Li, Z. et al. Reciprocal changes of Foxp3 expression in blood and intestinal mucosa in IBD patients responding to infliximab. Inflamm. Bowel Dis. 16, 1299-1310

Laboratory of Experimental Immunology, Catholic University of Leuven, Leuven, Belgium.
Inflammatory Bowel Diseases (Impact Factor: 4.46). 08/2010; 16(8):1299-310. DOI: 10.1002/ibd.21229
Source: PubMed


Immune therapies may act in inflammatory bowel diseases (IBD) by modulating regulatory T cells (Tregs). Therefore, we investigated the effect of infliximab (IFX) therapy on Forkhead box protein3 (Foxp3) T cells in blood and intestinal mucosa from Crohn's disease (CD) and ulcerative colitis (UC).
Forty patients with active IBD (23 CD / 17 UC) were treated with IFX 5 mg/kg intravenously at weeks 0, 2, 6, and each 8 weeks thereafter. Blood samples were obtained before every infusion and T-lymphocyte subsets were characterized by flow cytometry. Foxp3 expression in intestinal biopsies from 43 patients with active IBD (19 CD / 24 UC) before and after IFX infusion and from 6 controls were assessed by quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. Plasma C-reactive protein (CRP), clinical response, and endoscopic healing data were collected in parallel.
IFX therapy resulted in a significant and sustained relative increase of CD4(+)CD25(+)Foxp3(+) Treg and of CD4(+)CD25(-)Foxp3(+) Treg cells in peripheral blood (both P < 0.0001 compared to baseline), particularly in responders (both P < 0.05 compared to nonresponders). The change in CRP over time inversely correlated with the increase of CD25(+)Foxp3(+) cells (P < 0.001, r = -0.39) and durable clinical response was associated with a sustained increase of circulating Foxp3(+) cells. Surprisingly, IFX therapy downregulated mucosal mRNA and protein expression of Foxp3 in UC and CD responders (both P < 0.001) but not in nonresponders.
IFX therapy has opposite effects in Foxp3(+) Treg cells in blood and gut mucosa, which suggests a redistribution of this important T-cell subset.

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Available from: Jan Ceuppens, Nov 13, 2014
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    • "In IBD patients, data on Tregs have been somewhat conflicting. Recent studies showed that anti-TNFí µí»¼ treatment increases Treg level in the peripheral blood of IBD patients [21] [22] [23], especially in clinical responders [22] [23]. However, this has not been confirmed by the study of Grundström et al. [24]. "
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    ABSTRACT: Treg modulation has been hypothesized as one of the mechanisms by which antitumor necrosis factor α (TNFα) agents exert their action in rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). However, data in IBD are still conflicting. We evaluated CD4+CD25+FOXP3+ (Tregs) by flow cytometry in peripheral blood from 32 adult IBD patient before (T0) and after the induction of anti-TNFα therapy (T1). Eight healthy controls (HCs) were included. We also evaluated the number of FOXP3+ cells in the lamina propria (LP) in biopsies taken in a subset of patients and controls. Treg frequencies were significantly increased in peripheral blood from our patients after anti-TNFα therapy compared to T0. T1 but not T0 levels were higher than HC. The increase was detectable only in clinical responders to the treatment. A negative correlation was found among delta Treg levels and the age of patients or disease duration and with the activity score of Crohn's disease (CD). No significant differences were found in LP FOXP3+ cells. Our data suggest the possibility that in IBD patients the treatment with anti-TNFα may affect Treg percentages and that Treg modifications may correlate with clinical response, but differently in early versus late disease.
    08/2013; 2013(5):286368. DOI:10.1155/2013/286368
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    • "Two weeks after treatment, the number of circulating Tregs increased twice with a 2–3 fold increase in FoxP3 expression and a 2 fold enhancement in their suppressive function [61]. Interestingly, clinical responders to therapy with anti-TNF agents had durable clinical remission with sustained increases in the number of circulating FoxP3 positive cells [65] "
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    ABSTRACT: T regulatory cells (Tregs) play a critical role in the immunologic tolerance to the graft in transplantation. Thus, due to their immunosuppressive capability, ex vivo expanded Tregs may be used as a cellular therapy and an attractive novel strategy to control chronic rejection and eliminate need for lifelong pharmacological immunosuppression. Since Treg therapy is still in its infancy, initially Tregs still need to be applied in combination with pharmacological agents to prevent rejection. Fortunately, some of the medications have been shown to enhance the function and number of Tregs. In the clinic, different immunosuppressive regimens are used for individual patients for different types of organ transplantation. In this review, we present the most commonly used pharmacological agents for immunosuppression and discuss how they affect the Treg population. It is extremely difficult to dissect the effect of single agent on Tregs population in clinical settings since usually the combination of several medications is applied at the same time for graft protection. Nevertheless, experimental and clinical data indicate that thymoglobulin as immunosuppressive induction and mTOR inhibitors as immunosuppressive maintenance agents have the most beneficial effect on Treg population in the blood. Among supplemental agents promoting Tregs, anti-TNFα preparations have been in clinical use (in autoimmune diseases) for many years, so they are optimal candidates for testing in transplant settings in combination with Treg based cellular therapy.
    International immunopharmacology 03/2013; 16(3). DOI:10.1016/j.intimp.2013.02.015 · 2.47 Impact Factor
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    • "0.7 [0.5–3.1] CDAI 234 [194–256] 327 [312–374] HBI 9 [7] [8] [9] [10] 12 [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] "
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    ABSTRACT: Anti-TNF-α antibodies has been suggested to modulate regulatory T cell (Treg) percentages in rheumatoid arthritis, but results from studies of Crohn's disease (CD) are conflicting. We investigated dynamic changes of circulating Tregs in CD during treatment with the anti-TNF-α-antibody adalimumab (Humira®, Abbott Laboratories A/S, Emdrupvej 28C, DK-2100 Copenhagen). Blood samples from 26 CD patients were analysed using flow cytometry before and 1 and 26 weeks after initiation of adalimumab treatment to determine the percentage of Tregs among CD4+ T cells. In spite of a significant decline in disease activity scores and biochemical markers of inflammation, during the first week of treatment, we did not observe early modulating effects of adalimumab on Treg percentages. However, we found a long-term increase in Treg percentages in responders who had low Treg percentages (<5%) at baseline (p = 0.04). Treg percentage was inversely associated with disease activity (CD activity index or CDAI) (Spearman's rank correlation, ρ = -0.47, p = 0.02). High Treg percentages among CD4+ T cells at baseline predicted clinical response to adalimumab. Adalimumab treatment did not induce early modulatory effects on Treg percentage, even in responders. This finding suggests that adalimumab does not have a direct or selective effect on Tregs. However, Treg percentage was associated with disease activity and high Treg percentage predicted response to adalimumab.
    Scandinavian Journal of Gastroenterology 07/2011; 46(10):1206-14. DOI:10.3109/00365521.2011.603157 · 2.36 Impact Factor
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