Zhe Li1, Séverine Vermeire, Dominique Bullens, Marc Ferrante, Kristel Van Steen, Maja Noman, Paul Rutgeerts, Jan L Ceuppens, Gert Van Assche. 1. *Clinical Immunology Unit, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium; †Division of Gastroenterology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium; ‡Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium; and §Department of Bioinformatics-Statistical Genetics, Université de Liège, Liège, Belgium.
Abstract
BACKGROUND: A defect in regulatory T cells (Tregs) may be involved in the pathogenesis of inflammatory bowel diseases (IBD). Several subsets of human Foxp3+ Tregs (activated and resting Tregs) have now been identified, as well as an IL-10 and IFN-γ double producing Foxp3 type 1 regulatory-like T cell (Tr1L). We have quantified these Tregs in patients with active IBD and during therapy with infliximab (IFX). METHODS: Blood samples were obtained from healthy controls (n = 54) and patients with active IBD, either before (n = 62) or during IFX therapy (n = 75). Tregs were identified by immunofluorescent staining and flow cytometry analysis. Resting and activated Foxp3+ Tregs can be differentiated from Foxp3+ effector T cells (Foxp3+ Teff) by the expression of CD45RA. Tr1L are identified as CD4+CD45RA-CD25-CD127-Foxp3- T cells. RESULTS: A numerical deficiency of circulating resting Tregs, activated Treg cells, and Tr1L was documented in patients with active IBD. Baseline levels of these Treg subsets predicted clinical responses to IFX. We documented an upregulation of all 3 subsets during IFX therapy. Moreover, after therapy, significant differences in Treg subsets were seen between responders and nonresponders to IFX. Restoration of Tregs correlated with the clinical and biological response to IFX therapy. Trough serum levels of IFX positively correlated with the proportion of activated Treg cells and Tr1L during therapy. CONCLUSIONS: IFX therapy, when successful, results in upmodulation of the different types of Treg cells in the blood of patients with IBD. This effect might be relevant for understanding the mechanism of action of anti-TNF agents.
BACKGROUND: A defect in regulatory T cells (Tregs) may be involved in the pathogenesis of inflammatory bowel diseases (IBD). Several subsets of humanFoxp3+ Tregs (activated and resting Tregs) have now been identified, as well as an IL-10 and IFN-γ double producing Foxp3 type 1 regulatory-like T cell (Tr1L). We have quantified these Tregs in patients with active IBD and during therapy with infliximab (IFX). METHODS: Blood samples were obtained from healthy controls (n = 54) and patients with active IBD, either before (n = 62) or during IFX therapy (n = 75). Tregs were identified by immunofluorescent staining and flow cytometry analysis. Resting and activated Foxp3+ Tregs can be differentiated from Foxp3+ effector T cells (Foxp3+ Teff) by the expression of CD45RA. Tr1L are identified as CD4+CD45RA-CD25-CD127-Foxp3- T cells. RESULTS: A numerical deficiency of circulating resting Tregs, activated Treg cells, and Tr1L was documented in patients with active IBD. Baseline levels of these Treg subsets predicted clinical responses to IFX. We documented an upregulation of all 3 subsets during IFX therapy. Moreover, after therapy, significant differences in Treg subsets were seen between responders and nonresponders to IFX. Restoration of Tregs correlated with the clinical and biological response to IFX therapy. Trough serum levels of IFX positively correlated with the proportion of activated Treg cells and Tr1L during therapy. CONCLUSIONS:IFX therapy, when successful, results in upmodulation of the different types of Treg cells in the blood of patients with IBD. This effect might be relevant for understanding the mechanism of action of anti-TNF agents.
Authors: Maria E Joosse; Celia L Menckeberg; Lilian F de Ruiter; H Rolien C Raatgeep; Lisette A van Berkel; Ytje Simons-Oosterhuis; Irma Tindemans; A Femke M Muskens; Rudi W Hendriks; Remco M Hoogenboezem; Tom Cupedo; Lissy de Ridder; Johanna C Escher; Sharon Veenbergen; Janneke N Samsom Journal: Mucosal Immunol Date: 2018-08-20 Impact factor: 7.313
Authors: Wilhelmina Maria Cornelia Timmermans; Jan Alexander Michael van Laar; Petrus Martinus van Hagen; Menno Cornelis van Zelm Journal: Clin Transl Immunology Date: 2016-12-16
Authors: Megan R Sanctuary; Rick H Huang; Ashleigh A Jones; Marisa E Luck; Carol M Aherne; Paul Jedlicka; Edwin F de Zoeten; Colm B Collins Journal: Mucosal Immunol Date: 2018-10-16 Impact factor: 7.313