Journal article
Azithromycin Fails to Prevent Accelerated Airway Obliteration in T-bet-/- Mouse Lung Allograft Recipients
Transplantation proceedings, Vol.50(5), pp.1566-1574
06/01/2018
DOI: 10.1016/j.transproceed.2018.02.070
PMCID: PMC8136584
PMID: 29880387
Abstract
Cellular and molecular mechanisms of acute and chronic lung allograft rejection have yet to be clearly defined, and obliterative bronchiolitis (OB) remains the primary limitation to survival in lung transplant recipients (LTRs). We have previously shown that T-bet–deficient recipients of full major histocompatibility complex (MHC)-mismatched, orthotopic left lung transplants develop accelerated obliterative airway disease (OAD) in the setting of acute cellular rejection characterized by robust alloimmune CD8+ interleukin (IL)-17 and interferon (IFN)-γ responses that are attenuated with neutralization of IL-17. Azithromycin has been shown to be beneficial in some LTRs with bronchiolitis obliterans syndrome/OB. Here, we evaluated the effects of azithromycin on rejection pathology and T-cell effector responses in T-bet-/- recipients of lung transplants.
Orthotopic left lung transplantation was performed in BALB/c → B6 wild type or BALB/c → B6 T-bet-/- strain combinations as previously described. Mice treated with azithromycin received 10 mg/kg or 50 mg/kg subcutaneously daily. Lung allograft histopathology was analyzed at day 10 or day 21 post-transplantation, and neutrophil staining for quantification was performed using anti-myeloperoxidase. Allograft mononuclear cells were isolated at day 10 for T-cell effector cytokine response assessment using flow cytometry.
We show that while azithromycin significantly decreases lung allograft neutrophilia and CXCL1 levels and attenuates allospecific CD8+ IL-17 responses early post-transplantation, OAD persists in T-bet–deficient mice.
Our results indicate that lung allograft neutrophilia is not essential for the development of OAD in this model and suggest allospecific T-cell responses that remain despite marked attenuation of CD8+ IL-17 are sufficient for obliterative airway inflammation and fibrosis.
•The effects of azithromycin in a T-bet–deficient mouse lung transplantation model are studied.•Azithromycin significantly decreases both lung allograft neutrophilia and IL-17 responses.•Severe acute rejection pathology with obliterative airway inflammation and fibrosis persists despite azithromycin.
Details
- Title: Subtitle
- Azithromycin Fails to Prevent Accelerated Airway Obliteration in T-bet-/- Mouse Lung Allograft Recipients
- Creators
- E.A. Lendermon - University of PittsburghJ.M. Dodd-o - Johns Hopkins MedicineT.A. Coon - University of PittsburghX. Wang - University of PittsburghC.R. Ensor - University of PittsburghN. Cardenes - University of PittsburghC.L. Koodray - University of PittsburghH.L. Heusey - University of PittsburghM.F. Bennewitz - University of PittsburghP. Sundd - University of PittsburghG.C. Bullock - University of PittsburghI. Popescu - University of PittsburghL. Guo - University of PittsburghC.P. O'Donnell - University of Pittsburgh School of MedicineM. Rojas - University of PittsburghJ.F. McDyer - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Transplantation proceedings, Vol.50(5), pp.1566-1574
- DOI
- 10.1016/j.transproceed.2018.02.070
- PMID
- 29880387
- PMCID
- PMC8136584
- NLM abbreviation
- Transplant Proc
- ISSN
- 0041-1345
- eISSN
- 1873-2623
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 06/01/2018
- Academic Unit
- Pathology
- Record Identifier
- 9984697737002771
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