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.
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+ LTxpatients 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 humanLTxpatients, 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.
Authors: A Jaramillo; M A Smith; D Phelan; S Sundaresan; E Trulock; J Lynch; J Cooper; G A Patterson; T Mohanakumar Journal: Transplant Proc Date: 1999 Feb-Mar Impact factor: 1.066
Authors: A Elssner; F Jaumann; S Dobmann; J Behr; M Schwaiblmair; H Reichenspurner; H Fürst; J Briegel; C Vogelmeier Journal: Transplantation Date: 2000-07-27 Impact factor: 4.939
Authors: M Rizzo; K S SivaSai; M A Smith; E P Trulock; J P Lynch; G A Patterson; T Mohanakumar Journal: J Heart Lung Transplant Date: 2000-09 Impact factor: 10.247
Authors: D N Ionescu; A L Girnita; A Zeevi; R Duquesnoy; J Pilewski; B Johnson; S Studer; K R McCurry; S A Yousem Journal: Transpl Immunol Date: 2005-06-02 Impact factor: 1.708
Authors: S Sundaresan; T Mohanakumar; M A Smith; E P Trulock; J Lynch; D Phelan; J D Cooper; G A Patterson Journal: Transplantation Date: 1998-03-15 Impact factor: 4.939
Authors: J A de Andrade; J D Christie; C B Alexander; K R Young; D C McGiffin; G L Zorn; R M Jackson Journal: J Investig Med Date: 2001-03 Impact factor: 2.895
Authors: V Tiriveedhi; M Takenaka; S Ramachandran; A E Gelman; V Subramanian; G A Patterson; T Mohanakumar Journal: Am J Transplant Date: 2012-07-23 Impact factor: 8.086
Authors: Laurie D Snyder; Ziwei Wang; Dong-Feng Chen; Nancy L Reinsmoen; C Ashley Finlen-Copeland; W Austin Davis; David W Zaas; Scott M Palmer Journal: Chest Date: 2013-07 Impact factor: 9.410
Authors: Davide Scozzi; Mohsen Ibrahim; Cecilia Menna; Alexander S Krupnick; Daniel Kreisel; Andrew E Gelman Journal: Am J Transplant Date: 2016-07-25 Impact factor: 8.086
Authors: Chen Yang Kevin Zhang; Musawir Ahmed; Ella Huszti; Liran Levy; Sarah E Hunter; Kristen M Boonstra; Sajad Moshkelgosha; Andrew T Sage; Sassan Azad; Ricardo Zamel; Rasheed Ghany; Jonathan C Yeung; Oscar M Crespin; Courtney Frankel; Marie Budev; Pali Shah; John M Reynolds; Laurie D Snyder; John A Belperio; Lianne G Singer; S Samuel Weigt; Jamie L Todd; Scott M Palmer; Shaf Keshavjee; Tereza Martinu Journal: J Heart Lung Transplant Date: 2020-05-19 Impact factor: 10.247