The role of the IL23/IL17 axis in bronchiolitis obliterans syndrome after lung transplantation.
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.
Vanaudenaerde
B M
BM
Laboratory of Pneumology, Katholieke Universiteit Leuven, Leuven, Belgium.
De Vleeschauwer
S I
SI
Vos
R
R
Meyts
I
I
Bullens
D M
DM
Reynders
V
V
Wuyts
W A
WA
Van Raemdonck
D E
DE
Dupont
L J
LJ
Verleden
G M
GM
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
D020381:Interleukin-17; D053759:Interleukin-23; D012333:RNA, Messenger