Selective Deletion of Heparan Sulfotransferase Enzyme, Ndst1, in Donor Endothelial and Myeloid Precursor Cells Significantly Decreases Acute Allograft Rejection

Hao Chen, Sriram Ambadapadi, Dara Wakefield, Meeyong Bartee, Jordan R. Yaron, Liqiang Zhang, Stephanie A. Archer-Hartmann, Parastoo Azadi, Michelle Burgin, Chad Borges, Donghang Zheng, Kevin Ergle, Vishnu Muppala, Sufi Morshed, Kenneth Rand, William Clapp, Amanda Proudfoot, Alexandra Lucas

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Article number13433
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Sulfotransferases
Myeloid Cells
Allografts
Tissue Donors
Chemokines
Enzymes
Heparitin Sulfate
Disaccharides
Glycosaminoglycans
Glycocalyx
Inflammation
Transplants
Kidney
CXC Chemokines
Chemotaxis
Rejection (Psychology)
Therapeutics
Staining and Labeling
T-Lymphocytes
Gene Expression

ASJC Scopus subject areas

  • General

Cite this

Selective Deletion of Heparan Sulfotransferase Enzyme, Ndst1, in Donor Endothelial and Myeloid Precursor Cells Significantly Decreases Acute Allograft Rejection. / Chen, Hao; Ambadapadi, Sriram; Wakefield, Dara; Bartee, Meeyong; Yaron, Jordan R.; Zhang, Liqiang; Archer-Hartmann, Stephanie A.; Azadi, Parastoo; Burgin, Michelle; Borges, Chad; Zheng, Donghang; Ergle, Kevin; Muppala, Vishnu; Morshed, Sufi; Rand, Kenneth; Clapp, William; Proudfoot, Amanda; Lucas, Alexandra.

In: Scientific Reports, Vol. 8, No. 1, 13433, 01.12.2018.

Research output: Contribution to journalArticle

Chen, H, Ambadapadi, S, Wakefield, D, Bartee, M, Yaron, JR, Zhang, L, Archer-Hartmann, SA, Azadi, P, Burgin, M, Borges, C, Zheng, D, Ergle, K, Muppala, V, Morshed, S, Rand, K, Clapp, W, Proudfoot, A & Lucas, A 2018, 'Selective Deletion of Heparan Sulfotransferase Enzyme, Ndst1, in Donor Endothelial and Myeloid Precursor Cells Significantly Decreases Acute Allograft Rejection', Scientific Reports, vol. 8, no. 1, 13433. https://doi.org/10.1038/s41598-018-31779-7
Chen, Hao ; Ambadapadi, Sriram ; Wakefield, Dara ; Bartee, Meeyong ; Yaron, Jordan R. ; Zhang, Liqiang ; Archer-Hartmann, Stephanie A. ; Azadi, Parastoo ; Burgin, Michelle ; Borges, Chad ; Zheng, Donghang ; Ergle, Kevin ; Muppala, Vishnu ; Morshed, Sufi ; Rand, Kenneth ; Clapp, William ; Proudfoot, Amanda ; Lucas, Alexandra. / Selective Deletion of Heparan Sulfotransferase Enzyme, Ndst1, in Donor Endothelial and Myeloid Precursor Cells Significantly Decreases Acute Allograft Rejection. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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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.",
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AU - Chen, Hao

AU - Ambadapadi, Sriram

AU - Wakefield, Dara

AU - Bartee, Meeyong

AU - Yaron, Jordan R.

AU - Zhang, Liqiang

AU - Archer-Hartmann, Stephanie A.

AU - Azadi, Parastoo

AU - Burgin, Michelle

AU - Borges, Chad

AU - Zheng, Donghang

AU - Ergle, Kevin

AU - Muppala, Vishnu

AU - Morshed, Sufi

AU - Rand, Kenneth

AU - Clapp, William

AU - Proudfoot, Amanda

AU - Lucas, Alexandra

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