title: The role of the IL23/IL17 axis in bronchiolitis obliterans syndrome after lung transplantation.
abstract: Bronchiolitis obliterans syndrome (BOS) is the leading cause of death after lung transplantation. Treatment is challenging, as the precise pathophysiology remains unclear. We hypothesize that T(H)17 lineage plays a key role in the pathophysiology of BOS by linking T-cell activation to neutrophil influx and chronic inflammation. In a cross-sectional study, bronchoalveolar lavage (BAL) samples of 132 lung transplant recipients were analyzed. Patients were divided in four groups: stable or suffering from infection (INF), acute rejection (AR) or BOS. The upstream T(H)17 skewing (TGF-beta/IL1beta/IL6/IL23), T(H)17 counteracting (IL2), T(H)17 effector cytokine (IL17) and the principal neutrophil-attracting chemokine (IL8), were quantified at the mRNA or protein level in combination with the cell profiles. The BOS group (n = 36) showed an increase in IL1beta protein (x1.5), IL6 protein (x3), transforming growth factor-beta (TGF-beta) mRNA (x3), IL17 mRNA (x20), IL23 mRNA (x10), IL8 protein (x2), IL8 mRNA (x3) and a decrease in IL2 protein (x0.8). The infection group (n = 11) demonstrated an increase in IL1beta protein (x5), IL6 protein (x20), TGF-beta mRNA (x10), IL17 mRNA (x300), IL23 mRNA (x200) and IL8 protein (x6). The acute rejection group (n = 43) only revealed an increase in IL6 protein (x6) and IL8 protein (x2) and a decrease in IL2 protein (x0.7). Lymphocytes and neutrophils were increased in all groups compared to the stable (n = 42). Our findings demonstrate the IL23/IL17 axis to be involved in the pathophysiology of BOS potentially triggering the IL8-mediated neutrophilia. IL6, IL1beta and IL23 seem to be skewing cytokines and IL2 a counteracting cytokine for T(H)17 alignment. The involvement of TGF-beta could not be confirmed, either as T(H)17 steering or as counteracting cytokine.
authors.affiliation: Laboratory of Pneumology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: B M
authors.initials: BM
authors.lastname: Vanaudenaerde
authors.forename: S I
authors.initials: SI
authors.lastname: De Vleeschauwer
authors.forename: R
authors.initials: R
authors.lastname: Vos
authors.forename: I
authors.initials: I
authors.lastname: Meyts
authors.forename: D M
authors.initials: DM
authors.lastname: Bullens
authors.forename: V
authors.initials: V
authors.lastname: Reynders
authors.forename: W A
authors.initials: WA
authors.lastname: Wuyts
authors.forename: D E
authors.initials: DE
authors.lastname: Van Raemdonck
authors.forename: L J
authors.initials: LJ
authors.lastname: Dupont
authors.forename: G M
authors.initials: GM
authors.lastname: Verleden
mesh_terms: D000328:Adult; D001989:Bronchiolitis Obliterans / Q000378:metabolism / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000502:physiology*; D053759:Interleukin-23 / Q000502:physiology*; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D013577:Syndrome
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; D012333:RNA, Messenger