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Biomarkers can predict potential clinical responders to DIMS0150 a toll-like receptor 9 agonist in ulcerative colitis patients
© Kuznetsov et al.; licensee BioMed Central Ltd. 2014
Received: 15 November 2013
Accepted: 10 April 2014
Published: 23 April 2014
Glucocorticoids (GCS) remain one of the mainstay treatments in the management of ulcerative colitis (UC) but up to a third of patients will ultimately fail to respond and progress to a more severe and difficult to manage disease state. Previous clinical studies suggest that the Toll-Like Receptor 9 (TLR9) agonist DIMS0150 not only induces production of key anti-inflammatory cytokines as IL-10 but interestingly also enhances steroid sensitivity in steroid refractory UC patients. We investigated, in the context of a clinical study, whether a pre-selection of steroid response genes could identify steroid refractory UC subjects most likely to respond to DIMS0150 treatment.
In a non-interventional pilot study, blood from steroid refractory UC patients and healthy volunteers was taken and thirty-four previously described steroid response genes were analysed by real time PCR analysis. To establish clinical utility of the identified biomarkers, a placebo controlled, randomized, double blinded study in active steroid dependent and steroid resistant UC patients on concomitant steroid therapies was used (EudraCT number: 2006-001846-15).
We identified three potential biomarkers CD163, TSP-1 and IL-1RII whose response to steroids was significantly enhanced when DIMS0150 was applied. Thirty-four subjects were randomized to receive a single rectal administration of placebo or 30 mg of DIMS0150. Blood derived PBMCs were obtained prior to dosing and assayed for evidence of a steroid enhancing effect following steroid incubation in the presence of DIMS0150. Comparison to established steroid sensitivity marker IL-6 confirmed that clinical responders are steroid refractory UC patients. Upon study completion and un-blinding, the biomarker assay correctly predicted a clinical response in over 90% of the patients.
Using specific steroid response biomarkers, GCS refractory UC patients most likely to benefit from DIMS0150 treatment could be identified and illustrates the usefulness of a personalized treatment approach.
Ulcerative colitis (UC) is a disease characterised by chronic inflammation of the rectal and colonic mucosa. The medical management of UC is divided into treatment of active disease and maintenance of remission. The treatment of patients with UC aims to reduce inflammation and promote colon healing and mucosal recovery. In the majority of cases the disease may be controlled with conventional drugs including sulphasalazine (SASP), 5-aminosalicylic acid (5-ASA) and glucocorticosteroids (GCS) [1, 2]. GCS are one of the mainstay treatments in the management of inflammatory bowel disease (IBD). GCS are potent anti-inflammatory agents widely used for the suppression of inflammation in chronic diseases such as asthma, rheumatoid arthritis, IBD and autoimmune diseases . However, 20-50% of IBD patients will fail to respond to steroid therapy  resulting often in a more difficult to manage disease course. Failure to respond to GCS therapy is an indication for potential surgical intervention although immunomodulatory agents such as intravenous cyclosporine or tumor necrosis factor (TNF) inhibitors have demonstrated some effectiveness at reducing colectomy rates on a short-term basis [5, 6].
DNA based immunomodulatory sequence (DIMS0150) is a single stranded partially modified synthetic oligonucleotide of 19 bases in length. The drug functions as an immunomodulator by activating the Toll-Like Receptor 9 (TLR9) present in immune cells such as B-cells, macrophages and plasmacytoid dendritic cells (pDCs) that are found in abundance on mucosal surfaces such as the colonic mucosa. Through rectal administration of DIMS0150 in the form of an enema, the agent comes in direct contact with a large number of target cells thereby ensuring a robust immunomodulatory response. Activation of TLR9 by DIMS0150 results in the local production of potent anti-inflammatory cytokines such as IL-10 and type I interferons that have also interestingly been shown to increase steroid sensitivity in cells derived from steroid-resistant UC patients  and human monocytes .
Results from two previous clinical studies in UC patients treated with a single rectal dose of DIMS0150 have indicated that steroid refractory UC patients benefit from the treatment. In the first clinical study, a single dose of DIMS0150 was given to steroid unresponsive IBD patients on concomitant steroid therapies . The study illustrated that both single dose levels used (3 mg and 30 mg) were effective in inducing a clinical response. After one week five out of seven patients (70%) that received active treatment had a clinical response and two have remained, after more than 8 years, in GCS free remission. One of four patients receiving placebo responded but in a transient manner.
A larger phase II study evaluated the ability of DIMS0150 at four dose levels (0.3, 3, 30 and 100 mg) administered as a single rectal dose to induce clinical remission in 151 patients with mild or moderately active UC compared to placebo. No significant benefit was demonstrated at any dose level suggesting that the lack of efficacy was possibly due to the different patient target group (data not published). The target groups of these studies differed in two ways, firstly the second trial was conducted in less severe UC patients and secondly concomitant steroid therapy was an exclusion criteria. To investigate whether the effect of DIMS0150 in the first study could be linked to steroid sensitivity, we screened 34 known steroid response genes in an in vitro assay. Additionally, to be able to re-affirm whether steroid refractory UC subjects on concomitant steroid therapies are the relevant target group or whether the combination of DIMS0150 and steroid therapy is needed, a phase IIa proof of concept (PoC) study was conducted in steroid dependent or steroid resistant UC patients on concomitant steroid therapies addressing DIMS0150 at a single dose level of 30 mg.
According to European Crohn’s and Colitis organisation (ECCO) guidelines, the definition of steroid resistance is a failure to respond to 0.75 mg/Kg body weight intravenous administered steroids given over 3 to 5 days . Likewise, steroid dependency is defined as the inability to reduce steroid usage below 10 mg/day without recurrent active disease. We reasoned that to determine the clinical picture of steroid sensitivity by these means would greatly impact the rate of inclusion into the PoC study with many patients opting not to undergo these demanding procedures. Consequently, we employed the use interleukin 6 (IL-6) that has gained significant recognition as a suitable biomarker for determining the steroid sensitivity status of a subject in published research as well as its use in human clinical studies addressing steroid resistant disorders such as asthma and ulcerative colitis [11–14]. This PoC study also enabled us to evaluate the suitability of potential biomarkers for DIMS0150 whether they could be used to predict a clinical response.
The results from this PoC phase IIa study indicate that GCS refractory patients on concomitant GCS therapy respond more favourably to a single dose of DIMS0150 and the utility of the biomarkers CD163, TSP-1 and IL-6 in confirming the right target group and predicting a most likely response to DIMS0150 could be demonstrated. Using the biomarkers we could also demonstrate a steroid re-sensitizing effect in vivo following DIMS0150 treatment in a case report from a named patient basis program and confirm that after treatment with DIMS0150, GCS can be used to successfully treat a new disease flare in a patient.
Study design and patient population
Identification of potential steroid response biomarkers
A study including 9 steroid resistant active UC patients and 9 healthy volunteers (mean age of 44.7 and 44.3, female to male ratio of 2:7 and 6:3, 9 Caucasians and 8 Caucasians plus one Latin American, respectively) was performed to donate blood at one occasion in one study centre in Stockholm, Sweden.
Proof of concept (PoC) phase IIa study (EudraCT number: 2006-001846-15)
Baseline characteristics of study population proof of concept phase IIa study
DIMS0150 (n = 22)
Placebo (n = 12)
DIMS0150 (n = 22)
Placebo (n = 12)
Disease duration (days)
DAI score at screening
Beyond splenic flexure
Up to splenic flexure
Up to sigmoid descending junction
Up to recto-sigmoid junction
Number of subjects taking glucocorticoids medication during the study
Corticoids acting locally
Number of steroid medications (PT)
Prednisolone sodium phosphate
Number of steroid medications (PT)
Named patient-based treatment example
One chronic active treatment refractory UC patient (male, 50 years, pancolitis, Caucasian) was treated three times with DIMS0150 with four weeks between dosing occasions .
DIMS0150 is a fully synthetic oligodeoxynucleotide with the sequence 5′-G*G*A*ACA GTT CGT CCA T*G*G*C-3′ where (*) indicates phosphorothioate linkages, produced by Avecia (Milford, USA) and prepared as study drug by Apoteksbolaget AB, Production & Laboratory, Umeå, Sweden. The randomisation code was produced by a computer-generated procedure, which used the method of randomly permuted blocks. Double-blinding against water was accomplished by giving all study products identical appearance, packaging and labelling.
Blood collection and RNA isolation for IP-10 expression analysis
Whole blood (5 mL) from 26 patients of the PoC study (all patients included after Amendment 5 of original protocol) was collected in PAXtubes (PreAnalytiX, Hombrechtikon, Switzerland) just before drug administration and 4 hrs after. RNA isolation was performed according to the manufacturer’s guidelines using PAXgene Blood RNA Kit (Qiagen, Hilden, Germany).
Blood collection and PBMC isolation and stimulation
From 32 patients of the PoC study, 30 mL blood was collected in sodium heparin tubes (Venoject®, Teruma Sweden AB) and peripheral blood mononuclear cells (PBMC) isolated 24 hrs after collection by density gradient centrifugation using Ficoll-Paque Plus (Pharmacia Biotech, Stockholm, Sweden). PBMCs were washed three times in buffered saline solution, and resuspended in complete RPMI 1640 medium (Sigma, St. Louis, USA).
PBMCs were seeded in 96 well plates (0.5 x 106 cells/well), cells stimulated for 48 hrs with DIMS0150 (25 μM or 100 μM) in the presence or absence of Dexamethasone (10-6, 10-8, 10-10 M; Sigma). Cell supernatant was collected and kept at -20°C for cytokine analysis. The cells were covered with 50 μl/well of RLT-lysis buffer (Qiagen) containing 1% of β-mercaptoethanol and kept at -20°C for mRNA isolation.
IFN-γ, IL-6, IL-10, IP-10, and TNF-α were measured using cytometric bead array (CBA) flex kit (Becton Dickinson) according to the manufacturer’s instructions on a FACSArray flow cytometer using FCAP Array software (Becton Dickinson, New Jersey, USA). IFN-α was analyzed using human IFN-α Multi-subtype ELISA kit (PBL, Biomedical Laboratories, New Jersey, USA) and IFN-β was detected with human IFN-β ELISA kit (Fujirebio INC., Tokyo, Japan) according to the manufacturer’s instructions.
RNA isolation was performed using Qiagen RNeasy RNA isolation kit and Qiacube (Qiagen) according to manufacturer’s guidelines.
For first strand cDNA synthesis, 0.3-1.0 μg of total RNA/sample and 10pM of the Oligo-dT-primer (5′-dT20NV-3′) was taken. The reactions were performed using Superscript II according to the manufacture’s guidelines (Invitrogen, Carlsbad, USA).
Primer information qPCR
Forward primer sequence
Reverse primer sequence
Data analysis and statistics
Data analysis and graphing was performed in Microsoft Office EXCEL 2007 and GraphPad Prism 4.0c. The class membership analysis  was performed at Statistika Forskningsgruppen Stockholm, Sweden using STATA® (StataCorp LP, Texas, USA). All statistical analyses were performed in a 95% confidence interval.
Blood samples from 9 steroid resistant UC patients and 9 healthy volunteers were obtained with ethical approval from EPN (Regionala Etiska Prövningsnämnden, Stockholm, Sweden numbers 2005/1351-31/4 and 2005/1183-31/4 respectively).
The phase IIa study (EudraCT number: 2006-001846-15) was reviewed and approved by regional Independent Ethics Committees (IECs) and by the medical authorities in each country prior to inclusion of patients.
Named patient basis treatment was performed under the responsibility of the treating physician and with approval of the local ethic committee (Ethik-Komission der Ärztekammer Westfalen-Lippe und der Medizinischen Fakultät der Westfälischen Wilhelms-Universität Műnster, reference number 2008-360-f-S).
All patients had received written and verbal information concerning the study/treatment and signed an informed consent. From the named patient basis treated patient an additional written consent was obtained allowing the publication of individual clinical data.
DIMS0150 induces cytokines having a role in steroid sensitivity
Steroid response genes show steroid enhancing effect of DIMS0150
List of steroid response genes screened in biomarker assay
Toll-like receptor 9
Indoleamine 2,3-dioxygenase 1
Macrophage receptor with collagenous structure
Interleukin 1, beta
Interleukin-1 receptor type 1
Interleukin-1 receptor type 2
Interleukin-1 receptor antagonist
IL-1 receptor accessory protein
Interleukin 7 receptor, alpha
Interleukin-13 receptor subunit, alpha 2
Granzyme 1, serine esterase 3
Glucocorticoid-induced leucine zipper
Antigen CD49D; integrin alpha 4
Glucocorticoid nuclear receptor, isoform alpha
Glucocorticoid nuclear receptor, isoform beta
Glucocorticoid nuclear receptor, isoform gamma
Heat shock protein HSP 90, alpha
Heat shock protein HSP 90, beta
UDP glucuronosyltransferase 2
Insulin receptor substrate 1
Forkhead box protein P3
Histone deacetylase 2
Insulin-like growth factor binding protein 2
ATP-binding cassette, sub-family B (MDR/TAP), member 1
Vitamin D (1,25- dihydroxyvitamin D3) receptor
FK506 binding protein 5
Vascular endothelial growth factor
Serum- and glucocorticoid-inducible protein kinase
Interferon gamma receptor 1
DIMS0150 provides clinical benefit in patients with UC on concomitant steroid therapy
Summary of the efficacy data proof of concept phase IIa study
ITT population (n = 34)
Placebo (n = 12)
DIMS0150 (n = 22)
Clinical response 1
Week 1 (wk1)
Week 4 (wk4)
Sustained clinical response:
Wk1 and wk4
Clinical remission 2
Sustained clinical remission:
Wk1 and wk4
Histological response 3
Sustained histological response:
Wk4 and wk12
Histological remission 4
Sustained histological remission:
Wk4 and wk12
Clinical response paralleled with histological remission
Evidence of TLR9 activation by DIMS0150
Biomarkers identify two groups of differing steroid sensitivity
Blood derived PBMCs were isolated from 32 patients from the PoC phase IIa study at the time of screening, treated in vitro with Dexamethasone and/or DIMS0150 for 48 hrs and the expression levels of CD163, TSP-1, IL-1RII and IL-6 determined through qPCR analysis. In response to stimuli, levels of IL-6 are increased and the degree of suppression by GCS is indicative of the steroid sensitivity. Indeed, the ability of GCS to suppress the levels of induced IL-6 appears to be an accepted measure of steroid sensitivity as there appears to be a robust correlation with the clinical picture of steroid resistance [11, 13, 14]. The use of IL-6 circumvents the need for patients to undergo what are otherwise uncomfortable treatments such as taking high levels of steroid i.v. over a period of 5 days to determine the subjects’ steroid sensitivity.
Both biomarkers, IL-6 and CD163, were able to identify the same two groups, namely patients being resistant to steroids and those being similar to healthy controls and segregate between steroid refractory and sensitive patients. TSP-1 as well as IL-1RII could also segregate between two differing steroid sensitivity groups whereby the correlation between IL-6 and CD163 or TSP-1 was in both cases over 71% and IL-1RII showed only a correlation of about 45% (data not shown).
Biomarkers have high potential in predicting clinical response to DIMS0150
Upon PoC phase IIa completion, we determined whether there was a correlation between patients showing a reduced steroid sensitivity in the biomarker assay before treatment and clinical response. In other words, is steroid resistance a pre-requisite for a response to DIMS0150 and could this be used as a predictor. Of equal interest was to determine whether those subjects that had previously demonstrated in the biomarker assay that DIMS0150 could restore their in vitro steroid sensitivity had an actual clinical response to DIMS0150.
Area under the ROC curve (AUC) calculations for efficacy prediction of the biomarkers
Steroid response and enhancement
The results indicated that the three biomarkers, CD163, TSP-1 and IL-6, had singularly high predictive potential for a clinical response in subjects that demonstrated reduced levels of steroid sensitivity suggesting that refractory patients are more likely to respond to DIMS0150. Additionally, CD163 and TSP-1 demonstrated a strong positive correlation between subjects where a restored in vitro steroid sensitivity was observed upon DIMS0150 incubation and clinical response. IL-1RII had less discriminative potential due to strong patient variations (data not shown). However, the highest prediction values were achieved when all three biomarkers CD163, TSP-1 and IL-6 were considered for steroid resistance and, taking into account restoration of steroid sensitivity as determined by CD163 and TSP-1. This gave an AUC of 0.98 with 10-6 M Dexamethasone and 25 μM DIMS0150 in contrast to an AUC of 0.83 for IL-6 alone at the same concentrations (Table 5, see also Figure 5A).
Prediction of clinical response in DIMS0150 treated patients (n = 22) using CD163, TSP-1 and IL-6
Steroid response and enhancing
Summary of predictive potential of biomarkers CD163, TSP-1 and IL-6
Steroid response and enhancing
To determine whether using these biomarkers as a stratifying tool may have improved the clinical response rate, we performed a retrospective analysis using the study data. By removing all subjects that were neither steroid resistant nor showed an enhancing effect to DIMS0150 in the biomarker assay and retaining all those that proved positive in both criteria, the response rate in the treatment group would have increased from 32% to 60% (6/10) at wk1 and from 41% to 80% (8/10) at wk4. These data demonstrate a clear usefulness in being able to identify patients most likely to benefit from DIMS0150 treatment.
DIMS0150 restores steroid sensitivity in vivo
Gastrointestinal disorders like UC can dramatically affect the quality of life , and involves a life-long clinical management of the disease focusing on the induction and maintenance of remission. GCS remain the treatment of choice of initial therapy but about a third of the patients will fail to respond and further management requires a comprehensive understanding of the patients and the potential risks and benefits of further interventions making the disease course difficult to manage. The aim of the treatment with DIMS0150 is to help the patients remain in the group of easier manageable UC patients by restoring their steroid sensitivity.
The mechanisms behind steroid resistance are complex and numerous cytokines have been implicated as important factors. For example, Xystrakis and colleagues.  could show that by restoring otherwise deficient levels of IL-10 in steroid resistant asthmatics greatly improved their steroid responsiveness. In a more recent study performed with PBMCs derived from steroid resistant UC patients, the authors could demonstrate that addition of IL-10 to the PMBCs enhanced steroid sensitivity, whereas neutralizing IL-10 through addition of specific antibodies reduced steroid sensitivity .
Similar clinical observations have been demonstrated using type I interferons. For example, steroid resistant UC patients receiving daily intravenous injections of natural IFN-β experienced a rapid improvement of clinical symptoms . The ability of type I interferons to modulate steroid sensitivity gained further support from studies performed in steroid resistant asthmatics where treatment with IFN-α dramatically improved symptoms allowing their steroid dose to be tapered .
We could show that the TLR9 agonist DIMS0150 acts as an immunomodulatory compound by inducing IL-10, IL-6, type I interferons and IP-10 in vitro, the same cytokines/chemokines implied to be important in regaining steroid sensitivity. The induction of IP-10 in vivo in the phase IIa study correlates well with the in vitro IP-10 analysis suggesting that treatment with DIMS0150 is likely to induce the same steroid enhancing cytokines as previously recorded.
The biomarker CD163 belongs to a superfamily of cysteine-rich scavenger receptors (SRCR), several of which are involved in the innate immune response . CD163 is described to mediate anti-inflammatory effects  and its expression is strongly induced by anti-inflammatory mediators and GCS [20, 42]. Interestingly, some of these anti-inflammatory mediators that up-regulate CD163 on mRNA level in monocytes and macrophages are IL-6 and IL-10 [43–45], both of which are shown to be induced by DIMS0150.
Thrombospondin-1 belongs functionally to a group of diverse multidomain counteradhesive proteins influencing endothelial cell behaviour [46–48]. It could be shown that TSP-1 expression correlates with IL-10 expression in colon cancer with significant lower mean vessel counts suggesting that IL-10 stimulates expression of angiostatic factors as TSP-1 , linking also the second biomarker to a cytokine induced by DIMS0150. The identification of these marker genes and their relation to DIMS0150 induced cytokines are considered important factors in understanding how DIMS0150 restores steroid sensitivity.
To assess the clinical utility of CD163, TSP-1 and IL-1RII as predictors of clinical response, a PoC phase IIa study in steroid refractory or steroid dependent UC patients on concomitant steroid treatment was performed and the results compared to those of the steroid sensitivity marker IL-6. Although this study was somewhat limited in size, it was nevertheless deemed sufficiently large enough to provide a robust assessment of the biomarkers. We hypothesized that DIMS0150 should enhance steroid sensitivity leading to improvements of symptoms and a reduced disease activity score and that prior analysis using the biomarker genes should enable a prediction of clinical response. The clinical outcome of the study showed that approximately half of the DIMS0150 treated patients (10 of 22) responded to the treatment and that this observation was very much in line with the biomarker data obtained at the time of screening. Both IL-6 and CD163 analysis strongly suggested the presence of two groups of patients being included in the study. One group demonstrated a clear picture of steroid resistance and the other showed a steroid response similar to healthy volunteers. Patients with a reduced response to steroids as determined by CD163, TSP-1 or IL-6 were statistically more likely to respond to the DIMS0150 treatment. The predictive potential of the biomarkers could be illustrated by classification analysis of the expression data compared to clinical response or non-response following DIMS0150 treatment. All three markers demonstrated a high potential as surrogate markers for a DIMS0150 response with CD163 and TSP-1 being slightly more sensitive than IL-6 because of their ability to demonstrate the steroid re-sensitizing effect of DIMS0150. As expected, the combination of all three markers gave the best result with an AUC of 0.98. This equates to a correct prediction of clinical response in 90% (9/10) of patients classified as being steroid refractory according to the biomarker assay. Conversely, 91% (10/11) of patients whose steroid sensitivity was comparable to healthy controls failed to respond to DIMS0150 treatment. A possible interpretation would be, patients classified with the biomarkers as steroid refractory are indeed steroid refractory patients. By contrast, patients that show no difference to healthy could be inferred as steroid dependent. The validity of these interpretations can only be properly tested through additional clinical studies where subjects are included using the clinical definitions of steroid resistance and dependence as given in the ECCO guidelines .
Regarding the special case patient who received three doses of DIMS0150, the biomarker assay confirmed that the patient was steroid refractory at time of first dosing and classified as a potential responder to DIMS0150. Upon treatment with DIMS0150, a pronounced clinical response could be observed with the patient in complete remission at week 12. Further biomarker analysis at week 12 demonstrated that the patient most likely had regained steroid sensitivity that could be confirmed by treating an upcoming relapse successfully with GCS. While we have consistently recorded a steroid re-sensitizing effect for DIMS0150 in vitro, these in vivo data provide for the first time, evidence for a shift to improved steroid sensitivity in a steroid unresponsive patient following DIMS0150 treatment.
Based on these promising data, a placebo-controlled, multiple dose, double-blind, randomized phase III clinical study (NCT01493960) is currently on-going to assess the efficacy and safety of DIMS0150 as an add-on to current practice in chronic active treatment refractory UC patients.
This study will also provide a unique opportunity to gain further evidence for the observed in vivo shift in steroid sensitivity following DIMS0150 treatment and controlled steroid tapering combined with a long follow-up phase will gather information about reaching and length of steroid-free remission.
The work presented here demonstrates that the target group of DIMS0150 are ulcerative colitis patients showing a reduced steroid sensitivity and a clear utility of using appropriate biomarkers for the selection of patients most likely to benefit from DIMS0150 treatment has been illustrated. Using such an approach represents a step towards a more personalized form of healthcare and may aid physicians in making the most optimum treatment choices for the patient.
We thank Dr. Jan-Olov Persson, Statistika Forskningsgruppen Stockholm, Sweden for performing the class membership analysis and for his constructive comments.
- D’Haens G, Sandborn W, Feagan B, Geboes K, Hanauer SB, Irvine EJ, Lémann M, Marteau P, Rutgeerts P, Schölmerich J, Sutherland LR: A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterol. 2007, 132: 763-786. 10.1053/j.gastro.2006.12.038.View ArticleGoogle Scholar
- Schroeder KW, Tremaine WJ, Ilstrup DM: Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis: a randomized study. N Engl J Med. 1987, 317: 1625-1629. 10.1056/NEJM198712243172603.View ArticlePubMedGoogle Scholar
- Barnes PJ: Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci (Lond). 1998, 94: 557-572.View ArticleGoogle Scholar
- Farrell RJ, Kelleher D: Glucocorticoid resistance in inflammatory bowel disease. J Endocrinol. 2003, 178: 339-346. 10.1677/joe.0.1780339.View ArticlePubMedGoogle Scholar
- Rutgeerts P, Sandborn W, Feagan B, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, Colombel JF: Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005, 353: 2462-2476. 10.1056/NEJMoa050516.View ArticlePubMedGoogle Scholar
- Leblanc S, Allez M, Seksik P, Flourié B, Peeters H, Dupas JL, Bouguen G, Peyrin-Biroulet L, Duclos B, Bourreille A, Dewit O, Bouhnik Y, Michetti P, Chaussade S, Saussure P, Mary JY, Colombel JF, Lémann M, GETAID: Successive treatment with cyclosporine and infliximab in steroid-refractory ulcerative colitis. Am J Gastroenterol. 2011, 106: 771-777. 10.1038/ajg.2011.62.View ArticlePubMedGoogle Scholar
- Creed TJ, Lee RW, Newcomb PV, di Mambro AJ, Raju M, Dayan CM: The effects of cytokines on suppression of lymphocyte proliferation by dexamethasone. J Immunol. 2009, 183: 164-171. 10.4049/jimmunol.0801998.View ArticlePubMedGoogle Scholar
- Franchimont D, Martens H, Hagelstein MT, Louis E, Dewe W, Chrousos GP, Belaiche J, Geenen V: Tumor necrosis factor alpha decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone: potential regulation of the glucocorticoid receptor. J Clin Endocrinol Metab. 1999, 84: 2834-2839.PubMedGoogle Scholar
- Lofberg R, Neurath M, Ost A, Pettersson S: Topical NFκB p65 antisense oligonucleotide in patients with active distal colonic IBD: a randomized, controlled, pilot trial. Gastroenterol. 2001, 122 (Suppl.41): 503A-Google Scholar
- Stange EF, Travis SP, Vermeire S, Reinisch W, Geboes K, Barakauskiene A, Feakins R, Fléjou JF, Herfarth H, Hommes DW, Kupcinskas L, Lakatos PL, Mantzaris GJ, Schreiber S, Villanacci V, Warren BF, European Crohn’s and Colitis Organisation (ECCO): European evidence-based consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. J Crohns Colitis. 2008, 2: 1-23. 10.1016/j.crohns.2007.11.001.View ArticlePubMedGoogle Scholar
- Reinisch W, Gasché C, Tillinger W, Wyatt J, Lichtenberger C, Willheim M, Dejaco C, Waldhör T, Bakos S, Vogelsang H, Gangl A, Lochs H: Clinical relevance of serum interleukin-6 in Crohn’s disease: single point measurements, therapy monitoring, and prediction of clinical relapse. Am J Gastroenterol. 1999, 94: 2156-2164. 10.1111/j.1572-0241.1999.01288.x.View ArticlePubMedGoogle Scholar
- Linden M, Brattsand R: Effects of a corticosteroid, budenoside, on alveolar macrophage and blood monocyte secretion of cytokines: differential sensitivity of GM-CSF, IL-1beta, and IL-6. Pulm Pharmacol. 1994, 7: 43-47. 10.1006/pulp.1994.1004.View ArticlePubMedGoogle Scholar
- Bhavsar P, Hew M, Khorasani N, Torrego A, Barnes PJ, Adcock I, Chung KF: Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma. Thorax. 2008, 63: 784-790. 10.1136/thx.2007.090027.View ArticlePubMedGoogle Scholar
- Wine E, Mack DR, Hyams J, Otley AR, Markowitz J, Crandall WV, Leleiko N, Muise AM, Griffiths AM, Turner D: Interleukin-6 is associated with steroid resistance and reflects disease activity in severe pediatric ulcerative colitis. J Crohns Colitis. 2013, 7: 916-922. 10.1016/j.crohns.2012.12.012.View ArticlePubMedGoogle Scholar
- Musch E, Lutfi T, von Stein P, Zargari A, Admyre C, Malek M, Löfberg R, von Stein OD: Topical treatment with the toll-like receptor agonist DIMS0150 has potential for lasting relief of symptoms in patients with chronic active ulcerative colitis by restoring glucocorticoid sensitivity. Inflamm Bowel Dis. 2013, 19: 283-292. 10.1002/ibd.23019.View ArticlePubMedGoogle Scholar
- Naes T, Isaksson T, Feran T, Davies T: A user friendly guide to multivariate calibration and classification. 2002, Chichester, UK: NIR PublicationsGoogle Scholar
- Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, Adikibi T, Pridgeon C, Dallman M, Loke TK, Robinson DS, Barrat FJ, O’Garra A, Lavender P, Lee TH, Corrigan C, Hawrylowicz CM: Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest. 2006, 116: 146-155.View ArticlePubMedGoogle Scholar
- Simon HU, Seelbach H, Ehmann R, Schmitz M: Clinical and immunological effects of low-dose IFN-alpha treatment in patients with corticosteroid-resistant asthma. Allergy. 2003, 58: 1250-1255. 10.1046/j.1398-9995.2003.00424.x.View ArticlePubMedGoogle Scholar
- Galon J, Franchimont D, Hiroi N, Frey G, Boettner A, Ehrhart-Bornstein M, O’Shea JJ, Chrousos GP, Bornstein SR: Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J. 2002, 16: 61-71. 10.1096/fj.01-0245com.View ArticlePubMedGoogle Scholar
- Ogawa S, Lozach J, Benner C, Pascual G, Tangirala RK, Westin S, Hoffmann A, Subramaniam S, David M, Rosenfeld MG, Glass CK: Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell. 2005, 122: 707-721. 10.1016/j.cell.2005.06.029.View ArticlePubMedPubMed CentralGoogle Scholar
- Lang D, Knop J, Wesche H, Raffetseder U, Kurrle R, Boraschi D, Martin MU: The type II IL-1 receptor interacts with the IL-1 receptor accessory protein: a novel mechanism of regulation of IL-1 responsiveness. J Immunol. 1998, 161: 6871-6877.PubMedGoogle Scholar
- Renoir JM, Radanyi C, Faber LE, Baulieu EE: The non-DNA-binding heterooligomeric form of mammalian steroid hormone receptors contains a hsp90-bound 59-kilodalton protein. J Biol Chem. 1990, 265: 10740-10745.PubMedGoogle Scholar
- Wu W, Chaudhuri S, Brickley DR, Pang D, Karrison T, Conzen SD: Microarray analysis reveals glucocorticoid-regulated survival genes that are associated with inhibition of apoptosis in breast epithelial cells. Cancer Res. 2004, 64: 1757-1764. 10.1158/0008-5472.CAN-03-2546.View ArticlePubMedGoogle Scholar
- Gavin M, Rudensky A: Control of immune homeostasis by naturally arising regulatory CD4+ T cells. Curr Opin Immunol. 2003, 15: 690-696. 10.1016/j.coi.2003.09.011.View ArticlePubMedGoogle Scholar
- Lee KH, Meuer SC, Samstag Y: Cofilin: a missing link between T cell co-stimulation and rearrangement of the actin cytoskeleton. Eur J Immunol. 2000, 30: 892-899. 10.1002/1521-4141(200003)30:3<892::AID-IMMU892>3.0.CO;2-U.View ArticlePubMedGoogle Scholar
- Ito K, Jazrawi E, Cosio B, Barnes PJ, Chung KF: p65-activated histone acetyltransferase activity is repressed by glucocorticoids: mifepristone fails to recruit HDAC2 to the p65-HAT complex. J Biol Chem. 2001, 276: 30208-30215. 10.1074/jbc.M103604200.View ArticlePubMedGoogle Scholar
- Phillips K, Park MA, Quarrie LH, Boutinaud M, Lochrie JD, Flint DJ, Allan GJ, Beattie J: Hormonal control of IGF-binding protein (IGFBP-5 and IGFBP-2) secretion during differentiation of the HC11 mouse mammary epithelial cell line. J Mol Endocrinol. 2003, 31: 197-208. 10.1677/jme.0.0310197.View ArticlePubMedGoogle Scholar
- Vermeer H, Hendriks-Stegeman BI, van Suylekom D, Rijkers GT, van Buul-Offers SC, Jansen M: An in vitro bioassay to determine individual sensitivity to glucocorticoids: induction of FKBP51 mRNA in peripheral blood mononuclear cells. Mol Cell Endocrinol. 2004, 218: 49-55. 10.1016/j.mce.2003.12.011.View ArticlePubMedGoogle Scholar
- Egesten A, Eliasson M, Olin AI, Erjefält JS, Bjartell A, Sangfelt P, Carlson M: The proinflammatory CXC-chemokines GRO-alpha/CXCL1 and MIG/CXCL9 are concomitantly expressed in ulcerative colitis and decrease during treatment with topical corticosteroids. Int J Colorectal Dis. 2007, 22: 1421-1427. 10.1007/s00384-007-0370-3.View ArticlePubMedGoogle Scholar
- Koutroubakis IE, Tsiolakidou G, Karmiris K, Kouroumalis EA: Role of angiogenesis in inflammatory bowel disease. Inflamm Bowel Dis. 2006, 12: 515-523. 10.1097/00054725-200606000-00012.View ArticlePubMedGoogle Scholar
- Webster MK, Goya L, Firestone GL: Immediate-early transcriptional regulation and rapid mRNA turnover of a putative serine/threonine protein kinase. J Biol Chem. 1993, 268: 11482-11485.PubMedGoogle Scholar
- Harris DP, Goodrich S, Gerth AJ, Peng SL, Lund FE: Regulation of IFN-gamma production by B effector 1 cells: essential roles for T-bet and the IFN-gamma receptor. J Immunol. 2005, 174: 6781-6790. 10.4049/jimmunol.174.11.6781.View ArticlePubMedGoogle Scholar
- Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Löfberg R: A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. Gut. 2000, 47: 404-409. 10.1136/gut.47.3.404.View ArticlePubMedPubMed CentralGoogle Scholar
- Vollmer J, Jurk M, Samulowitz U, Lipford G, Forsbach A, Wüllner M, Tluk S, Hartmann H, Kritzler A, Müller C, Schetter C, Krieg AM: CpG oligodeoxynucleotides stimulate IFN-gamma-inducible protein-10 production in human B cells. J Endotoxin Res. 2004, 10: 431-438.PubMedGoogle Scholar
- Krieg AM, Efler SM, Wittpoth M, Al Adhami MJ, Davis HL: Induction of systemic TH1-like innate immunity in normal volunteers following subcutaneous but not intraveneous administration of CpG 7909, a synthetic B-class CpG oligodeoxynucleotide TLR9 agonist. J Immunother. 2004, 27: 460-471. 10.1097/00002371-200411000-00006.View ArticlePubMedGoogle Scholar
- Jurk M, Schulte B, Kritzler A, Noll B, Uhlmann E, Wader T, Schetter C, Krieg AM, Vollmer J: C-Class CpG ODN: sequence requirements and characterization of immunostimulatory activities on mRNA level. Immunobiol. 2004, 209: 141-154. 10.1016/j.imbio.2004.02.006.View ArticleGoogle Scholar
- Rachmilewitz D: Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. BMJ. 1989, 298: 82-86. 10.1136/bmj.298.6666.82.View ArticlePubMedPubMed CentralGoogle Scholar
- Oxelmark L, Magnusson A, Löfberg R, Hillerås P: Group-based intervention program in inflammatory bowel disease patients: effects on quality of life. Inflamm Bowel Dis. 2007, 13: 182-190. 10.1002/ibd.20061.View ArticlePubMedGoogle Scholar
- Musch E, Andus T, Malek M, Chrissafidou A, Schulz M: Successful treatment of steroid refractory active ulcerative colitis with natural interferon-beta - an open long-term trial. Z Gastroenterol. 2007, 45: 1235-1240. 10.1055/s-2007-963378.View ArticlePubMedGoogle Scholar
- Herzig CTA, Waters RW, Baldwin CL, Telfer JC: Evolution of the CD163 family and its relationship to the bovine gamma delta T cell co-receptor WC1. BMC Evol Biol. 2010, 10: 181-View ArticlePubMedPubMed CentralGoogle Scholar
- Moestrup SK, Møller HJ: CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. Ann Med. 2004, 5: 347-354.View ArticleGoogle Scholar
- Van den Heuvel MM, Tensen CP, van As JH, Van den Berg TK, Fluitsma DM, Dijkstra CD, Döpp EA, Droste A, Van Gaalen FA, Sorg C, Högger P, Beelen RH: Regulation of CD163 on human macrophages: cross-linking of CD163 induces signaling and activation. J Leukoc Biol. 1999, 66: 858-866.PubMedGoogle Scholar
- Schaer CA, Schoedon G, Imhof A, Kurrer MO, Schaer DJ: Constitutive endocytosis of CD163 mediates hemoglobin-heme uptake and determines the noninflammatory and protective transcriptional response of macrophages to hemoglobin. Circ Res. 2006, 99: 943-950. 10.1161/01.RES.0000247067.34173.1b.View ArticlePubMedGoogle Scholar
- Buechler C, Ritter M, Orso E, Langmann T, Klucken J, Schmitz G: Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J Leukoc Biol. 2000, 67: 97-103.PubMedGoogle Scholar
- Sulahian TH, Högger P, Wahner AE, Goulding NJ, Sorg C, Droste A, Stehling M, Wallace PK, Morganelli PM, Guyre PM: Human monocytes express CD163, which is upregulated by IL-10 and identical to p155. Cytokine. 2000, 12: 1312-1321. 10.1006/cyto.2000.0720.View ArticlePubMedGoogle Scholar
- Chiquet-Ehrismann R: Inhibition of cell adhesion by anti-adhesive molecules. Curr Opin Cell Biol. 1995, 7: 715-719. 10.1016/0955-0674(95)80114-6.View ArticlePubMedGoogle Scholar
- Chen H, Herndon ME, Lawler J: The cell biology of thrombospondin-1. Matrix Biol. 2000, 19: 597-614. 10.1016/S0945-053X(00)00107-4.View ArticlePubMedGoogle Scholar
- Lamy L, Foussat A, Brown EJ, Bornstein P, Ticchioni M, Bernard A: Interactions between CD47 and thrombospondin reduce inflammation. J Immunol. 2007, 178: 5930-5939. 10.4049/jimmunol.178.9.5930.View ArticlePubMedGoogle Scholar
- Kawakami T, Tokunaga T, Hatanaka H, Tsuchida T, Tomii Y, Osada H, Onoda N, Morino F, Nagata J, Kijima H, Yamazaki H, Abe Y, Osamura Y, Ueyama Y, Nakamura M: Interleukin 10 expression is correlated with thrombospondin expression and decreased vascular involvement in colon cancer. Int J Oncol. 2001, 18: 487-491.PubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/14/79/prepub
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