Publications by authors named "Ilse van Brussel"

20 Publications

  • Page 1 of 1

The tele-transition of toxicity management in routine oncology care during the severe acute respiratory syndrome (SARS-CoV-2) pandemic.

Br J Cancer 2021 04 9;124(8):1366-1372. Epub 2021 Feb 9.

Department of Oncology, Antwerp University Hospital Antwerp, Antwerp, Belgium.

Background: Telehealth modalities were introduced during the SARS-CoV-2 pandemic to assure continuation of cancer care and maintain social distance.

Methods: This is a retrospective cohort analysis of our telehealth expansion programme. We adapted two existing patient-reported outcome (PRO) telemonitoring tools that register and (self-)manage toxicities to therapy, while screening for SARS-CoV-2-related symptoms. Outpatients from a tertiary cancer centre were enrolled. The adapted PRO interface allowed for uniform registration of SARS-CoV-2-related symptoms and effective triage of patients at home where we also implemented systematic throat washings, when available.

Results: Three hundred and sixty patients registered to the telemonitoring systems from March 13 to May 15, 2020. Four prespecified SARS-CoV-2 alarms resulted in three patients with positive PCR testing. Other Covid-19 symptoms (fever 5× and cough 2×) led to pretreatment triage resulting in 1 seroconversion after initial negative testing. One of the 477 throat washings proved positive.

Conclusions: The rapid adoption of an amended PRO (self-)registrations and toxicity management system was feasible and coordinated screening for Covid-19. Continued clinical cancer care was maintained, with significant decreased waiting time. The systemic screening with throat washings offered no real improvement.
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http://dx.doi.org/10.1038/s41416-020-01235-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039036PMC
April 2021

Prescreening for COVID-19 in patients receiving cancer treatment using a patient-reported outcome platform.

ESMO Open 2020 06;5(3):e000817

Department of Medical Oncology, MOCA, University Hospital Antwerp (UZA), Antwerp, Belgium; Department of Molecular Imaging, Pathology, Radiotherapy & Oncology (MIPRO), Center for Oncological Research (CORE), Antwerp University, Antwerp, Belgium.

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http://dx.doi.org/10.1136/esmoopen-2020-000817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307523PMC
June 2020

AMTRA: a multicentered experience of a web-based monitoring and tailored toxicity management system for cancer patients.

Support Care Cancer 2021 Feb 9;29(2):859-867. Epub 2020 Jun 9.

Department of Oncology, Multidisciplinary Oncological Center Antwerp, MOCA, University Hospital Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium.

Background: Technology-based interventions are increasingly being introduced in routine clinical cancer care. There is a need for reliable systems to monitor treatment-related toxicity in a standardized manner. Such electronic tools bridge the gap in providing quality home-based monitoring.

Methods: From July 2017 to December 2017, we performed a multicentered, non-randomized prospective cohort analysis with patients who were receiving routine chemotherapy for various solid tumors, using a web-based patient-reported toxicity registration, management, and intervention system called AMTRA (ambulatory Monitoring of cancer Therapy using an interactive Application) linked to the homecare nursing organization Remedus®. Twelve common toxicities plus pain and two biometrics could be registered daily or more frequently as required. These were processed centrally to generate tailored advice for lesser symptoms or a phone call from a dedicated nurse in case of severe or prolonged toxicity. A compliance tool to monitor oral therapies was incorporated in the system.

Results: One hundred sixty-eight patients (92%) were enrolled, with 31,514 registrations analyzed. One hundred eight patients reported severe toxicity (> 1461 registrations), resulting in 102 clinical interventions ranging from self-management advice, supplemental consultations to hospitalizations. Compliance to oral chemotherapy was high using AMTRA with a median of 98.7% (95 confidence interval (CI) [93.5-100.0%]). Seventy-nine percent of patients stated that the availability of AMTRA self-reports was useful in communication with the care provider, while 75% felt more in control while managing their treatment.

Conclusions: The application of an interactive PRO-system in routine symptom management of cancer patients allowed standardized documentation of toxicities and recorded a high compliance with oral treatment. It allows for rapid interaction for toxicities and cancer-related symptoms experienced at home.
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http://dx.doi.org/10.1007/s00520-020-05550-6DOI Listing
February 2021

Long-Term Depletion of Conventional Dendritic Cells Cannot Be Maintained in an Atherosclerotic Zbtb46-DTR Mouse Model.

PLoS One 2017 6;12(1):e0169608. Epub 2017 Jan 6.

Laboratory of Physiopharmacology, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium.

Background And Aims: Increased evidence suggests a pro-atherogenic role for conventional dendritic cells (cDC). However, due to the lack of an exclusive marker for cDC, their exact contribution to atherosclerosis remains elusive. Recently, a unique transcription factor was described for cDC, namely Zbtb46, enabling us to selectively target this cell type in mice.

Methods: Low-density lipoprotein receptor-deficient (Ldlr-/-) mice were transplanted with bone marrow from Zbtb46-diphtheria toxin receptor (DTR) transgenic mice following total body irradiation. Zbtb46-DTR→Ldlr-/- chimeras were fed a Western-type diet for 18 weeks while cDC were depleted by administering diphtheria toxin (DT).

Results: Although we confirmed efficient direct induction of cDC death in vitro and in vivo upon DT treatment of Zbtb46-DTR mice, advanced atherosclerotic plaque size and composition was not altered. Surprisingly, however, analysis of Zbtb46-DTR→Ldlr-/- chimeras showed that depletion of cDC was not sustained following 18 weeks of DT treatment. In contrast, high levels of anti-DT antibodies were detected.

Conclusions: Because of the observed generation of anti-DT antibodies and consequently the partial depletion of cDC, no clear decision can be taken on the role of cDC in atherosclerosis. Our results underline the unsuitability of Zbtb46-DTR→Ldlr-/- mice for studying the involvement of cDC in maintaining the disease process of atherosclerosis, as well as of other chronic inflammatory diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169608PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5218565PMC
August 2017

Linking CD11b (+) Dendritic Cells and Natural Killer T Cells to Plaque Inflammation in Atherosclerosis.

Mediators Inflamm 2016 9;2016:6467375. Epub 2016 Mar 9.

Laboratory of Physiopharmacology, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, 2610 Antwerp, Belgium.

Atherosclerosis remains the leading cause of death and disability in our Western society. To investigate whether the dynamics of leukocyte (sub)populations could be predictive for plaque inflammation during atherosclerosis, we analyzed innate and adaptive immune cell distributions in blood, plaques, and lymphoid tissue reservoirs in apolipoprotein E-deficient (ApoE(-/-)) mice and in blood and plaques from patients undergoing endarterectomy. Firstly, there was predominance of the CD11b(+) conventional dendritic cell (cDC) subset in the plaque. Secondly, a strong inverse correlation was observed between CD11b(+) cDC or natural killer T (NKT) cells in blood and markers of inflammation in the plaque (including CD3, T-bet, CCR5, and CCR7). This indicates that circulating CD11b(+) cDC and NKT cells show great potential to reflect the inflammatory status in the atherosclerotic plaque. Our results suggest that distinct changes in inflammatory cell dynamics may carry biomarker potential reflecting atherosclerotic lesion progression. This not only is crucial for a better understanding of the immunopathogenesis but also bares therapeutic potential, since immune cell-based therapies are emerging as a promising novel strategy in the battle against atherosclerosis and its associated comorbidities. The cDC-NKT cell interaction in atherosclerosis serves as a good candidate for future investigations.
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http://dx.doi.org/10.1155/2016/6467375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804096PMC
December 2016

Feasibility of an interactive electronic self-report tool for oral cancer therapy in an outpatient setting.

Support Care Cancer 2016 08 30;24(8):3567-71. Epub 2016 Mar 30.

Department of Oncology, Multidisciplinary Oncological Center Antwerp, MOCA, University Hospital Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium.

Background: The introduction of oral anti-cancer agents provides a convenient administration route for chronic cancer treatment to outpatients. Health information technology through web-based applications or other electronic tools can offer a platform to improve treatment compliance, symptom management, and patient-provider communication.

Purpose: The purposes of this study were to test the feasibility and clinical utility of an electronic self-report device (RemeCoach) for patients or their caregivers and to register and prospectively evaluate the quality of data generated.

Patients And Methods: Patients using Teysuno® (S-1) for advanced gastrointestinal carcinoma used a pre-programmed device in order to register compliance to treatment and six clinical parameters. Real-time data were collected onto a central platform, which processed the data by an algorithm. This algorithm stratified the data into different grades based on the Common Terminology Criteria for Adverse Events (CTCAE v4.0).

Results: From December 2013 to March 2014, 11 patients (5 men, 6 women) were enrolled. Compliance to the device was high, six patients (55 %) registered timely intake of medication (demonstrating >95 % treatment compliance). Agreement between patients' and clinicians' reported toxicity was substantial for nausea, but discrepant for fatigue, hand-foot syndrome, and mucositis.

Conclusion: The use of an interactive self-report tool is feasible, reliable, and acceptable to outpatients. The RemeCoach and the algorithm devised will be further developed as an interactive patient-reported outcome (PRO) system, to improve early detection of side effects in an outpatient setting. Further studies are needed to confirm these data and to explore the relationship between optimal patient support and efficacy of treatment.
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http://dx.doi.org/10.1007/s00520-016-3186-2DOI Listing
August 2016

Fluorescent activated cell sorting: an effective approach to study dendritic cell subsets in human atherosclerotic plaques.

J Immunol Methods 2015 Feb 17;417:76-85. Epub 2014 Dec 17.

Lab of Physiopharmacology, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.

Different immune cell types are present within atherosclerotic plaques. Dendritic cells (DC) are of special interest, since they are considered as the 'center of the immuniverse'. Identifying inflammatory DC subtypes within plaques is important for a better understanding of the lesion pathogenesis and pinpoints their contribution to the atherosclerotic process. We have developed a flow cytometry-based method to characterize and isolate different DC subsets (i.e. CD11b(+), Clec9A(+) and CD16(+) conventional (c)DC and CD123(+) plasmacytoid (p)DC) in human atherosclerotic plaques. We revealed a predominance of pro-inflammatory CD11b(+) DC in advanced human lesions, whereas atheroprotective Clec9A(+) DC were almost absent. CD123(+) pDC and CD16(+) DC were also detectable in plaques. Remarkably, plaques from distinct anatomical locations exhibited different cellular compositions: femoral plaques contained less CD11b(+) and Clec9A(+) DC than carotid plaques. Twice as many monocytes/macrophages were observed compared to DC. Moreover, relative amounts of T cells/B cells/NK cells were 6 times as high as DC numbers. For the first time, fluorescent activated cell sorting analysis of DC subsets in human plaques indicated a predominance of CD11b(+) cDC, in comparison with other DC subsets. Isolation of the different subsets will facilitate detailed functional analysis and may have significant implications for tailoring appropriate therapy.
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http://dx.doi.org/10.1016/j.jim.2014.12.010DOI Listing
February 2015

Impaired gait pattern as a sensitive tool to assess hypoxic brain damage in a novel mouse model of atherosclerotic plaque rupture.

Physiol Behav 2015 Feb 20;139:397-402. Epub 2014 Nov 20.

Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.

Apolipoprotein E deficient (ApoE(-/-)) mice with a heterozygous mutation in the fibrillin-1 gene (Fbn1(C1039G+/-)) show spontaneous atherosclerotic plaque ruptures, disturbances in cerebral flow and sudden death when fed a Western-type diet (WD). The present study focused on motor coordination and spatial learning of ApoE(-/-) Fbn1(C1039G+/-) mice on WD for 20 weeks (n=21). ApoE(-/-) mice on WD (n=24) and ApoE(-/-) Fbn1(C1039G+/-) mice on normal diet (ND, n=21) served as controls. Starting from 10 weeks of diet, coordination was assessed every two weeks by the following tests: gait analysis, stationary beam, wire suspension and accelerating rotarod. The Morris water maze test was performed after 13 weeks of diet to study spatial learning. At the end of the experiment (20 weeks of WD), the mice were sacrificed and the brachiocephalic artery and brain were isolated. From 12 weeks onward, gait analysis of ApoE(-/-) Fbn1(C1039G+/-) mice on WD revealed a progressive increase in track width as compared to ApoE(-/-) mice on WD and ApoE(-/-) Fbn1(C1039G+/-) mice on ND (at 20 weeks: 29.8±0.6 mm vs. 25.8±0.4 mm and 26.0±0.5 mm). Moreover, the stationary beam test showed a decrease in motor coordination of ApoE(-/-) Fbn1(C1039G+/-) mice on WD at 18 and 20 weeks. The wire suspension test and accelerating rotarod could not detect signs of motor impairment. Spatial learning was also not affected. Histological analysis of the brachiocephalic artery showed larger and more stenotic plaques in ApoE(-/-) Fbn1(C1039G+/-) mice on WD. Furthermore, the parietal cortex of ApoE(-/-) Fbn1(C1039G+/-) mice on WD showed pyknotic nuclei as a sign of hypoxia and the percentage of pyknosis correlated with track width. In conclusion, gait analysis may be an efficient method for analyzing hypoxic brain damage in the ApoE(-/-) Fbn1(C1039G+/-) mouse model. This test could be of value to assess the effect of potential anti-atherosclerotic therapies in mice.
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http://dx.doi.org/10.1016/j.physbeh.2014.11.047DOI Listing
February 2015

Poly(I:C) as cancer vaccine adjuvant: knocking on the door of medical breakthroughs.

Pharmacol Ther 2015 Feb 2;146:120-31. Epub 2014 Oct 2.

Center for Oncological Research, University of Antwerp, B-2610 Antwerp, Belgium; Tumor Immunology Group, Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, B-2650 Edegem, Belgium; Center for Cell Therapy & Regenerative Medicine, Antwerp University Hospital, B-2650 Edegem, Belgium. Electronic address:

Although cancer vaccination has yielded promising results in patients, the objective response rates are low. The right choice of adjuvant might improve the efficacy. Here, we review the biological rationale, as well as the preclinical and clinical results of polyinosinic:polycytidylic acid and its derivative poly-ICLC as cancer vaccine adjuvants. These synthetic immunological danger signals enhanced vaccine-induced anti-tumor immune responses and contributed to tumor elimination in animal tumor models and patients. Supported by these results, poly-ICLC-containing cancer vaccines are currently extensively studied in the ongoing trials, making it highly plausible that poly-ICLC will be part of the future approved cancer immunotherapies.
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http://dx.doi.org/10.1016/j.pharmthera.2014.09.010DOI Listing
February 2015

Tolerogenic dendritic cell vaccines to treat autoimmune diseases: can the unattainable dream turn into reality?

Autoimmun Rev 2014 Feb 9;13(2):138-50. Epub 2013 Oct 9.

Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. Electronic address:

Autoimmune diseases affect about one in 15 individuals in developed countries and are characterized by a breakdown in immune tolerance. Current therapeutic approaches against destructive immune responses in autoimmune diseases are based on non-specific agents systemically suppressing the function of many immune effector cells. This indiscriminate immunosuppression, however, often causes serious and sometimes life-threatening side effects. Therefore, the need for more specific treatments resulting in lower toxicity and longer-term solutions is high. Because of the established role of dendritic cells (DCs) in maintaining the balance between immunity and tolerance, tolerogenic (tol)DCs might be novel therapeutic targets to prevent undesirable (auto-)immune responses. The idea behind tolDC therapy is that it is a highly targeted, antigen-specific treatment that only affects the auto-reactive inflammatory response. The therapeutic potential of tolDCs has already been proven in experimental animal models of different autoimmune disorders as well as with in vitro experiments using ex vivo generated human tolDCs, thus the challenge remains in bringing tolDC therapy to the clinic, although first clinical trials have been conducted. In this review, we will extensively discuss the use of tolDCs for induction of antigen-specific tolerance in several autoimmune disease settings, from bench to bedside, including currently applied strategies to generate tolDCs as well as technical difficulties and challenges in the field.
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http://dx.doi.org/10.1016/j.autrev.2013.09.008DOI Listing
February 2014

Does patient-tailored immunotherapy pave the way for new renal cell carcinoma treatment perspectives?

Transl Androl Urol 2013 Jun;2(2):85-8

1 Laboratory of Pharmacology, University of Antwerp, B-2610 Antwerp, Belgium ; 2 Division of Nephrology-Hypertension, Antwerp University Hospital, B-2650 Edegem, Antwerp, Belgium ; 3 Laboratory of Physiopharmacology, University of Antwerp, B-2610 Antwerp, Belgium ; 4 Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (VAXINFECTIO), University of Antwerp, B-2610 Antwerp, Belgium.

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http://dx.doi.org/10.3978/j.issn.2223-4683.2012.10.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708222PMC
June 2013

Potential use of dendritic cells for anti-atherosclerotic therapy.

Curr Pharm Des 2013 ;19(33):5873-82

Laboratory of Pharmacology, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Antwerp, Belgium.

The chronic inflammatory nature of atherosclerosis is nowadays widely accepted. Dendritic cells (DCs) are likely to play a crucial role in directing innate and adaptive immunity against altered (self-)antigens, such as oxidized low density lipoproteins (oxLDL). DCs are found in early lesions and their numbers become even higher when the lesion progresses. DCs are most abundant in areas of neovascularization where they are often found near T cells. All stages from precursors to fully mature DCs are present in human plaques. Treatment of atherosclerosis is currently based on reducing risk factors, e.g. by use of statins and beta-blockers. Some of these pharmacological agents also show anti-inflammatory properties and consequently can affect DC function. Yet, many patients remain at risk for acute coronary events, and new therapies to treat atherosclerosis are needed. One therapeutic strategy is based on isolation of patient's DCs that are then pulsed with appropriate antigen(s) ex vivo, e.g. (immunogenic components of) oxLDL or total extract of atherosclerotic plaque tissue, and returned to the blood stream. Other approaches to ensure immune protection include generation of tolerogenic DCs, or using DCs to deplete detrimental Th1 or Th17 cells. However, the future lies in direct targeting of DCs by manipulating functions of different DC subsets. Therefore, it would be useful to isolate plaque-resident DCs to be able to identify unique antigen(s) on their surface. The challenge is to selectively identify regulatory molecules and novel therapies to inhibit DC migration and function during atherogenesis, without affecting normal DC function under physiological conditions.
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http://dx.doi.org/10.2174/1381612811319330006DOI Listing
April 2014

Transcript and protein analysis reveals better survival skills of monocyte-derived dendritic cells compared to monocytes during oxidative stress.

PLoS One 2012 15;7(8):e43357. Epub 2012 Aug 15.

Laboratory of Cellular and Molecular Cardiology, University of Antwerp, Wilrijk, Antwerp, Belgium.

Background: Dendritic cells (DCs), professional antigen-presenting cells with the unique ability to initiate primary T-cell responses, are present in atherosclerotic lesions where they are exposed to oxidative stress that generates cytotoxic reactive oxygen species (ROS). A large body of evidence indicates that cell death is a major modulating factor of atherogenesis. We examined antioxidant defence systems of human monocyte-derived (mo)DCs and monocytes in response to oxidative stress.

Methods: Oxidative stress was induced by addition of tertiary-butylhydroperoxide (tert-BHP, 30 min). Cellular responses were evaluated using flow cytometry and confocal live cell imaging (both using 5-(and-6)-chloromethyl-2,7-dichlorodihydrofluorescein diacetate, CM-H(2)DCFDA). Viability was assessed by the neutral red assay. Total RNA was extracted for a PCR profiler array. Five genes were selected for confirmation by Taqman gene expression assays, and by immunoblotting or immunohistochemistry for protein levels.

Results: Tert-BHP increased CM-H(2)DCFDA fluorescence and caused cell death. Interestingly, all processes occurred more slowly in moDCs than in monocytes. The mRNA profiler array showed more than 2-fold differential expression of 32 oxidative stress-related genes in unstimulated moDCs, including peroxiredoxin-2 (PRDX2), an enzyme reducing hydrogen peroxide and lipid peroxides. PRDX2 upregulation was confirmed by Taqman assays, immunoblotting and immunohistochemistry. Silencing PRDX2 in moDCs by means of siRNA significantly increased CM-DCF fluorescence and cell death upon tert-BHP-stimulation.

Conclusions: Our results indicate that moDCs exhibit higher intracellular antioxidant capacities, making them better equipped to resist oxidative stress than monocytes. Upregulation of PRDX2 is involved in the neutralization of ROS in moDCs. Taken together, this points to better survival skills of DCs in oxidative stress environments, such as atherosclerotic plaques.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0043357PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419731PMC
January 2013

Optimizing dendritic cell-based immunotherapy: tackling the complexity of different arms of the immune system.

Mediators Inflamm 2012 18;2012:690643. Epub 2012 Jul 18.

Laboratory of Pharmacology, Department of Translational Pathophysiological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, 2610 Antwerp, Belgium.

Earlier investigations have revealed a surprising complexity and variety in the range of interaction between cells of the innate and adaptive immune system. Our understanding of the specialized roles of dendritic cell (DC) subsets in innate and adaptive immune responses has been significantly advanced over the years. Because of their immunoregulatory capacities and because very small numbers of activated DC are highly efficient at generating immune responses against antigens, DCs have been vigorously used in clinical trials in order to elicit or amplify immune responses against cancer and chronic infectious diseases. A better insight in DC immunobiology and function has stimulated many new ideas regarding the potential ways forward to improve DC therapy in a more fundamental way. Here, we discuss the continuous search for optimal in vitro conditions in order to generate clinical-grade DC with a potent immunogenic potential. For this, we explore the molecular and cellular mechanisms underlying adequate immune responses and focus on most favourable DC culture regimens and activation stimuli in humans. We envisage that by combining each of the features outlined in the current paper into a unified strategy, DC-based vaccines may advance to a higher level of effectiveness.
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http://dx.doi.org/10.1155/2012/690643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407661PMC
November 2012

Everolimus triggers cytokine release by macrophages: rationale for stents eluting everolimus and a glucocorticoid.

Arterioscler Thromb Vasc Biol 2012 May 16;32(5):1228-35. Epub 2012 Feb 16.

Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.

Objective: Stent-based delivery of the mammalian target of rapamycin (mTOR) inhibitor everolimus is a promising strategy for the treatment of coronary artery disease. We studied potential adverse effects associated with mTOR inhibition.

Methods And Results: Macrophages in culture were either treated with everolimus or starved to inhibit mTOR. Everolimus led to inhibition of protein translation, activation of p38 MAPK, and the release of proinflammatory cytokines (eg, IL-6, TNFα) and chemokines (eg, MCP1, Rantes) before induction of autophagic death. These effects were also observed with rapamycin, but not after starvation. Everolimus-induced cytokine release was similar in macrophages lacking the essential autophagy gene Atg7 but was inhibited when macrophages were cotreated with p38 MAPK inhibitor SB202190 or the glucocorticoid clobetasol. Combined stent-based delivery of clobetasol and everolimus in rabbit plaques downregulated TNFα expression as compared with everolimus-treated plaques but did not affect the ability of everolimus to induce macrophage clearance.

Conclusions: mTOR inhibition by everolimus triggers cytokine release in macrophages through inhibition of protein translation and p38 activation. These findings provide a rationale for combined local treatment of atherosclerotic plaques with everolimus and an anti-inflammatory agent.
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http://dx.doi.org/10.1161/ATVBAHA.112.245381DOI Listing
May 2012

Dendritic cells in human atherosclerosis: from circulation to atherosclerotic plaques.

Mediators Inflamm 2011 2;2011:941396. Epub 2011 Oct 2.

Division of Cardiology, Department of Translational Pathophysiological Research, Faculty of Medicine, University of Antwerp, Wilrijk, Belgium.

Background: Atherosclerosis is a chronic inflammatory disease with atherosclerotic plaques containing inflammatory infiltrates predominantly consisting of monocytes/macrophages and activated T cells. More recent is the implication of dendritic cells (DCs) in the disease. Since DCs were demonstrated in human arteries in 1995, numerous studies in humans suggest a role for these professional antigen-presenting cells in atherosclerosis.

Aim: This paper focuses on the observations made in blood and arteries of patients with atherosclerosis. In principal, flow cytometric analyses show that circulating myeloid (m) and plasmacytoid (p) DCs are diminished in coronary artery disease, while immunohistochemical studies describe increased intimal DC counts with evolving plaque stages. Moreover, mDCs and pDCs appear to behave differently in atherosclerosis. Yet, the origin of plaque DCs and their relationship with blood DCs are unknown. Therefore, several explanations for the observed changes are postulated. In addition, the technical challenges and discrepancies in the research field are discussed.

Future: Future studies in humans, in combination with experimental animal studies will unravel mechanisms leading to altered blood and plaque DCs in atherosclerosis. As DCs are crucial for inducing but also dampening immune responses, understanding their life cycle, trafficking and function in atherosclerosis will determine potential use of DCs in antiatherogenic therapies.
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http://dx.doi.org/10.1155/2011/941396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184502PMC
January 2012

Immunohistochemical characterisation of dendritic cells in human atherosclerotic lesions: possible pitfalls.

Pathology 2011 Apr;43(3):239-47

Division of Cardiology, Department of Translational Pathophysiological Research, University of Antwerp, Wilrijk, Belgium.

Background: Previously we demonstrated decreased blood myeloid (m) and plasmacytoid (p) dendritic cell (DC) counts in atherosclerotic patients. Therefore, we examined whether DCs, in particular DC precursors, accumulate in human plaques.

Methods: Blood DC antigen (BDCA)-1, CD11c (mDCs), BDCA-2, CD123 (pDCs), langerin, fascin, S-100 (immature/mature DCs), and CD1a and CD83 (mature DCs) were investigated by immunohistochemistry of carotid arteries obtained by endarterectomy (EAS, frozen n = 11, fixed n = 11) or autopsy (fixed, n = 87).

Results: Fascin and S-100 required formaldehyde fixation, other markers needed cryo-preservation. BDCA-1, BDCA-2, langerin, and S-100 appeared specific for intimal DCs, unlike CD123 and fascin (staining endothelial cells), CD11c and CD1a (staining monocytes, foam cells) or CD83 (staining lymphocytes). BDCA-1 and BDCA-2 cells were detected in EAS, preferentially near microvessels. S-100 cells increased successively from intimal thickening, via pathological intimal thickening, fibrous cap atheroma and finally complicated plaques. Fascin cells followed the same pattern, but were more abundant. However, in lesions containing microvessels (complicated plaques, plaque shoulders and most EAS) this was partly explained by fascin positive endothelial cells. Even complicated plaques contained relatively few mature CD83 DCs.

Conclusions: Accumulation of BDCA-1 and BDCA-2 around neovessels showed that mDCs and pDCs are recruited to advanced plaques, which is in line with the previously described decline of circulating blood DCs in patients with coronary artery disease. Unexpectedly, several DC markers yielded false positive signals. Hence, some accounts on numbers, trafficking and activation of DCs in atherosclerotic plaques may require re-evaluation.
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http://dx.doi.org/10.1097/PAT.0b013e328344e266DOI Listing
April 2011

Decreased numbers of peripheral blood dendritic cells in patients with coronary artery disease are associated with diminished plasma Flt3 ligand levels and impaired plasmacytoid dendritic cell function.

Clin Sci (Lond) 2011 May;120(9):415-26

Department of Cardiology, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.

We investigated whether activation of circulating DCs (dendritic cells) or levels of Flt3L (FMS-like tyrosine kinase 3 ligand) and GM-CSF (granulocyte/macrophage colony-stimulating factor), haematopoietic growth factors important for DC differentiation, could account for reduced blood DC numbers in CAD (coronary artery disease) patients. Concentrations of Flt3L and GM-CSF were measured in plasma from CAD patients (n = 15) and controls (n = 12). Frequency and phenotype of mDCs (myeloid dendritic cells) and pDCs (plasmacytoid dendritic cells) were analysed by multicolour flow cytometry in fresh blood, and after overnight incubation with TLR (Toll-like receptor)-4 or -7 ligands LPS (lipopolysaccharide) or IQ (imiquimod). DC function was measured by IL (interleukin)-12 and IFN (interferon)-α secretion. Circulating numbers of CD11c+ mDCs and CD123+ pDCs and frequencies of CD86+ and CCR-7+ (CC chemokine receptor type 7) mDCs, but not pDCs, were declined in CAD. In addition, plasma Flt3L, but not GM-CSF, was lower in patients and positively correlated with blood DC counts. In response to LPS, mDCs up-regulated CD83 and CD86, but CCR-7 expression and IL-12 secretion remained unchanged, similarly in patients and controls. Conversely, pDCs from patients had lower CD83 and CCR-7 expression after overnight incubation and had a weaker IQ-induced up-regulation of CD83 and IFN-α secretion. In conclusion, our results suggest that reduced blood DC counts in CAD are, at least partly, due to impaired DC differentiation from bone marrow progenitors. Decreased levels of mDCs are presumably also explained by activation and subsequent migration to atherosclerotic plaques or lymph nodes. Although mDCs are functioning normally, pDCs from patients appeared to be both numerically and functionally impaired.
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http://dx.doi.org/10.1042/CS20100440DOI Listing
May 2011

Expression of dendritic cell markers CD11c/BDCA-1 and CD123/BDCA-2 in coronary artery disease upon activation in whole blood.

J Immunol Methods 2010 Oct 1;362(1-2):168-75. Epub 2010 Oct 1.

Division of Cardiology, University of Antwerp, Wilrijk, Belgium.

Objectives: Previous in vivo studies on dendritic cell (DC) enumeration in coronary artery disease (CAD) were not always consistent. Therefore, we investigated by flow cytometry whether this was due to CAD-related differences in expression of subset markers for myeloid (m)DCs (blood DC antigen (BDCA)-1, CD11c) and plasmacytoid (p)DCs (BDCA-2, CD123), before and after in vitro stimulation with Toll-like receptor ligands.

Results: Our data showed that circulating DCs decline in CAD, irrespective of the DC subset marker that was used for enumeration. Upon in vitro activation, BDCA-2 was downregulated, whereas CD11c and CD123 were upregulated. This implies that the expression ratios CD11c/BDCA-1 and CD123/BDCA-2 can assess DC activation. Comparing these ratios between controls and CAD patients showed no differences in blood DC activation in both groups.

Conclusions: This study suggests that when different DC numbers are found between two study populations, the DC activation status from both groups always needs to be verified, since a decrease in BDCA-2(+) pDCs or an increase in CD11c(+) mDCs or CD123(+) pDCs can be due to the altered expression of these markers during activation. Given that CD11c, BDCA-1, CD123 and BDCA-2 are more abundantly expressed on blood DCs than typical activation markers like CD83, CD86 or CCR-7, the use of the ratios is an easy and reliable way to determine DC activation in whole blood assays.
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http://dx.doi.org/10.1016/j.jim.2010.09.031DOI Listing
October 2010

Changes in blood dendritic cell counts in relation to type of coronary artery disease and brachial endothelial cell function.

Coron Artery Dis 2010 Mar;21(2):87-96

Department of Cardiology, University of Antwerp, B-2610 Wilrijk, Belgium.

Background: Recently we reported a decline of circulating myeloid (m) and plasmacytoid (p) dendritic cells (DCs) in patients with coronary artery disease (CAD). This study also determined the total blood DC numbers and focused on effects of extent (one vs. three-vessel disease) and type (stable vs. unstable) of CAD, and on endothelial cell function.

Methods: Patients undergoing diagnostic coronarography were enrolled in four groups: control patients (atypical chest pain, <50% narrowing, n=15), stable one-vessel (n=15), stable three-vessel (n=15), and unstable one-vessel CAD (n=16). Total blood DCs were identified as lineage (lin) and HLADR, and DC subtypes with blood DC antigen (BDCA)-1 for mDCs and BDCA-2 for pDCs. Flow-mediated dilatation (FMD) was measured in the brachial artery.

Results: Numbers of total blood DCs, mDCs and pDCs declined in CAD patients compared with control patients, but without differences between the CAD groups. Interleukin-6 and high sensitivity C-reactive protein displayed inverse associations with mDCs. A FMD below the median of the study population, use of beta-blockers or of lipid-lowering drugs was associated with increased mDCs, whereas pDCs were similar. Interestingly, the effects of drugs and FMD were additive with that of CAD.

Conclusion: This study indicates that lower blood DCs do not result from medication intake or endothelial dysfunction, and are an overall systemic effect of atherosclerosis rather than CAD type (stable or unstable) or number of stenotic coronary arteries. In view of discrete associations with cytokines, FMD, beta-blockers and statins, mDCs and pDCs seem to behave differently and may influence inflammation during atherosclerosis in different ways.
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http://dx.doi.org/10.1097/MCA.0b013e3283368c0eDOI Listing
March 2010