In Crohn's Disease, Anti-TNF-α Treatment Changes the Balance between Mucosal IL-17, FOXP3, and CD4 Cells

Veera Hölttä,Paula Klemetti,Mia Westerholm-Ormio,Erkki Savilahti,Martti Färkkilä,Taina Sipponen,Outi Vaarala,Kaija-Leena Kolho,Harri M Salo

doi:10.5402/2012/505432

Abstract

Aim. In Crohn's disease (CD), anti-TNF-α treatment is a potent medication. We aimed to characterize the effect of anti-TNF-α treatment on T effector and regulatory cells. Material and Methods. We studied T-effector and regulatory cells on cellular and mRNA levels in intestinal biopsy samples from 13 Crohn's disease patient. Biopsies were obtained at baseline and 3 months after anti-TNF-α treatment, and from 14 inflammation-free control subjects. Results. Patients had higher numbers of ileal IL-17+ and forkhead box P3 (FOXP3)+ cells than did control subjects, both before ( P ≤ 0.001 and P ≤ 0.05, resp.) and after the anti-TNF-α treatment (P ≤ 0.01, P ≤ 0.01). Intestinal interferon-γ and IL-17 mRNA expression was higher in Crohn's disease and remained elevated after anti-TNF-α treatment. The ratio of IL-17+ cells to CD4+ cells decreased (P ≤ 0.05) and compared to baseline the ratio of IL-17+ cells to FOXP3+ was lower after treatment (P ≤ 0.05). Conclusions. TNF-α-blocking agents improved intestinal balance between IL-17+ T-effector and regulatory T cells, although intestinal IL-17 upregulation remained elevated.

Highlights

Chronic intestinal inflammation characterizes Crohn’s disease (CD), the etiology of which is incompletely understood, but likely intestinal microflora components cause aberrant immune responses
In CD, a marked decrease in Crohn’s disease endoscopic index of severity (CDEIS) associated with a decreasing ratio of intestinal IL-17+ cells related to the numbers of CD4+ cells and forkhead box P3 (FOXP3)+ cells
These results suggest that anti-Tumour necrosis factor (TNF)-α treatment leads to an improved balance between regulatory T cells and IL-17 effector T cells

Summary

Introduction

Chronic intestinal inflammation characterizes Crohn’s disease (CD), the etiology of which is incompletely understood, but likely intestinal microflora components cause aberrant immune responses. Discovery of NOD2 genetic polymorphism has identified CARD15 allele as a risk factor for CD and supports the important role of the innate immune system in CD pathogenesis. Biological agents contribute to the repertoire of medical treatment of CD: tumor necrosis factor- (TNF-) α blocking therapy is effective in inducting and maintaining remission [7, 8]. In active CD, infliximab induces rapid clinical improvement as well as rapid endoscopic and histological healing [9]; the cessation of anti-TNF-α therapy tends to lead to a disease relapse. Conventional therapies fail to normalize the numbers of IL-17+ cells in the ileal lamina propria (LP), even during endoscopic remission [4]. Whether TNF-α-blocking therapy normalizes the number of intestinal Th17 cells remains unknown. Few studies of infliximab’s effect on Th17 cells exist in rheumatoid arthritis infliximab, which seems to reduce peripheral Th17 cells [11]

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