Interleukin-17 and airway inflammation: a longitudinal airway biopsy study after lung transplantation.
BACKGROUND
Interleukin-17 (IL-17) is a pro-inflammatory cytokine produced from CD4+ T cells and is associated with neutrophilia in infection, ischemia-reperfusion injury, and possibly acute and chronic rejection (bronchiolitis obliterans syndrome, or BOS) after lung transplantation (LTx). Everolimus (ERL) decreases acute rejection, possibly via decreasing airway CD4+ cells and neutrophils. This prospective study aims to assess: (1) the possible role of IL-17 as a link between LTx clinical outcomes (such as infection, acute rejection and BOS) and airway immunopathologic measures from endobronchial biopsy (EBB) and bronchoalveolar lavage (BAL); and (2) any differences in IL-17 production between ERL and azathioprine (AZA)-based immunosuppression.


METHODS
This sub-study, from a larger, prospective clinical ERL vs AZA randomized, controlled trial, examines EBB IL-17 expression, relating this to clinical outcomes, BAL and EBB cell counts. EBB IL-17 staining was measured by immunohistologic techniques and expressed as cells per square millimeter of lamina propria.


RESULTS
Thirty-four LTx patients were randomized in a double-blind study (ERL = 19, AZA = 15) and underwent a total of 113 bronchoscopies over a 3-year follow-up period. Twenty-six EBBs were taken from LTx recipients with BOS of at least Grade 0p (10 patients). Univariate associations correlated IL-17 positively with EBB CD8+ cells (R2 = 0.010, p = 0.001) and negatively with days post-LTx (R2 = 0.07, p = 0.002). In a multivariate model, IL-17 variability was explained by: days post-LTx (6.2%, p = 0.02); EBB CD8+ (5.9%, p = 0.02); cytomegalovirus mismatch (6.1%, p = 0.02); BAL lymphocyte percentage (4.2%, p = 0.05); and clinical infection (3.7%, p = 0.06).


CONCLUSIONS
IL-17 is associated with the early post-LTx time period and airway CD8+ cells. Unexpectedly, rejection grade, BOS, BAL IL-8 and neutrophil counts are not associated. ERL appears not to directly affect IL-17, despite its effects on CD4 cells.
Snell
Gregory I
GI
Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital and Monash University, Melbourne, Victoria, Australia. g.snell@alfred.org.au
Levvey
Bronwyn J
BJ
Zheng
Ling
L
Bailey
Michael
M
Orsida
Bernadette
B
Williams
Trevor J
TJ
Kotsimbos
Tom C
TC
D001379:Azathioprine / Q000494:pharmacology; D001706:Biopsy; D018893:Bronchoalveolar Lavage; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D004311:Double-Blind Method; D000068338:Everolimus; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D016040:Lung Transplantation / Q000009:adverse effects / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011014:Pneumonia / Q000378:metabolism* / Q000473:pathology*; D011446:Prospective Studies; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology
D007166:Immunosuppressive Agents; D020381:Interleukin-17; D000068338:Everolimus; D001379:Azathioprine; D020123:Sirolimus