Non-HLA Antibodies Impact on C4d staining, Stellate Cell Activation and Fibrosis in Liver Allografts

Jacqueline G. OʼLeary, Anthony J. Demetris, Aurélie Philippe, Robert Freeman, Junchao Cai, Harald Heidecke, Cory Smith, Brent Hart, Linda W. Jennings, Rusan Catar, Mathew Everly, Goran B. Klintmalm, Duska Dragun

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

BACKGROUND: Recent data has shown an increased risk for rejection, fibrosis progression, and death in liver transplant (LT) recipients with preformed or de novo HLA donor-specific alloantibodies (DSA). However, the role of non-HLA autoantibodies and the interaction between HLA DSA and non-HLA autoantibodies remains uncharacterized. METHODS: We analyzed 1269 primary LT recipients from 1/2000-4/2009 with known HLA DSA status for Angiotensin II Type-1 Receptor and Endothelin-1 Type A receptor autoantibodies(anti-AT1R-Abs and anti-ETAR-Abs respectively) pre-LT and year-1 post-LT. RESULTS: Preformed non-HLA autoantibodies alone did not impact outcomes. In multivariable modeling, the combination of preformed non-HLA autoantibodies and HLA-DSA were associated with an increased risk for death [Hazard Ratio (HR)=1.66; p=0.02] especially if the HLA DSA was of the IgG3 subclass (HR=2.28; p=0.01). A single de novo non-HLA autoantibody was associated with an increased risk for TCMR or AMR rejection(68% vs. 41%, p=0.01) and fibrosis progression (HR=1.84; p=0.02). Biopsies with de novo non-HLA autoantibodies revealed a new sinusoidal C4d staining pattern when compared to HLA DSA(71% vs. 3%; p<0.001). Liver sinusoidal endothelial cell(LSEC) activation and stellate cell activation was increased in patients with non-HLA autoantibodies in the location of C4d positivity. CONCLUSIONS: A non-HLA autoantibody combined with a preformed HLA DSA is associated with an increased mortality risk. Isolated de novo anti-AT1R-Abs and/or anti-ETAR-Abs are associated with an increased risk of rejection and fibrosis progression. The novel location of C4d staining in proximity to LSEC capillarization and stellate cell activation demonstrates allograft injury in proximity to non-HLA autoantibody binding.

Original languageEnglish (US)
JournalTransplantation
DOIs
StateAccepted/In press - Jun 29 2017

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Liver Cirrhosis
Autoantibodies
Isoantibodies
Allografts
Staining and Labeling
Antibodies
Tissue Donors
Liver
Fibrosis
Endothelial Cells
Transplants
Angiotensin Type 1 Receptor
Endothelin-1
Immunoglobulin G
Biopsy
Mortality
Wounds and Injuries

ASJC Scopus subject areas

  • Transplantation

Cite this

Non-HLA Antibodies Impact on C4d staining, Stellate Cell Activation and Fibrosis in Liver Allografts. / OʼLeary, Jacqueline G.; Demetris, Anthony J.; Philippe, Aurélie; Freeman, Robert; Cai, Junchao; Heidecke, Harald; Smith, Cory; Hart, Brent; Jennings, Linda W.; Catar, Rusan; Everly, Mathew; Klintmalm, Goran B.; Dragun, Duska.

In: Transplantation, 29.06.2017.

Research output: Contribution to journalArticle

OʼLeary, JG, Demetris, AJ, Philippe, A, Freeman, R, Cai, J, Heidecke, H, Smith, C, Hart, B, Jennings, LW, Catar, R, Everly, M, Klintmalm, GB & Dragun, D 2017, 'Non-HLA Antibodies Impact on C4d staining, Stellate Cell Activation and Fibrosis in Liver Allografts', Transplantation. https://doi.org/10.1097/TP.0000000000001853
OʼLeary, Jacqueline G. ; Demetris, Anthony J. ; Philippe, Aurélie ; Freeman, Robert ; Cai, Junchao ; Heidecke, Harald ; Smith, Cory ; Hart, Brent ; Jennings, Linda W. ; Catar, Rusan ; Everly, Mathew ; Klintmalm, Goran B. ; Dragun, Duska. / Non-HLA Antibodies Impact on C4d staining, Stellate Cell Activation and Fibrosis in Liver Allografts. In: Transplantation. 2017.
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abstract = "BACKGROUND: Recent data has shown an increased risk for rejection, fibrosis progression, and death in liver transplant (LT) recipients with preformed or de novo HLA donor-specific alloantibodies (DSA). However, the role of non-HLA autoantibodies and the interaction between HLA DSA and non-HLA autoantibodies remains uncharacterized. METHODS: We analyzed 1269 primary LT recipients from 1/2000-4/2009 with known HLA DSA status for Angiotensin II Type-1 Receptor and Endothelin-1 Type A receptor autoantibodies(anti-AT1R-Abs and anti-ETAR-Abs respectively) pre-LT and year-1 post-LT. RESULTS: Preformed non-HLA autoantibodies alone did not impact outcomes. In multivariable modeling, the combination of preformed non-HLA autoantibodies and HLA-DSA were associated with an increased risk for death [Hazard Ratio (HR)=1.66; p=0.02] especially if the HLA DSA was of the IgG3 subclass (HR=2.28; p=0.01). A single de novo non-HLA autoantibody was associated with an increased risk for TCMR or AMR rejection(68{\%} vs. 41{\%}, p=0.01) and fibrosis progression (HR=1.84; p=0.02). Biopsies with de novo non-HLA autoantibodies revealed a new sinusoidal C4d staining pattern when compared to HLA DSA(71{\%} vs. 3{\%}; p<0.001). Liver sinusoidal endothelial cell(LSEC) activation and stellate cell activation was increased in patients with non-HLA autoantibodies in the location of C4d positivity. CONCLUSIONS: A non-HLA autoantibody combined with a preformed HLA DSA is associated with an increased mortality risk. Isolated de novo anti-AT1R-Abs and/or anti-ETAR-Abs are associated with an increased risk of rejection and fibrosis progression. The novel location of C4d staining in proximity to LSEC capillarization and stellate cell activation demonstrates allograft injury in proximity to non-HLA autoantibody binding.",
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T1 - Non-HLA Antibodies Impact on C4d staining, Stellate Cell Activation and Fibrosis in Liver Allografts

AU - OʼLeary, Jacqueline G.

AU - Demetris, Anthony J.

AU - Philippe, Aurélie

AU - Freeman, Robert

AU - Cai, Junchao

AU - Heidecke, Harald

AU - Smith, Cory

AU - Hart, Brent

AU - Jennings, Linda W.

AU - Catar, Rusan

AU - Everly, Mathew

AU - Klintmalm, Goran B.

AU - Dragun, Duska

PY - 2017/6/29

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N2 - BACKGROUND: Recent data has shown an increased risk for rejection, fibrosis progression, and death in liver transplant (LT) recipients with preformed or de novo HLA donor-specific alloantibodies (DSA). However, the role of non-HLA autoantibodies and the interaction between HLA DSA and non-HLA autoantibodies remains uncharacterized. METHODS: We analyzed 1269 primary LT recipients from 1/2000-4/2009 with known HLA DSA status for Angiotensin II Type-1 Receptor and Endothelin-1 Type A receptor autoantibodies(anti-AT1R-Abs and anti-ETAR-Abs respectively) pre-LT and year-1 post-LT. RESULTS: Preformed non-HLA autoantibodies alone did not impact outcomes. In multivariable modeling, the combination of preformed non-HLA autoantibodies and HLA-DSA were associated with an increased risk for death [Hazard Ratio (HR)=1.66; p=0.02] especially if the HLA DSA was of the IgG3 subclass (HR=2.28; p=0.01). A single de novo non-HLA autoantibody was associated with an increased risk for TCMR or AMR rejection(68% vs. 41%, p=0.01) and fibrosis progression (HR=1.84; p=0.02). Biopsies with de novo non-HLA autoantibodies revealed a new sinusoidal C4d staining pattern when compared to HLA DSA(71% vs. 3%; p<0.001). Liver sinusoidal endothelial cell(LSEC) activation and stellate cell activation was increased in patients with non-HLA autoantibodies in the location of C4d positivity. CONCLUSIONS: A non-HLA autoantibody combined with a preformed HLA DSA is associated with an increased mortality risk. Isolated de novo anti-AT1R-Abs and/or anti-ETAR-Abs are associated with an increased risk of rejection and fibrosis progression. The novel location of C4d staining in proximity to LSEC capillarization and stellate cell activation demonstrates allograft injury in proximity to non-HLA autoantibody binding.

AB - BACKGROUND: Recent data has shown an increased risk for rejection, fibrosis progression, and death in liver transplant (LT) recipients with preformed or de novo HLA donor-specific alloantibodies (DSA). However, the role of non-HLA autoantibodies and the interaction between HLA DSA and non-HLA autoantibodies remains uncharacterized. METHODS: We analyzed 1269 primary LT recipients from 1/2000-4/2009 with known HLA DSA status for Angiotensin II Type-1 Receptor and Endothelin-1 Type A receptor autoantibodies(anti-AT1R-Abs and anti-ETAR-Abs respectively) pre-LT and year-1 post-LT. RESULTS: Preformed non-HLA autoantibodies alone did not impact outcomes. In multivariable modeling, the combination of preformed non-HLA autoantibodies and HLA-DSA were associated with an increased risk for death [Hazard Ratio (HR)=1.66; p=0.02] especially if the HLA DSA was of the IgG3 subclass (HR=2.28; p=0.01). A single de novo non-HLA autoantibody was associated with an increased risk for TCMR or AMR rejection(68% vs. 41%, p=0.01) and fibrosis progression (HR=1.84; p=0.02). Biopsies with de novo non-HLA autoantibodies revealed a new sinusoidal C4d staining pattern when compared to HLA DSA(71% vs. 3%; p<0.001). Liver sinusoidal endothelial cell(LSEC) activation and stellate cell activation was increased in patients with non-HLA autoantibodies in the location of C4d positivity. CONCLUSIONS: A non-HLA autoantibody combined with a preformed HLA DSA is associated with an increased mortality risk. Isolated de novo anti-AT1R-Abs and/or anti-ETAR-Abs are associated with an increased risk of rejection and fibrosis progression. The novel location of C4d staining in proximity to LSEC capillarization and stellate cell activation demonstrates allograft injury in proximity to non-HLA autoantibody binding.

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