Therapy with anti-TNF alpha Antibody Enhances Number and Function of Foxp(3+) Regulatory T Cells in Inflammatory Bowel Diseases

Background: Inflammatory bowel diseases (IBDs) are associated with up-regulation of TNF alpha, hyperactivation of proinflammatory effector T cells (Teffs) and inefficient control by regulatory CD4(+)CD25(+)Foxp3(+) T cells (Tregs). The aim of this prospective study was to investigate the short-term impact of treatment of IBD patients with anti-TNF alpha antibodies (infliximab or adalimumab) on the frequency, phenotype, and suppressive function of Tregs. Methods: Active IBD patients including 16 with Crohn's disease and 9 with ulcerative colitis were treated with anti-TNF alpha mAb. PBMCs were harvested immediately before and 2 weeks after the first injection. The frequency and phenotype of circulating CD4(+)CD25(+)Foxp3(+) Tregs were analyzed by flow cytometry, and their suppressive function was assessed by the ability of purified CD4(+)CD25(+)CD127(-) Tregs to inhibit the proliferation of allogenic CD4(+)CD25(-) Teffs. Results: CD4(+)CD25(+)Foxp3(+) Treg frequency was significantly lower in active IBD patients than in controls (2.8% +/- 0.4% vs. 4.6% +/- 0.6%, respectively; P = 0.01). On day 14 following the first anti-TNF alpha infusion, the frequency of circulating Tregs was significantly enhanced in IBD patients (4.0% +/- 0.5% vs. 2.8% +/- 0.4%, before treatment; P = 0.001), with a 2- to 3-fold increase in the intensity of Foxp3 expression. In addition, infliximab treatment enhanced the suppressive function of circulating Tregs, as shown by inhibition of Teff proliferation at a 1:8 Treg/Teff ratio (28% +/- 5% vs. 66% +/- 10%, after treatment; P = 0.04). Conclusions: These data demonstrate that anti-TNF alpha treatment of active IBD rapidly enhances the frequency of functional Foxp3(+) Tregs in blood and potentiates their suppressive function. This indicates that Treg potentiation may represent an unanticipated outcome of anti-TNF alpha biotherapy in IBD.