PMID- 20691611
OWN - NLM
STAT- MEDLINE
DCOM- 20110316
LR  - 20211020
IS  - 1557-3117 (Electronic)
IS  - 1053-2498 (Print)
IS  - 1053-2498 (Linking)
VI  - 29
IP  - 12
DP  - 2010 Dec
TI  - Synergistic effect of antibodies to human leukocyte antigens and defensins in 
      pathogenesis of bronchiolitis obliterans syndrome after human lung 
      transplantation.
PG  - 1330-6
LID - 10.1016/j.healun.2010.05.036 [doi]
AB  - 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 beta-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 beta-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 beta-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 alpha-defensin and beta-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 alpha-defensins stimulated beta-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.
CI  - Copyright (c) 2010 International Society for Heart and Lung Transplantation. 
      Published by Elsevier Inc. All rights reserved.
FAU - Saini, Deepti
AU  - Saini D
AD  - Department of Surgery, Washington University School of Medicine, St. Louis, 
      Missouri 63110, USA.
FAU - Angaswamy, Nataraju
AU  - Angaswamy N
FAU - Tiriveedhi, Venkataswarup
AU  - Tiriveedhi V
FAU - Fukami, Naohiko
AU  - Fukami N
FAU - Ramachandran, Sabarinathan
AU  - Ramachandran S
FAU - Hachem, Ramsey
AU  - Hachem R
FAU - Trulock, Elbert
AU  - Trulock E
FAU - Meyers, Brian
AU  - Meyers B
FAU - Patterson, Alexander
AU  - Patterson A
FAU - Mohanakumar, Thalachallour
AU  - Mohanakumar T
LA  - eng
GR  - R01 HL056643/HL/NHLBI NIH HHS/United States
GR  - R01 HL056643-13A1/HL/NHLBI NIH HHS/United States
GR  - HL056643/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100805
PL  - United States
TA  - J Heart Lung Transplant
JT  - The Journal of heart and lung transplantation : the official publication of the 
      International Society for Heart Transplantation
JID - 9102703
RN  - 0 (Antibodies, Anti-Idiotypic)
RN  - 0 (HLA Antigens)
RN  - 0 (alpha-Defensins)
RN  - 0 (beta-Defensins)
RN  - 0 (human neutrophil peptide 1)
RN  - 0 (human neutrophil peptide 2)
RN  - 0 (human neutrophil peptide 3)
RN  - EC 1.11.1.7 (Peroxidase)
SB  - IM
MH  - Animals
MH  - Antibodies, Anti-Idiotypic/analysis/*blood
MH  - Bronchiolitis Obliterans/etiology/*immunology
MH  - Bronchoalveolar Lavage Fluid/chemistry/immunology
MH  - Disease Models, Animal
MH  - Epithelial Cells/immunology
MH  - Graft Rejection/immunology
MH  - HLA Antigens/*immunology
MH  - Humans
MH  - Lung Transplantation/adverse effects/*immunology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Neutrophil Infiltration
MH  - Peroxidase/analysis
MH  - alpha-Defensins/analysis/*immunology
MH  - beta-Defensins/*biosynthesis/blood
PMC - PMC2991612
MID - NIHMS227367
COIS- There is no financial or professional conflict of interest by any of the authors 
      of this manuscript.
EDAT- 2010/08/10 06:00
MHDA- 2011/03/17 06:00
PMCR- 2011/12/01
CRDT- 2010/08/10 06:00
PHST- 2010/03/24 00:00 [received]
PHST- 2010/05/14 00:00 [revised]
PHST- 2010/05/26 00:00 [accepted]
PHST- 2010/08/10 06:00 [entrez]
PHST- 2010/08/10 06:00 [pubmed]
PHST- 2011/03/17 06:00 [medline]
PHST- 2011/12/01 00:00 [pmc-release]
AID - S1053-2498(10)00423-7 [pii]
AID - 10.1016/j.healun.2010.05.036 [doi]
PST - ppublish
SO  - J Heart Lung Transplant. 2010 Dec;29(12):1330-6. doi: 
      10.1016/j.healun.2010.05.036. Epub 2010 Aug 5.