@article{2649be43439a4c71972c0927b7a68c83,
title = "Selective Deletion of Heparan Sulfotransferase Enzyme, Ndst1, in Donor Endothelial and Myeloid Precursor Cells Significantly Decreases Acute Allograft Rejection",
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.",
author = "Hao Chen and Sriram Ambadapadi and Dara Wakefield and Meeyong Bartee and Yaron, {Jordan R.} and Liqiang Zhang and Archer-Hartmann, {Stephanie A.} and Parastoo Azadi and Michelle Burgin and Chad Borges and Donghang Zheng and Kevin Ergle and Vishnu Muppala and Sufi Morshed and Kenneth Rand and William Clapp and Amanda Proudfoot and Alexandra Lucas",
note = "Funding Information: This work was supported by the National Institutes of Health (Grant number 1RC1HL100202-01), the American Heart Association (Grant numbers 0855421 E, 12GRNT120/0313, and 17GRNT33460327) and University of Florida Gatorade (Grant number 00115070) to A.L. This research was also supported in part by the National Institutes of Health (NIH)-funded Research Resource for Integrated Glycotechnology (NIH grant no. 5P41GM10339024) to P.A. at the Complex Carbohydrate Research Center. We would like to thank Dr. Jeffrey Esko (UCSD) for his advice and expertise in glycosaminoglycans and Dr. Barbara Munk for her help in proofing and revising this manuscript. Funding Information: Competing Interests: For potential COI, we would note that Dr. A. Lucas has previously been affiliated with a small Biotechnology company in Canada, but that company was not involved in this research and is no longer functioning. Dr. Lucas has submitted patents on M-T7 and to Ndst1 modification with antisense oligonucleotides to Ndst1 in transplant. We do have older patents related to the chemokine modulating protein, M-T7 and have had active research grants funded by the American Heart Association as well as NIH funding. Publisher Copyright: {\textcopyright} 2018, The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41598-018-31779-7",
language = "English (US)",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}