Azithromycin Fails to Prevent Accelerated Airway Obliteration in T-bet Mouse Lung Allograft Recipients

Overview

Journal Transplant Proc

Specialty General Surgery

Date 2018 Jun 9

PMID 29880387

Citations 1

Authors

E A Lendermon

J M Dodd-O

T A Coon

X Wang

C R Ensor

N Cardenes

C L Koodray

H L Heusey

M F Bennewitz

P Sundd

G C Bullock

I Popescu

L Guo

C P ODonnell

M Rojas

J F McDyer

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Citing Articles

Cross-Regulation of F-Box Protein FBXL2 with T-bet and TNF-α during Acute and Chronic Lung Allograft Rejection.

Das A, Wang X, Wei J, Hoji A, Coon T, Popescu I J Immunol. 2022; 209(9):1788-1795.

PMID: 36113884 PMC: 9588753. DOI: 10.4049/jimmunol.2200245.

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