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P070. Activation of the Th9/Th17 pathway in inflammatory bowel disease patients failing anti‑TNF therapy

P070. Activation of the Th9/Th17 pathway in inflammatory bowel disease patients failing anti‑TNF therapy

N. Nalleweg1, B. Weigmann1, R. Atreya1, A. Hartmann2, M. Neurath1, J. Mudter1

1Universital Hospital Erlangen, Medical Clinic 1, Erlangen, Germany; 2Institute for Pathology, Erlangen, Germany

Background: A new subpopulation of CD4+ T cells has recently been described, that is able to produce the cytokine IL‑9. The data show that IL‑9 can be produced to a considerable extent by Th17 cells. So far, no data are known dealing with the secretion of IL‑9 in inflammatory bowel diseases.

Methods: Biopsies (colon) were taken from patients with Crohn's disease (CD) and ulcerative colitis (UC), isolation of mRNA, quantitative PCR of TNF, IL‑6, IL‑9, IL‑17, IL‑21, IL‑22, CCL20, IL‑18R1, IL‑23R, CXCR3 and IRF‑4 were performed. Histological scoring of the inflammation level (IL0–3). Correlation of the cytokine expression with the inflammation level.

Cross-sectional study: Comparison of patients failing anti‑TNF therapy with patients who responded to the treatment.

Prospective study: Acquisition of UC and CD patients before and 8–12 weeks after initiation of therapy with anti‑TNF antibodies and biopsy sampling at the different time points, respectively.

Results: In the cross-sectional study UC (n = 27) and CD (n = 21) showed an overexpression of the Th17 cytokines IL‑17, IL‑21 and IL‑22 as compared to control patients (CO, n = 9). The expression depended on the degree of inflammation. IL‑9 was significantly increased in UC compared with CO; no statistical significance was observed for CD. IL‑17, IL‑21, IL‑22 and CCL20, latter is expressed by Th17 cells, were significantly overexpressed as well. A positive correlation between IL‑17 and CCL20 (r = 0.6) could be shown for CD and UC; for the Th17 marker CXCR3 no correlation could be observed. A medium correlation was found between IL‑17 and IL‑23R (r = 0.56) for UC; however not for CD. Contrary, there was a positive correlation between IL‑17 and IL‑18R1 (r = 0.56) in CD. Expression of IL‑17 was significantly higher for CD and UC anti‑TNF therapy non-responders. IL‑9, IL‑21 and IL‑22 were significantly overexpressed in non-responders compared to responders. In prospective studies (n = 6) a significant increase of the IL‑17 production was observed for non-responders.

Conclusions: IL‑9 is overexpressed in UC. The IL‑17 signalling pathway presents a possible escape pathway for patients failing anti‑TNF therapy treatment. Possibly the Th17 phenotypes differ between CD and UC.

1. Ghoreschi (2010), Generation of pathogenic T(H)17 cells in the absence of TGF‑b signaling, Nature.

2. Veldhoen (2008), Transforming growth factor‑b ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9‑producing subset, Nature Immunology.