Abstract 16198: Modifying Heparan Suflate Glycoasminoglycan Content and Chemokine Binding in Transplanted Donor Organs Improves Vascular Inflammation and Rejection

Abstract

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 E 209 I retained activity in both Ndst1 -/- and WT donors while but R 171 E was active only in WT. The third mutant F 137 D 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.