Synergistic Effect of Antibodies to Human Leukocyte Antigens and Defensins in Pathogenesis of Bronchiolitis Obliterans Syndrome After Human Lung Transplantation

Overview

Journal J Heart Lung Transplant

Publisher Elsevier

Specialties Cardiology & Vascular Diseases
General Surgery
Pulmonary Medicine

Date 2010 Aug 10

PMID 20691611

Citations 17

Authors

Deepti Saini

Nataraju Angaswamy

Venkataswarup Tiriveedhi

Naohiko Fukami

Sabarinathan Ramachandran

Ramsey Hachem

Elbert Trulock

Brian Meyers

Alexander Patterson

Thalachallour Mohanakumar

Affiliations

Soon will be listed here.

Abstract

Background: This study aims to determine the role of antibodies to donor-mismatched human leukocyte antigen (HLA) developed during the post-transplant period in inducing defensins and their synergistic role in the pathogenesis of chronic rejection, bronchiolitis obliterans syndrome (BOS), after human lung transplantation (LTx).

Methods: Bronchoalveolar lavage (BAL) and serum from 21 BOS+ LTx patients were assayed for β-defensins human neutrophil peptides (HNP) 1-3 (enzyme-linked immunosorbent assay [ELISA]) and anti-HLA antibodies (Luminex, Luminex Corp, Austin, TX). Human airway epithelial cells (AEC) were treated with anti-HLA antibodies, HNP-1/2, or both, and the levels of β-defensin were measured by ELISA. Using a mouse model of obliterative airway disease induced by anti-major histocompatibility (MHC) class-I antibodies, we quantitatively and qualitatively determined neutrophil infiltration by myeloperoxidase (MPO) staining and activity by MPO assay, and defensin levels in the BAL.

Results: In human LTx patients, higher defensin levels correlated with presence of circulating anti-HLA antibodies (p < 0.05). AEC treated with anti-HLA antibodies or HNP-1/2, produced β-defensin with synergistic effects in combination (612 ± 06 vs 520 ± 23 pg/ml anti-HLA antibody, or 590 ± 10 pg/ml for HNP treatment; p < 0.05). Neutrophil numbers (6-fold) and activity (5.5-fold) were higher in the lungs of mice treated with anti-MHC antibodies vs control. A 2-fold increase in α-defensin and β-defensin levels was also present in BAL on Day 5 after anti-MHC administrations.

Conclusions: Anti-HLA antibodies developed during the post-transplant period and α-defensins stimulated β-defensin production by epithelial cells, leading to increased cellular infiltration and inflammation. Chronic stimulation of epithelium by antibodies to MHC and resulting increased levels of defensins induce growth factor production and epithelial proliferation contributing to the development of chronic rejection after LTx.

Citing Articles

The Effects of IL-23/IL-18-Polarized Neutrophils on Renal Ischemia-Reperfusion Injury and Allogeneic-Skin-Graft Rejection in Mice.

Wu C, Xu J, Zhang Z, Wei D, Xu Y, Zhao Y Biomedicines. 2023; 11(12).

PMID: 38137369 PMC: 10740676. DOI: 10.3390/biomedicines11123148.

Bronchoalveolar bile acid and inflammatory markers to identify high-risk lung transplant recipients with reflux and microaspiration.

Zhang C, Ahmed M, Huszti E, Levy L, Hunter S, Boonstra K J Heart Lung Transplant. 2020; 39(9):934-944.

PMID: 32487471 PMC: 7483994. DOI: 10.1016/j.healun.2020.05.006.

Modulation of Human Neutrophil Peptides on Killing, Epithelial Cell Inflammation and Mesenchymal Stromal Cell Secretome Profiles.

Dai Q, Morita Y, Huang Y, Liaw P, Wu J, Khang J J Inflamm Res. 2020; 12:335-343.

PMID: 31908518 PMC: 6927223. DOI: 10.2147/JIR.S219276.

HLA and lung transplantation.

Ju L, Suberbielle C, Li X, Mooney N, Charron D Front Med. 2018; 13(3):298-313.

PMID: 29974325 DOI: 10.1007/s11684-018-0636-x.

Plasma levels of alarmin HNPs 1-3 associate with lung dysfunction after cardiac surgery in children.

Liu X, Chen Q, Luo Y, Hu Y, Lai D, Zhang X BMC Pulm Med. 2017; 17(1):218.

PMID: 29282039 PMC: 5745992. DOI: 10.1186/s12890-017-0558-4.

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