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P031. Simultaneously restoration of Foxp3 (+) regulatory T cells subsets, type 1-like regulatory T cells and B cells correlates with clinical response to infliximab therapy for IBD

Z. Li1, S. Vermeire1, D. Bullens2, M. Ferrante1, K. Van Steen3, M. Noma1, P. Rutgeerts1, J.L. Ceuppens2, G. Van Assche4, 1Catholic University of Leuven, IBD Group, Division of Gastroenterology, Leuven, Belgium, 2Catholic University of Leuven, Lab of Clinical Immunology, Leuven, Belgium, 3University de Liège, Dept of Bioinformatics-Statistical Genetics, Liège, Belgium, 4Catholic University of Leuven, IBD Group, Division of Gastroenterology, Lab of Clinical Immunology, Leuven, Belgium

Background

Infliximab (IFX) therapy increases circulating Foxp3 (+) T cells in patients (pts) with Crohn's disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), psoriasis & Behçet's disease. Co-expression of CD45RA & Foxp3 distinguishes resting & active Treg (rTreg & aTreg) from Foxp3 (+) effector T cells (Teff). IFX up-regulates blood memory B cells in RA. In IBD, IgM (+) memory B cells are decreased. CD19(+) B cells in the inflamed intestinal mucosa predicts long lasting remission to IFX in CD. IL-10/IFNg producing Tr1-like cells (Tr1L) have been characterized in human blood. Genetically modified B cells induce Tr1L in vivo. Recently resting B cells have a role in expanding Foxp3+Treg.

We aimed to investigate the kinetics of these cells in pts with IBD during IFX therapy.

Methods

Blood was taken from healthy controls (HC, N = 37) and pts with IBD (70 CD, 39 UC) before & during IFX therapy (5 mg/kg IV 0–2-6 and q8 wks). The 3 subsets of Foxp3 T cells, Tr1L and B cells were assessed by flow cytometry after staining for CD4, CD45RA, Foxp3, CD25, CD127 and CD19. Assessment of symptoms, endoscopic healing & histological improvement was used to label pts as responders (RS) or non-responders (NRS) at 4 to 12 weeks after start of therapy.

Results

Pts with active IBD before therapy had low circulating rTreg, aTreg, Foxp3Teff, Tr1L and B cells, compared with HC. Changes in these 5 populations with IFX treatment are represented in Table 1.

Significant differences between RS and NRS were seen only for aTreg, B cells and Tr1L (p = 0.0067, <0.001, <0.001), but not in rTreg and Foxp3Teff (p = 0.32, 0.72).

CRP negatively correlated with rTreg, aTreg, Tr1L (as %of CD4T cells) & B cells (absolute number) (p = 0.0011, r = − 0.32; p < 0.001, r = − 0.40; p < 0.001, r = − 0.39; p = 0.044, r = − 0.21).

B cells positively correlated with rTreg, aTreg & Tr1L (absolute number) (p = 0.002, r = 0.31; p < 0.001, r = 0.49; p < 0.001, r = 0.37).

Table 1
 BTRSNRSHC
   p p p
rTreg0.43±0.0801.57±0.21<0.0011.14±0.24<0.0011.47±0.16<0.001
aTreg0.62±0.122.70±0.26<0.0011.48±0.330.00572.40±0.17<0.001
Foxp3+Teff2.38±0.273.19±0.240.093.02±0.410.253.75±0.340.002
Tr1L4.79±0.6826.09±2.21<0.0018.92±1.000.01316.82±1.7<0.001
B cells0.17±0.020.25±0.030.0350.14±0.010.310.27±0.020.002
p: p-value compared to BT (baseline before therapy); RS: responder; NRS: non responder; HC: healthy control; N = 25; 59; 15; 37. 106/L blood mean±SEM for Tr1L, 109/L for others.

Conclusion

Circulating Foxp3T cells, Tr1L & B cells are decreased in active IBD and an increase in these cells (except for Foxp3Teff) correlates with biological response and/or with the clinical response to IFX. The positive correlation between B cells and Foxp3Treg subsets or Tr1L suggests there might be a cross talk between B cells & Tregs.