 2015 by American Heart Association, Inc.