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P027. Th1/Th17 profiles in Crohn's disease: A cross sectional single centre study in postoperative Crohn's disease

P027. Th1/Th17 profiles in Crohn's disease: A cross sectional single centre study in postoperative Crohn's disease

A.U. Murugananthan1, D. Bernardo1, P. Tozer1, C.T. Tee1, E.R. Mann1, A.L. Hart1, N. Arebi2, S.C. Knight1, H.O. Al-Hassi1

1Antigen Presentation Research Group, Imperial College, London, United Kingdom; 2St Mark's Hospital, London, United Kingdom

Rationale and Aims: Th1 and Th17 pathways have been implicated in Crohn's disease (CD). Within postoperative resection samples healthy ileum shows high TGFβ levels in patients who subsequently develop recurrence [1], with TGFβ being a known activator of the Th17 response. Other studies show CD to be dominated by a Th1 cytokine profile, with high levels of IFNγ [2], which reduce the Th17 and augment the Th1 responses. Th1/Th17 responses in postoperative CD have not been examined. We aimed to study tissue Th1/Th17 cytokine secretion after in-vitro biopsy culture in postoperative CD.

Methods: Colonoscopy was undertaken in postoperative CD patients. Recurrence graded as no/minimal inflammation (Rutgeert Score [RS] ≤ i1) or progressive inflammation (RS ≥ i2). Ileal biopsies were cultured overnight and cell free supernatants obtained. Cytokines (IL-2, IL-4, IL10, IL17 TNF a, INFγ and IL6) were assessed in the supernatants by flow cytometry using cytometric bead array (Becton Dickinson™). Statistical analysis was via unpaired t-tests.

Results: Consecutive patients attending endoscopy (n = 24, 9m/15f) were identified over a 1-year period. Mean age 45.0 yrs and time from I-C resection was 5.8 years. 5 patients were smokers. Drugs were thiopurines 13, Infliximab 1 and nil 10. Endoscopic severity was i0 n = 5, i1 n = 6, i2 n = 5, i3 n = 3, i4 n = 5. Mean cytokine concentrations from supernatants are shown below.

 Mean Cytokine Level ± SEM (pg/ml)
CytokineRutgeert Score ≤ 1Rutgeert Score ≥ 2
IL-22.4±0.12.3±0.1
IL-40.3±0.20.5±0.3
IL-62469.1±969.25485.7±2020
IL-107.3±4.84.6±0.8
TNF-α1.6±0.12.7±1.5
IFN-γ1.3±0.26.6±2.1
IL-17a0.5±0.42.5±0.7

Comparison between RS ≤ 1 and ≥2 showed that pro-inflammatory cytokines IL17a (p < 0.02) and IFNγ (p < 0.03) were significantly higher in RS i2-i4 neo terminal ileum as compared with RS i0–i1. The regulatory cytokine IL-10 was significantly higher in patients with RS ≤ 1 (p < 0.038).

Conclusions: Cytokine profiles in the group with RS ≥ 2, show higher levels of IL 17a and IFNγ and reduced IL10 compared to RS ≤ 1. This profile supports the Th17 and Th1 mediated response as one of the early instigators of endoscopic progression in postoperative CD. Our observation is consistent with findings of a T cell subset capable of producing cytokines involved in both Th1 and Th17 responses [3]. Previous therapies directed at Th1 pathway e.g. anti-IL-12p40 antibody ustekinumab and anti-IFNγ Fontolizumab failed to show significant clinical benefit in CD. Given our findings, targeting the Th17 pathway e.g. with anti-IL-23 antibodies and anti-IL17 may deliver an improved therapeutic outcome.

1. Scarpa, M et al. TGF-beta1 and IGF-1 Production and Recurrence of Crohn's Disease After Ileo-Colonic Resection. J Surg Res, 152(1), 24–31, 2008.

2. Colpaert, S et al. In vitro analysis of interferon gamma (IFN-gamma) and interleukin-12 (IL-12) production and their effects in ileal Crohn's disease. Eur Cytokine Netw 13, 431–437, 2002.

3. Boniface, K et al. Human Th17 cells comprise heterogeneous subsets including IFN-gamma-producing cells with distinct properties from the Th1 lineage. J Immunol 185, 679–687, 2010.