Endothelial cell antibodies associated with novel targets and increased rejection

Annette Jackson, Tara K. Sigdel, Marianne Delville, Szu Chuan Hsieh, Hong Dai, Serena M Bagnasco, Robert A. Montgomery, Minnie M. Sarwal

Research output: Contribution to journalArticle

Abstract

The initial contact point between a recipient's immune system and a transplanted graft is the vascular endothelium. Clinical studies suggest a pathogenic role for non-HLA antiendothelial cell antibodies (AECAs) in allograft rejection; however, evidence linking AECAs of known specificity to in vivo vascular injury is lacking. Here, we used high-density protein arrays to identify target antigens for AECAs isolated from the sera of recipients of kidney transplants experiencing antibody-mediated rejection in the absence of donor-specific HLA antibodies. Four antigenic targets expressed on endothelial cells were identified: endoglin, Fms-like tyrosine kinase-3 ligand, EGF-like repeats and discoidin I-like domains 3, and intercellular adhesion molecule 4; the first three have been implicated in endothelial cell activation and leukocyte extravasation. To validate these findings, ELISAs were constructed, and sera from an additional 150 renal recipients were tested. All four AECAs were detected in 24% of pretransplant sera, and they were associated with post-transplant donor-specific HLA antibodies, antibody-mediated rejection, and early transplant glomerulopathy. AECA stimulation of endothelial cell cultures increased adhesion molecule expression and production of inflammatory cytokines: regulated on activation, normal T cell expressed and secreted PDGF and RESISTIN. These correlations between in vitro experiments and in vivo histopathology suggest that AECAs activate the vascular endothelium, amplifying the alloimmune response and increasing microvascular damage. Given the growing number of transplant candidates, a better understanding of the antigenic targets, beyond HLA, and mechanisms of immune injury will be essential for improving long-term allograft survival.

Original languageEnglish (US)
Pages (from-to)1161-1171
Number of pages11
JournalJournal of the American Society of Nephrology
Volume26
Issue number5
DOIs
StatePublished - May 1 2015

Fingerprint

Endothelial Cells
Antibodies
Vascular Endothelium
Allografts
Serum
Tissue Donors
Transplants
Kidney
Protein Array Analysis
Antibody Specificity
Vascular System Injuries
Graft Rejection
Cell Adhesion Molecules
Epidermal Growth Factor
anti-endothelial cell antibody
Immune System
Leukocytes
Cell Culture Techniques
Enzyme-Linked Immunosorbent Assay
Cytokines

ASJC Scopus subject areas

  • Nephrology

Cite this

Endothelial cell antibodies associated with novel targets and increased rejection. / Jackson, Annette; Sigdel, Tara K.; Delville, Marianne; Hsieh, Szu Chuan; Dai, Hong; Bagnasco, Serena M; Montgomery, Robert A.; Sarwal, Minnie M.

In: Journal of the American Society of Nephrology, Vol. 26, No. 5, 01.05.2015, p. 1161-1171.

Research output: Contribution to journalArticle

Jackson, A, Sigdel, TK, Delville, M, Hsieh, SC, Dai, H, Bagnasco, SM, Montgomery, RA & Sarwal, MM 2015, 'Endothelial cell antibodies associated with novel targets and increased rejection', Journal of the American Society of Nephrology, vol. 26, no. 5, pp. 1161-1171. https://doi.org/10.1681/ASN.2013121277
Jackson, Annette ; Sigdel, Tara K. ; Delville, Marianne ; Hsieh, Szu Chuan ; Dai, Hong ; Bagnasco, Serena M ; Montgomery, Robert A. ; Sarwal, Minnie M. / Endothelial cell antibodies associated with novel targets and increased rejection. In: Journal of the American Society of Nephrology. 2015 ; Vol. 26, No. 5. pp. 1161-1171.
@article{daf5824e83ea4c60a8df51fbb4144862,
title = "Endothelial cell antibodies associated with novel targets and increased rejection",
abstract = "The initial contact point between a recipient's immune system and a transplanted graft is the vascular endothelium. Clinical studies suggest a pathogenic role for non-HLA antiendothelial cell antibodies (AECAs) in allograft rejection; however, evidence linking AECAs of known specificity to in vivo vascular injury is lacking. Here, we used high-density protein arrays to identify target antigens for AECAs isolated from the sera of recipients of kidney transplants experiencing antibody-mediated rejection in the absence of donor-specific HLA antibodies. Four antigenic targets expressed on endothelial cells were identified: endoglin, Fms-like tyrosine kinase-3 ligand, EGF-like repeats and discoidin I-like domains 3, and intercellular adhesion molecule 4; the first three have been implicated in endothelial cell activation and leukocyte extravasation. To validate these findings, ELISAs were constructed, and sera from an additional 150 renal recipients were tested. All four AECAs were detected in 24{\%} of pretransplant sera, and they were associated with post-transplant donor-specific HLA antibodies, antibody-mediated rejection, and early transplant glomerulopathy. AECA stimulation of endothelial cell cultures increased adhesion molecule expression and production of inflammatory cytokines: regulated on activation, normal T cell expressed and secreted PDGF and RESISTIN. These correlations between in vitro experiments and in vivo histopathology suggest that AECAs activate the vascular endothelium, amplifying the alloimmune response and increasing microvascular damage. Given the growing number of transplant candidates, a better understanding of the antigenic targets, beyond HLA, and mechanisms of immune injury will be essential for improving long-term allograft survival.",
author = "Annette Jackson and Sigdel, {Tara K.} and Marianne Delville and Hsieh, {Szu Chuan} and Hong Dai and Bagnasco, {Serena M} and Montgomery, {Robert A.} and Sarwal, {Minnie M.}",
year = "2015",
month = "5",
day = "1",
doi = "10.1681/ASN.2013121277",
language = "English (US)",
volume = "26",
pages = "1161--1171",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "5",

}

TY - JOUR

T1 - Endothelial cell antibodies associated with novel targets and increased rejection

AU - Jackson, Annette

AU - Sigdel, Tara K.

AU - Delville, Marianne

AU - Hsieh, Szu Chuan

AU - Dai, Hong

AU - Bagnasco, Serena M

AU - Montgomery, Robert A.

AU - Sarwal, Minnie M.

PY - 2015/5/1

Y1 - 2015/5/1

N2 - The initial contact point between a recipient's immune system and a transplanted graft is the vascular endothelium. Clinical studies suggest a pathogenic role for non-HLA antiendothelial cell antibodies (AECAs) in allograft rejection; however, evidence linking AECAs of known specificity to in vivo vascular injury is lacking. Here, we used high-density protein arrays to identify target antigens for AECAs isolated from the sera of recipients of kidney transplants experiencing antibody-mediated rejection in the absence of donor-specific HLA antibodies. Four antigenic targets expressed on endothelial cells were identified: endoglin, Fms-like tyrosine kinase-3 ligand, EGF-like repeats and discoidin I-like domains 3, and intercellular adhesion molecule 4; the first three have been implicated in endothelial cell activation and leukocyte extravasation. To validate these findings, ELISAs were constructed, and sera from an additional 150 renal recipients were tested. All four AECAs were detected in 24% of pretransplant sera, and they were associated with post-transplant donor-specific HLA antibodies, antibody-mediated rejection, and early transplant glomerulopathy. AECA stimulation of endothelial cell cultures increased adhesion molecule expression and production of inflammatory cytokines: regulated on activation, normal T cell expressed and secreted PDGF and RESISTIN. These correlations between in vitro experiments and in vivo histopathology suggest that AECAs activate the vascular endothelium, amplifying the alloimmune response and increasing microvascular damage. Given the growing number of transplant candidates, a better understanding of the antigenic targets, beyond HLA, and mechanisms of immune injury will be essential for improving long-term allograft survival.

AB - The initial contact point between a recipient's immune system and a transplanted graft is the vascular endothelium. Clinical studies suggest a pathogenic role for non-HLA antiendothelial cell antibodies (AECAs) in allograft rejection; however, evidence linking AECAs of known specificity to in vivo vascular injury is lacking. Here, we used high-density protein arrays to identify target antigens for AECAs isolated from the sera of recipients of kidney transplants experiencing antibody-mediated rejection in the absence of donor-specific HLA antibodies. Four antigenic targets expressed on endothelial cells were identified: endoglin, Fms-like tyrosine kinase-3 ligand, EGF-like repeats and discoidin I-like domains 3, and intercellular adhesion molecule 4; the first three have been implicated in endothelial cell activation and leukocyte extravasation. To validate these findings, ELISAs were constructed, and sera from an additional 150 renal recipients were tested. All four AECAs were detected in 24% of pretransplant sera, and they were associated with post-transplant donor-specific HLA antibodies, antibody-mediated rejection, and early transplant glomerulopathy. AECA stimulation of endothelial cell cultures increased adhesion molecule expression and production of inflammatory cytokines: regulated on activation, normal T cell expressed and secreted PDGF and RESISTIN. These correlations between in vitro experiments and in vivo histopathology suggest that AECAs activate the vascular endothelium, amplifying the alloimmune response and increasing microvascular damage. Given the growing number of transplant candidates, a better understanding of the antigenic targets, beyond HLA, and mechanisms of immune injury will be essential for improving long-term allograft survival.

UR - http://www.scopus.com/inward/record.url?scp=84929339088&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929339088&partnerID=8YFLogxK

U2 - 10.1681/ASN.2013121277

DO - 10.1681/ASN.2013121277

M3 - Article

C2 - 25381426

AN - SCOPUS:84929339088

VL - 26

SP - 1161

EP - 1171

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 5

ER -