Embed Size (px)
Citation preview
ERS SHORT-TERM RESEARCH TRAINING FELLOWSHIP
KORTHAGEN Nicoline Marianne
Fellowship Number STRTF 217-2010
ERS SHORT-TERM RESEARCH TRAINING FELLOWSHIPS APPLICATION
No. STRTF 217-2010 – Ms. Nicoline Marianne KORTHAGEN Section 1 – Fellowship Sought
Fellowship number: STRTF 217-2010
Title of proposed project: YKL-40 and alternatively activated macrophages in Idiopathic pulmonary fibrosis
ERS Fellowship programme: STRTF
Keywords: Idiopathic Pulmonary Fibrosis YKL-40 Alternatively activated Macrophages Cytokines
Expected starting date: 01.03.2011
Expected finishing date: 01.06.2011
Do you intend to return home after the Fellowship?
Yes
What are you plans after the Fellowship?
The results of this research fellowship will be included in my PhD thesis. The research techniques obtained during this fellowship will be continued in the Netherlands on the dutch IPF cohort and research facilities, laboratory assistance and salary will be available during the finishing of my PhD thesis. In addition, research on alternatively activated macrophages will be expanded to include other diffuse interstitial lung diseases and possibly all other lung diseases.
Section 2 – Applicant personal details
Title:
Last name:
Ms.
KORTHAGEN
First names: Nicoline Marianne
Gender Female
Date of birth: 20.02.1981
Nationality: NETHERLANDS
Present position: Junior Researcher
Since when: 01.09.2007
Name and address of the home institution:
St Antonius Hospital Koekoekslaan 1 3435 CM Nieuwegein
Country: NETHERLANDS
Telephone: +31 88 320 4425
E-mail: [email protected]
ERS membership number: 244572
Are you now based in your Home country?:
Yes
Home/Host address: Laan van Chartroise 2 3552 EV Utrecht Section 3 – Home supervisor
Title:
Last name:
Dr.
GRUTTERS
First names: Jan
Present position: Pulmonary Physician and supervisor of the ILD-research center
Since when: 2003 Name and address of the home institution:
St Antonius hospital Koekoekslaan 1 3435 CM Nieuwegein
Country: NETHERLANDS
Telephone: +31 306092428
Fax: +31 306052001
E-mail: [email protected]
ERS member? Yes
ERS membership number: 78076 Section 4 – Host supervisor
Title:
Last name:
Prof.
PRASSE
First names: Antje
Present position: Researcher lung disease
Since when: 2000
Name and address of the home institution:
university clinic freiburg
Country: GERMANY
Telephone: +49 761 270-3720
Fax:
E-mail: [email protected]
ERS member? Yes
ERS membership number: 55840
Section 5 – Professional qualifications and experience of the applicant
Postdoctoral researcher since:
--
PhD holder since: --
MSc holder since 2006
MD holder since --
Other:
List degrees/diplomas/field of study/ years in which obtained and name of institutes):
MSc in Biology, obtained in 2006 at Utrecht University, specialization in human cellular and molecular biology
Number of years fulltime research experience
6
Please provide other information on your research experience (part time, full time, while working, while studying, etc.)
3 years while studying, including 3 different full time research internships and the writing of a thesis. 3 years full time as a junior researcher at the St Antonius Hospital
Number of years professional experience (list: years, position, name of employer)
3 years as a junior researcher at the St Antonius Hospital
Last two positions:
Position 1
Name of employer
From-To:
Junior Researcher
St Antonius Hospital, Nieuwegein, The Netherlands
2007-2010
Position 2
Name of employer
From-To:
student researcher
Numico Research, Bosrandweg, Wageningen, The Netherlands
2005-2006
Do you have 1 first author publication:
No - -
Main publication as a
co-author:
Section 6 – ERS Fellowship application details Number of publications in international peer-reviewed periodicals as per date of this application
In English: 5
In other language: 0
Professional societies or associations of which you are a member:
NRS (netherlands respiratory society)
Curriculum Vitae
Personal informationName: Nicoline M. KorthagenNationality: Dutch Date of Birth: February 20th 1981, Maarssen, The NetherlandsCivil Status: Married, no childrenAddress: Laan van Chartroise 2
3552 EV UtrechtThe Netherlands
E-mail: [email protected]: +31 (0)6-27237146Languages: Fluent in Dutch and English. Working knowledge of German and French.
Work address:Department of PulmonologySt Antonius HospitalKoekoekslaan 13435 CM Nieuwegein
E-mail: [email protected]: +31 (0) 30 609 2428
Present employmentsept 2007-aug 2010: Junior researcher at St Antonius Hospital and Utrecht University. Supervision: Prof. Dr. J.M.M. van den Bosch MD, Dr J.C. Grutters MD, and Dr C.H.M. van Moorsel.Provisional title: The influence of genetic and molecular pathways on susceptibility and progression of Idiopathic Pulmonary Fibrosis.Applied techniques: Patient data and sample collection, multivariate analysis, survival analysis, DNA/RNA/cell isolation, SNP genotyping array, genetic linkage analysis, meta-analysis, genetic association tests, ELISA, SSP/RT/HRM-PCR, immunohistochemistry.
Education2000-2006: MSc in Biology at Utrecht University
Research experience:Sept 2005-July 2006, internship at Numico Research BV, Wageningen, The Netherlands and the Pharmacology department of the Utrecht University. Supervision: Dr. L. E. M. Willemsen. Title: Effects of probiotics on the immune system: an in vitro model mimicking the intestinal mucosa.
Sept 2004-April 2005, internship at the Institute for Risk Assessment Sciences, Utrecht University.Supervision: Dr. J. van Meeuwen.Title: Co-culture of primary human fibroblasts and MCF-7 breast cancer cells: Effects of flavonoids on an in vitro model for breast cancer.
May-June 2004, written a thesis at the Microbiology department of the Utrecht University.Supervision: Dr. M. BosTitle: The TAT protein transport system
Sept 2003- May 2004, internship at the Endocrinology department of the Utrecht University.
Supervision: Dr. A. M. M. van Pelt. Title: The effects of estradiol and PDGF on prenatal rat gonocytes.
1999-2000: Propaedeuse (1st yr foundation programme) of Natural Sciences and Innovational technology at Utrecht University
Honors and AwardsYoung investigator award from the Netherlands Respiratory Society for the best abstractsubmitted by a young investigator to the NRS 2nd spring meeting in April 2010. Title: Elevated BALF YKL-40 levels in IPF patients are associated with survival and lung function loss.
Research interestsFibrotic lung disease, translational-clinical research, medical genetics, signal transduction pathways, stem cells, immunology, cancer biology.
Publications(1) Korthagen NM, van Moorsel CH, Barlo NP, Ruven HJ, Kruit A, Heron M, van den Bosch
JM, Grutters JC. Serum and BALF YKL-40 levels are predictors of survival in idiopathic pulmonary fibrosis. Accepted for publication in Respiratory Medicine on 10 september 2010.
(2) de Kivit S, van Hoffen E, Korthagen N, Garssen J, Willemsen LEM. Apical TLR ligation of intestinal epithelial cells drives a Th1-polarized regulatory or inflammatory type effector response in vitro. Immunobiology 2010 Aug 21. Epub ahead of print.
(3) Korthagen NM, Nagtegaal MM, van Moorsel CH, Kazemier KM, van den Bosch JM, Grutters JC. MRP14 is elevated in the bronchoalveolar lavage fluid of fibrosing interstitial lung diseases. Clin Exp Immunol 2010 Jun 9.
(4) van Hoffen E, Korthagen NM, de Kivit S, Schouten B, Bardoel B, Duivelshof A, et al. Exposure of intestinal epithelial cells to UV-killed Lactobacillus GG but not Bifidobacterium breve enhances the effector immune response in vitro. Int Arch Allergy Immunol 2010; 152(2):159-68.
(5) van Meeuwen JA, Korthagen N, de Jong PC, Piersma AH, van den Berg M. (Anti)estrogenic effects of phytochemicals on human primary mammary fibroblasts, MCF-7 cells and their co-culture. Toxicol Appl Pharmacol 2007 Jun 15; 221(3):372-83.
Papers submitted to peer-reviewed journalsBarlo NP, van Moorsel CH, Nagtegaal MN, Korthagen NM, Rijkers GT, Ruven HJ, van den Bosch JM, Grutters JC. Genetic variation in CCL18 gene influences CCL18 expression and correlates with survival in IPF. Submitted
Participation in conferencesApril 2010 NRS spring meeting, Amersfoort, The Netherlands (oral presentation)Sept 2009 ERS Annual congress,Vienna, Austria (poster)April 2009 NRS spring meeting, Arnhem, The Netherlands (poster)Jan 2008 Lungfibrosis symposium, Utrecht, The Netherlands Jan 2009 Lungfibrosis symposium, Utrecht, The NetherlandsOkt 2008 ERS Annual congress, Berlin, Germany (poster)
Reviewer activitiesPerformed 2 reviews for Clinical and Experimental Immunology in the last year
Publications(1) Korthagen NM, van Moorsel CH, Barlo NP, Ruven HJ, Kruit A, Heron M, van den
Bosch JM, Grutters JC. Serum and BALF YKL-40 levels are predictors of survival in idiopathic pulmonary fibrosis. Accepted for publication in Respiratory Medicine on 10 september 2010.
(2) de Kivit S, van Hoffen E, Korthagen N, Garssen J, Willemsen LEM. Apical TLR ligation of intestinal epithelial cells drives a Th1-polarized regulatory or inflammatory type effector response in vitro. Accepted for publication in Immunobiology on 16 august 2010.
(3) Korthagen NM, Nagtegaal MM, van Moorsel CH, Kazemier KM, van den Bosch JM, Grutters JC. MRP14 is elevated in the bronchoalveolar lavage fluid of fibrosing interstitial lung diseases. Clin Exp Immunol 2010 Jun 9.
(4) van Hoffen E, Korthagen NM, de Kivit S, Schouten B, Bardoel B, Duivelshof A, et al. Exposure of intestinal epithelial cells to UV-killed Lactobacillus GG but not Bifidobacterium breve enhances the effector immune response in vitro. Int Arch Allergy Immunol 2010; 152(2):159-68.
(5) van Meeuwen JA, Korthagen N, de Jong PC, Piersma AH, van den Berg M. (Anti)estrogenic effects of phytochemicals on human primary mammary fibroblasts, MCF-7 cells and their co-culture. Toxicol Appl Pharmacol 2007 Jun 15; 221(3):372-83.
Papers submitted to peer-reviewed journalsBarlo NP, van Moorsel CH, Nagtegaal MN, Korthagen NM, Rijkers GT, Ruven HJ, van den Bosch JM, Grutters JC. Genetic variation in CCL18 gene influences CCL18 expression and correlates with survival in IPF. Submitted
The role of YKL-40 in the pathological processes associated with alternatively activated macrophages and their effect on IPF pathology.
Background: Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive lung disease characterized by interstitial remodelling and fibrosis. Median survival in IPF is approximately 3 years, but can vary between a few months and over 6 years. YKL-40 is a protein that is elevated in patients with asthma, inflammation and cancer. Recently, we found that YKL-40 levels in serum and lavage fluid of patients with IPF were increased and were correlated to survival. None of the patients with both low serum and lavage values died of respiratory insufficiency, while high values correlated significantly with shorter survival.The precise function of YKL-40 is unknown, but it was found to drive inflammatory and fibrotic processes by activation of macrophages. At the proposed host institution it was recently found that in IPF patients, alveolar macrophages have shifted from the normal (M1) to the alternatively activated M2 phenotype and that these cells are involved in the pathogenesis of IPF. Therefore, together we want to study the role of YKL-40 in the alternative activation of macrophages and in disease progression in IPF.
Aim: Identify the role of YKL-40 in the alternative activation of macrophages and their association with survival in IPF patients.
Work plan: Three months are required to perform the following experiments:- Expose cultured macrophages and monocytes to YKL-40 and determine changes in
macrophage activation markers.- Determine production of YKL-40 by cultured stimulated and unstimulated
macrophages and monocytes from IPF patients and healthy controls and determine the correlation of YKL-40 and M2 marker levels to patients' survival time.
Reasons for selecting the host: Prof Dr Müller-Quernheim and Dr Prasse from Freiburg University Medical Centre, head one of the main and internationally respected ILD-research centres worldwide. They recently introduced the concept that alternative macrophage activation is driving IPF pathology and showed that alternatively activated macrophages are present in IPF lung.
Value of the project for the home institute: Alternatively activated macrophages are proposed to determine lung pathology in several lung diseases. Being able to isolate and measure these cells and their cytokines will give insight into the cellular processes involved in IPF and other lung diseases. This may result in diagnostic and prognostic tools for the clinician and could be essential for the identification and development of therapeutic targets in the future.
Value of the project for my career: In research, it has always been my intention to combine the study of biological processes with clinically relevant questions. Present research has resulted in several papers that combine genetic and protein findings with clinical outcome. However, these studies leave large gaps in our understanding of the biological processes that are involved. I would like to bridge the gap between cellular and clinical research by validating the importance of my findings in cell culture experiments with patient material. I would have this opportunity in Freiburg. This research will be a follow-up of the YKL-40 studies on the correlation of YKL-40 with IPF-survival that I have just completed and will be a major part of my PhD-thesis. I realise that I need to go abroad to have a career in life sciences, in order to expand my network and experience and find new input and insight for
my research. In addition, IPF is a sporadic disease and therefore funding, networking opportunities and collaboration are largely dependent on international collaboration. Therefore, this project is a valuable next step in building a career in ILD-research.
Scientific rationale:
IPFIPF is the most prevalent chronic fibrosing interstitial lung disease. It is a devastating, progressive disease, characterized by inflammation and fibrotic remodelling. The prognosis is very poor, because the disease is always fatal and has a median survival time of only three years. Treatment most often includes prednisolone, azathioprine and N-acetylcysteine but therapeutic benefits are extremely limited or even absent. Apart from lung transplantation for eligible patients, there are currently no effective therapies. The pathogenesis of IPF is very poorly understood but is thought to involve, alveolar epithelial cell dysfunction, fibroblast growth and accumulation of extracellular matrix (ECM) components in response to aberrant wound healing. In bronchoalveolar lavage fluid (BALF) of IPF patients increased levels of Transforming Growth Factor-B (TGF-B) and other cytokines and chemokines have been found (1;2). TGF-β is thought to stimulate epithelial-mesenchymal transition and ECM production. However, levels of TGF-B or other cytokinesdo not correlate with survival of IPF patients. Recently, we found that YKL-40 levels are associated with survival in IPF patients.
YKL-40YKL-40 is a chitinase-like protein involved in tissue remodelling, inflammation, fibrosis and tumorigenesis. Elevated serum levels have been found in various diseases including cancer, liver cirrhosis, astma and sarcoidosis.
In IPF patients, increased levels of YKL-40 were found (3;4). In our group, we investigated YKL-40 in a cohort of 85 IPF patients. We measured serum YKL-40 levels in 384 healthy controls and found the median YKL-40 levels in serum was 37 ng/ml with an inter quartile range (IQR) of 27-53 ng/ml. In the IPF patients the median serum YKL-40 level was 109 ng/ml with an IQR of 68-265 ng/ml. BALF YKL-40 levels were very low in healthy controls (n=43) with a median of 5 ng/ml and an IQR of 0-11 ng/ml. In patients (n=60) the median BALF YKL-40 level was 12 ng/ml with an IQR of 8-24 ng/ml.
Cox regression modelling and Kaplan-Meier analysis revealed that both serum and BALF levels were associated with survival in IPF patients. Survival data was available from 79 patients with serum YKL-40 levels and 58 patients with BALF YKL-40 levels. There were several cut-off points for both serum and BALF values that resulted in significantly shorter survival in the patient group with high YKL-40 levels which confirms this finding was not coincidental. The optimum cut-off point, defined by the survival status at a given time point, was determined using ROC-curve analysis. The greatest differences were found at 36 months after diagnosis. Cox regression analysis showed there were no confounding factors. Kaplan-Meier analysis comparing patients with serum YKL-40 levels above 79 ng/ml (n=60) and below 79 ng/ml (n=19) resulted in a significant difference of p<0.01. After 48 moths, 52% of patients in the group with high serum YKL-40 levels had died compared to 14% in the group with low serum YKL-40 levels.The optimum cut-off point for BALF YKL-40 was 17 ng/ml and this also resulted in a difference with p<0.01 using Kaplan-Meier analysis with log-rank test. The 4-year survival
rate in patients with high BALF YKL-40 levels (n=18) was 28% compared to 69% in the group with low BALF YKL-40 levels (n=40).
Remarkably, combining the cut-off points of serum and BALF YKL-40 levels resulted in even better prediction (figure 1). In the patient group with low serum YKL-40 levels and low BALF YKL-40 levels none of the patients died from respiratory insufficiency.
Figure 1Kaplan-meier survival analysis grouped by baseline YKL-40 levels. Patients that were still alive, that were transplantedor died from a cause unrelated to IPF were censored in the survival analysis. In the group with both low serum YKL-40 and low BALF YKL-40 there were no IPF related deaths within 48 months after diagnosis. Patients with both high serum YKL-40 and high BALF YKL-40 had significantly worse survival estimates than patients who had either high serum YKL-40 or highBALF YKL-40 (p<0.01, χ2=13.09).
Our data suggests that serum and BALF YKL-40 reflect different pathological processes. In addition, there was no correlation between serum and BALF YKL-40 levels suggesting they do not have the same source. Immunohistochemistry in both healthy and IPF lungs showed that the most likely source of BALF YKL-40 is alveolar macrophages. However, no correlation was found between BALF YKL-40 levels and BALF macrophage counts in patients or healthy controls. In addition, immunohistochemical staining of the lung revealed that not all alveolar macrophages are positive for YKL-40 while increased numbers of positive macrophages in the lung correlate with increased BALF levels of YKL-40 (5). This suggests YKL-40 is produced by a subset of alveolar macrophages.
Increased numbers of alternatively activated macrophages (M2) have been found in the lungs of IPF patients and it was postulated that M2 macrophages determine the fibrotic response in interstitial lung disease (6;7).
Alternatively activated macrophagesAlternatively activated macrophages (M2) are distinguished from ‘normal’ M1 macrophages by the expression of CD163, mannose receptor (MRC-1, CD206) and Ym1/2. M2 macrophages also express several fibrotic mediators such as interleukin (IL)-10, IL-13 and
Survival time (months)4842363024181260
Cu
mu
lati
ve S
urv
ival
1,0
0,8
0,6
0,4
0,2
0,0
censored (n=6)censored (n=21)censored (n=10)serum >79 ng/ml and BALF >17ng/ml (n=17)Serum >79 ng/ml or BALF >17 ng/ml (n=31)Serum <79 ng/ml and BALF <17ng/ml (n=10)
Serum and BALF YKL-40
Survival time (months)
platelet derived growth factor (PDGF). Their activation is mediated by T-helper 2 cytokines, mainly IL-4 and IL-13 in contrast to the normal inflammatory pathway via IFN-γ that leads to M1 macrophages. M2 macrophages are thought to influence many processes such as inflammation, repair, tumorigenesis and fibrosis, but it is assumed that their main function is to stimulate tissue repair after inflammation (8).
In animal models, M2 macrophages have been implicated in pathogenic processes. Mice with dysfunctional M2 macrophages suffer from delayed healing and excessive fibrosis (9). When pulmonary fibrosis was induced in mice by virus infection, M2 macrophages were recruited to the areas with fibrosis and hyperplasia (10). In the murine model for IPF with bleomycin-induced pulmonary fibrosis, it was shown that alternatively activated M2 macrophages are associated with an increase in collagen deposition (6).
Increased expression of IL-13 by alveolar macrophages has been found in IPF patients, and this leads to increased TGF-β production and fibrosis (11;12).Researchers from the proposed host institution at Freiburg showed that M2 macrophages were involved in IPF pathology and that alveolar macrophages from IPF patients expressed enhanced levels of M2 markers (7). They also found that M2 macrophages produce C-Cchemokine motif ligand (CCL)18, a protein associated with IPF survival (Prasse et al, 2009). In addition, they produce IL-1Ra, a protein also implicated in IPF pathology (2;7). Murray et al, found increased levels of M2-associated proteins in the lungs of IPF patients (n=13) that were highest in patients with progressive disease (6), suggesting that survival of IPF patients might be correlated to M2-associated protein expression.
Remarkably, the Ym1 and Ym2 proteins specifically produced by M2 macrophages are also chitinase-like lectins belonging to the same family as YKL-40. In addition, two other members of this protein family, YKL-39 and SI-CLP, were produced by macrophages stimulated with IL-4 and TGF-β but not by macrophages stimulated with IFN-γ, and therefore seem specific for M2 macrophages (13;14).
YKL-40 has also been implicated in macrophage activation. Incubation of alveolar macrophages with YKL-40 caused the release of proinflammatory and fibrogenic chemokines in a dose dependent manner (5). In YKL-40 knockout mice the capacity for Th2 response was reduced and the ability of IL-13 to induce tissue inflammation and fibrosis was markedly diminished (15). It is possible that the effect of IL-13 on macrophage activation is mediated by YKL-40.
We hypothesise that perpetuation of the pro-fibrotic milieu in the lung of IPF-patients is driven by local YKL-40 production that causes a shift in macrophages towards an alternatively activated phenotype.
Continuation of the work at the home instituteThe 3 months in Freiburg will be used to master the techniques used to culture and stimulate macrophages and to obtain data on the effects of YKL-40 both in IPF patients and healthy controls.After this period I will be able to return to the home institute for at least six months to continue the investigations and finish my PhD studies. Laboratory facilities, materials and a laboratory technician will be available at the home institute to enable continuation the investigation on the Dutch cohort of patients. This will enable us to validate findings related to diagnosis and prognosis in an independent cohort. Because the home institute is a tertiary
referral centre for interstitial lung diseases with a long history of biomedical research, there is no problem obtaining sufficient patient samples. In addition, there will be an opportunity to investigate alternative macrophage activation in other lung diseases. Initially, we will study other fibrotic diseases such as NSIP, hypersensitivity pneumonitis and fibrotic sarcoidosis to see if there are similarities or whether the amount of alternatively activated macrophages could be used for diagnostic purposes. Subsequently, this research could be expanded to include other lung diseases such as COPD. Our hospital is well equipped and accustomed to implement new techniques. This will ensure that any findings that could benefit patients will be rapidly available in daily clinical practice.
In addition, we would like to emphasise that this research project would open the door to a long-term collaboration between our two institutes. Sharing research experience and scientific and clinical knowledge will enhance the quality at both institutes. In addition, both institutes have gathered a relatively large amount of data and samples and combining them will lead to new findings, more accurate results and easier clinical implementation.
Reference List(1) Cao B, Guo Z, Zhu Y, Xu W. The potential role of PDGF, IGF-1, TGF-beta expression
in idiopathic pulmonary fibrosis. Chin Med J (Engl ) 2000 September;113(9):776-82.(2) Vasakova M, Sterclova M, Kolesar L, Slavcev A, Pohunek P, Sulc J, Striz I. Cytokine
gene polymorphisms and BALF cytokine levels in interstitial lung diseases. Respir Med 2009 May;103(5):773-9.
(3) Furuhashi K, Suda T, Nakamura Y, Inui N, Hashimoto D, Miwa S, Hayakawa H, Kusagaya H, Nakano Y, Nakamura H, Chida K. Increased expression of YKL-40, a chitinase-like protein, in serum and lung of patients with idiopathic pulmonary fibrosis. Respir Med 2010 March 26.
(4) Korthagen NM, van Moorsel CH, Barlo NP, Ruven HJ, Kruit A, Heron M, van den Bosch JM, Grutters JC. Serum and BALF YKL-40 levels are predictors of survival in idiopathic pulmonary fibrosis. Respiratory Medicine 2010.
(5) Letuve S, Kozhich A, Arouche N, Grandsaigne M, Reed J, Dombret MC, Kiener PA, Aubier M, Coyle AJ, Pretolani M. YKL-40 is elevated in patients with chronic obstructive pulmonary disease and activates alveolar macrophages. J Immunol 2008 October 1;181(7):5167-73.
(6) Murray LA, Rosada R, Moreira AP, Joshi A, Kramer MS, Hesson DP, Argentieri RL, Mathai S, Gulati M, Herzog EL, Hogaboam CM. Serum amyloid P therapeutically attenuates murine bleomycin-induced pulmonary fibrosis via its effects on macrophages. PLoS ONE 2010;5(3):e9683.
(7) Pechkovsky DV, Zalutskaya OM, Ivanov GI, Misuno NI. Calprotectin (MRP8/14 protein complex) release during mycobacterial infection in vitro and in vivo. FEMS Immunol Med Microbiol 2000 September;29(1):27-33.
(8) Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity 2010 May 28;32(5):593-604.
(9) Wilson MS, Wynn TA. Pulmonary fibrosis: pathogenesis, etiology and regulation. Mucosal Immunol 2009 March;2(2):103-21.
(10) Mora AL, Torres-Gonzalez E, Rojas M, Corredor C, Ritzenthaler J, Xu J, Roman J, Brigham K, Stecenko A. Activation of alveolar macrophages via the alternative pathway in herpesvirus-induced lung fibrosis. Am J Respir Cell Mol Biol 2006 October;35(4):466-73.
(11) Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A. IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and
fibrosis. Nat Med 2006 January;12(1):99-106.(12) Hancock A, Armstrong L, Gama R, Millar A. Production of interleukin 13 by alveolar
macrophages from normal and fibrotic lung. Am J Respir Cell Mol Biol 1998 January;18(1):60-5.
(13) Gratchev A, Schmuttermaier C, Mamidi S, Gooi L, Goerdt S, Kzhyshkowska J. Expression of Osteoarthritis Marker YKL-39 is Stimulated by Transforming Growth Factor Beta (TGF-beta) and IL-4 in Differentiating Macrophages. Biomark Insights 2008;3:39-44.
(14) Kzhyshkowska J, Mamidi S, Gratchev A, Kremmer E, Schmuttermaier C, Krusell L, Haus G, Utikal J, Schledzewski K, Scholtze J, Goerdt S. Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway. Blood 2006 April 15;107(8):3221-8.
(15) Lee CG, Hartl D, Lee GR, Koller B, Matsuura H, Da Silva CA, Sohn MH, Cohn L, Homer RJ, Kozhich AA, Humbles A, Kearley J, Coyle A, Chupp G, Reed J, Flavell RA, Elias JA. Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13-induced tissue responses and apoptosis. J Exp Med 2009 May 11;206(5):1149-66.
BIOGRAPHICAL SKETCHNAME
Johannes Cornelis GruttersPOSITION TITLE
pulmonary physician DEGREE(S)
MD, PhDEDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and inclFFFude postdoctoral training.)
INSTITUTION AND LOCATIONDEGREE
(if applicable) YEAR(s) FIELD OF STUDY
University Nijmegen, NLMD 1985-92 Medicine
Bosch Medicenter, Den Bosch, NL Resident 1992-93 Internal Medicine
St. Antonius Hospital Nieuwegein & University Medical Center Utrecht, NL
Specialist Registrar Pulmonology
1993-2000 Respiratory Medicine
Royal Brompton Hospital & Imperial College, London, UK Research
2000-01 Clinical Genomics & Interstitial Lung Diseases
Doctoral degree (PhD) Thesis on ‘Genetic polymorphisms and phenotypes in sarcoidosis’, University Utrecht, Netherlands, October 17, 2003 (ISBN: 90-393-3514-1)
Positions and Honors.
2002 present: pulmonary physician St. Antonius Hospital Nieuwegein/Utrecht and Division Heart & Lung, University Medical Center Utrecht with expertise in interstitial lung diseases (ILD), and participating in the Lung Transplant Program
2009 present: head of training pulmonology St. Antonius Hospital Nieuwegein
2003 present: supervisor ILD-research center Interstitial Lung Diseases
2009: member ILD Task Force of the Netherlands Respiratory Society (NRS)
2005 present: member Editorial Board of the journal ‘Sarcoidosis, Vasculitis and Diffuse Lung Diseases’
2004 present: member Medical Advisory Board of the Dutch Pulmonary Fibrosis Patient Coalition
2006 present: member ’Medical Advisory Board of the Dutch Sarcoidosis Patient Coalition
2008 present: member Dutch and Worldwide LAM Patient Coalition
2009: member Scientific Advisory Board of the Netherlands Asthma Foundation
Research Support: external funding
2010 Dutch Sarcoidosis Patient Coalition “Sarcoidosis and exercise induced fatigue”: 27.500 €
2009 ZonMw subsidie, projectnr 11-330-1076; international projectnr 76 with title “European Pulmonary Alveolar Proteinosis Network: Molecular Determinants of Causes, Variability and Outcome”: 33.000 €
2007 Dutch Sarcoidosis Patient Coalition “Post-sarcoidosis fatigue syndrome”: 55.837 €
PRINCIPAL INVESTIGATOR: (LAST NAME, First, middle initial)
ATS Grant Application Form – 2007 - 9 -
Co-Supervisor of successfully completed PhD-projects
1. R. Janssen; Thesis on ‘Pneumoproteins in interstitial lung diseases’, University Utrecht, Netherlands, September 13, 2006 (ISBN: 90-8559-196-1)
2. Kruit; Thesis on ‘Gene polymorphisms in fibrotic sarcoidosis’, University Utrecht, Netherlands, September 27, 2006 (ISBN: 978-9039343074)
3. H. Endeman; Thesis on ‘Clinical characteristics and innate immunity in patients with community-acquired pneumonia’, University Utrecht, Netherlands, May 12, 2009 (ISBN: 978-9090241333)
4. M. Heron; Thesis on ‘Immunological markers of cell activation in sarcoidosis’, University Utrecht, Netherlands, January 21, 2010 (ISBN 978-90-9024920-9)
Co-Supervisor current PhD-projects at our institute:
5. R.G.M. Keijsers; PhD-project on ‘Molecular imaging with 18-FDG-PET in sarcoidosis’ (2005-doctoral degree at University Utrecht planned in December 2010)
6. M. Veltkamp; PhD-project on ‘Pattern recognition receptors and intracellular pathogens in Dutch sarcoidosis patients’ (2005-doctoral degree at University Utrecht planned February 2011)
7.I.H.E. Korenromp; PhD-project on ‘Post-sarcoidosis fatigue syndrome: a psychoneuroimmunologic approach’(2006-present)
8. N. Barlo; PhD-project on ‘Prognostic markers for idiopathic pulmonary fibrosis’ (2007-present)
9. N. Korthagen; PhD-project on ‘Markers of pathogenic processes in Idiopathic Interstitial Pneumonias (IIPs)’ (2007-present)
10. L. Kastelijn; PhD-project on ‘Biomarkers and the development of bronchiolitis obliterans syndrome after lung transplantation’(2009-present)
International invitations for oral presentations / chairs (last 5 years)
ERS Annual Congress, Barcelona, September 20, 2010 (chair)
11th International ILD Symposium Leuven, March 20, 2010 (presentation)
ERS Annual Congress, Berlin, October 6, 2008 (chair)
.Bronkhorst Colloquium, Blankenberge, February 2, 2007 (presentation)
ERS Annual Congress, Munich, September 2-6, 2006 (chair)
Congress of Czech Respiratory Society, Hradec Kralove, June 16, 2006 (presentation)
AMI Annual Conference, Orlando, March 26, 2006 (presentation)
ERS Annual Congress, Copenhagen, September 18-21, 2005 (presentation and chair)
WASOG Congress, Denver, June 12-15, 2005 (chair)
International Symposium on Pulmonary Manifestations of Systemic Diseases, Leuven, March
17-19, 2005 (presentation)
1. Korthagen NM, van Moorsel CH, Barlo NP, Ruven HJ, Kruit A, Heron M, van den Bosch JM, Grutters JC. Serum and BALF YKL-40 levels are predictors of survival in idiopathic pulmonary fibrosis. Accepted for publication in Respiratory Medicine on Sept 10 2010.
2. Thomeer M, Grutters JC, Wuyts WA, Willems S, Demedts MG. Clinical use of biomarkers of survival in pulmonary fibrosis. Respiratory Research 2010;11:89.
3. Korthagen NM, Nagtegaal MM, van Moorsel CH, Kazemier KM, van den Bosch JM, Grutters JC. MRP14 is elevated in the bronchoalveolar lavage fluid of fibrosing interstitial lung diseases. Clin Exp Immunol 2010;161(2):342-7.
4. Barlo NP, van Moorsel CH, Kazemier KM, van den Bosch JM, Grutters JC. Potential role of endothelin-1 in pulmonary fibrosis: from the bench to the clinic. Am J Respir Cell Mol Biol. 2010 May;42(5):633.
5. Barlo NP, van Moorsel CH, Ruven HJT, Zanen P, van den Bosch JM, Grutters JC. Surfactant protein-D predicts survival in patients with idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis. 2009; 26:155-61
6. Kruit A, Grutters JC, Ruven HJ, van Moorsel CC, van den Bosch JM. A CHI3L1 gene polymorphism is associated with serum levels of YKL-40, a novel sarcoidosis marker. Respir Med 2007; 101(7):1563-71.
7. De Lavalaye J, Grutters JC, van de Garde EMW, van Buul MMC, van den Bosch JMM, Windhorst AD, Verzijlbergen FJ. Imaging of fibrogenesis in patients with idiopathic pulmonary fibrosis with cis-4-[18F]-Fluoro-L-Proline PET. Mol Imaging Biol 2009; 11(2):123-7.
8. Heron M, Grutters JC, van Velzen-Blad H, Veltkamp M, Claessen AME, van den Bosch JMM. Increased expression of CD16, CD69 and VLA-1 on blood monocytes in active sarcoidosis. Chest 2008; 134(5):1001-8.
9. Aziz ZA, Wells AU, Bateman ED, Copley SJ, Desai SR, Grutters JC, Milne DG, Phillips GD, Smallwood D, Wiggins J, Wilsher ML, Hansell DM. Interstitial lung disease: effects of thin-section CT on clinical decision making. Radiology 2006; 238(2): 725-33.
10. van Moorsel CH, van Oosterhout MF, Barlo NP, de Jong PA, van der Vis JJ, Ruven HJ, van Es HW, van den Bosch JM, Grutters JC. SFTPC mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a Dutch cohort. Am J Respir Crit Care Med. 2010 Jul 23. Epub ahead of print
11. Sato H, Woodhead FA, Ahmad T, Grutters JC, Spagnolo P, van den Bosch JM, Maier LA, Newman LS, Nagai S, Izumi T, Wells AU, du Bois RM, Welsh KI. Sarcoidosis HLA class II genotyping distinguishes differences of clinical phenotype across ethnic groups. Hum Mol Genet. 2010; Epub ahead of print
12. Kastelijn EA, van Moorsel CH, Rijkers GT, Ruven HJ, Karthaus V, Kwakkel-van Erp JM, van de Graaf EA, Zanen P, van Kessel DA, Grutters JC, van den Bosch JM. Polymorphisms in innate immunity genes associated with development of bronchiolitis
obliterans after lung transplantation. Journal of Heart & Lung Transplantation 2010; 29(6):665-671.
13. Post MC, Boomsma MF, van Heesewijk JP, Grutters JC, van der Heyden J. Cardiac magnetic resonance imaging showing complete resolution of subendocardial involvement in Churg-Strauss syndrome. Journal of Thoracic Imaging 2010; Epub ahead of print.
14. Krivokuca I, van de Graaf EA, van Kessel DA, van den Bosch JM, Grutters JC, Kwakkel-van Erp JM. Pulmonary embolism and pulmonary infarction after lung transplantation. Clinical & Applied Thrombosis/Hemostasis 2010; Epub ahead of print.
15. Kastelijn EA, Rijkers GT, van Moorsel CH, Zanen P, Kwakkel-van Erp JM, van de Graaf EA, van Kessel DA, Grutters JC, van den Bosch JM. Systemic and exhaled cytokine and chemokine pofiles are associated with the development of bronchiolitis obliterans syndrome. Journal of Heart & Lung Transplantation 2010;29:997-1008
16. Veltkamp M, van Moorsel CH, Rijkers GT, Ruven HJ, van den Bosch JM, Grutters JC. Toll-like receptor (TLR)-9 genetics and function in sarcoidosis. Clinical & Experimental Immunology 2010;162:68-74
17. Kastelijn EA, van Moorsel CH, Ruven HJ, Karthaus V, Kwakkel-van JM, van de Graaf EA, Zanen P, Kessel DA, Grutters JC, van den Bosch JM. Genetic polymorphisms in MMP7 and reduced serum levels associate with the development of bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant. 2010 Jun;29:680-6
18. Keijsers RG, Grutters JC, van Velzen-Blad H, van den Bosch JM, Oyen WJ, Verzijlbergen FJ. (18)F-FDG PET patterns and BAL cell profiles in pulmonary sarcoidosis. Eur J Nucl Med Mol Imaging. 2010 Jun;37:1181-8
19. Heron M, Claessen AM, Grutters JC, van den Bosch JMM. T cell activation profiles in different granulomatous interstitial lung diseases - a role for CD8(+)CD28(null) cells? Clin Exp Immunol 2010 May;160(2):256-65.
20. Clement DS, Postma G, Rothova A, Grutters JC, Prokop M, de Jong PA. Intraocular sarcoidosis: association of clinical characteristics of uveitis with positive chest high-resolution computed tomography findings. Br J Ophthalmol. 2010 Feb;94(2):219-22.
21. Heron M, Grutters JC, van Moorsel CH, Ruven HJ, Huizinga TW, van der Helm-van Mil AH, Claessen AM, van den Bosch JM. Variation in IL7R predisposes to sarcoid inflammation. Genes Immun. 2009; 10: 647-53.
22. Heron M, Grutters JC, Van Moorsel CH, Ruven HJ, Kazemier KM, Claessen AM, Van den Bosch JM. Effect of variation in ITGAE on risk of sarcoidosis, CD103 expression, and chest radiography. Clin Immunol. 2009; 133: 117-25.
23. Fortunati E, Kazemier KM, Grutters JC, Koenderman L, Van den Bosch JM. Human neutrophils switch to an activated phenotype after homing to the lung irrespective of inflammatory disease. Clin Exp Immunol. 2009; 155(3):559-66.
24. Endeman H, Cornips MC, Grutters JC, van den Bosch JM, Ruven HJ, van Velzen-Blad H, Rijkers GT, Biesma DH. The Fcgamma receptor IIA-R/R131 genotype is
associated with severe sepsis in community-acquired pneumonia. Clin Vaccine Immunol. 2009; 16(7):1087-90.
25. Herpers BL, Endeman H, de Jong BA, de Jongh BM, Grutters JC, Biesma DH, van Velzen-Blad H. Acute-phase responsiveness of mannose-binding lectin in community-acquired pneumonia is highly dependent upon MBL2 genotypes. Clin Exp Immunol. 2009; 156(3):488-94.
26. Keijsers RG, Verzijlbergen FJ, Oyen WJ, van den Bosch JM, Ruven HJ, van Velzen-Blad H, Grutters JC. 18F-FDG PET, genotype-corrected ACE and sIL-2R in newly diagnosed sarcoidosis. Eur J Nucl Med Mol Imaging. 2009; 36(7):1131-7.
27. Nieuwenhuizen L, de Groot PG, Grutters JC, Biesma DH. A review of pulmonary coagulopathy in acute lung injury, acute respiratory distress syndrome and pneumonia. Eur J Haematol. 2009; 82(6):413-25.
28. Vandenbroucke E, Grutters JC, Altenburg J, Boersma WG, Ter Borg EJ, van den Bosch JM. Rituximab in life threatening antisynthetase syndrome. Rheumatol Int. 2009; 29: 1499-502.
29. Kruit A, Tilanus-Linthorst MM, Boonstra JG, van Schaik RH, Grutters JC, van den Bosch JM, Ruven HJ. MUC1 568 A/G genotype-dependent cancer antigen 15-3 levels in breast cancer patients. Clin Biochem. 2009; 42(7-8):662-5.
30. Keijsers RG, Verzijlbergen JF, van Diepen DM, van den Bosch JM, Grutters JC. 18F-FDG PET in sarcoidosis: an observational study in 12 patients treated with infliximab. Sarcoidosis Vasc Diffuse Lung Dis. 2008; 25(2):143-9.
31. Endeman H, Schelfhout V, Voorn P, Velzen-Blad H, Grutters JC, Biesma DH. Clinical features predicting failure of pathogen identification in patients with community acquired pneumonia. Scan J Infect Diseases 2008; 40(9):715-20.
32. Keijsers R, Verzijlbergen FJ, Rensing BJWM, Grutters JC. Cardiac sarcoidosis: a challenge to measure disease activity. J Nucl Cardiol 2008; 15:595-8.
33. Huisman P, Grutters JC, van den Bosch JMM. Pulmonale alveolaire proteïnose: ziekte door stapeling van surfactans en nieuwe behandeling met sargramostim. Ned Tijdschr Geneesk 2008; 152:1450-4.
34. Endeman H, Herpers BL, de Jong B, Voorn P, Grutters JC, van Velzen-Blad H, Biesma DH. Mannose-binding lectin genotypes in susceptibility to community acquired pneumonia. Chest 2008; 134(6):1135-40.
35. Janssen R, Vlaminckx BJM, Seldenrijk CA, Voorn GP, Grutters JC. Strongyloides stercoralis hyperinfection mimicking accelerated form of idiopathic pulmonary fibrosis. Lancet Infect Dis 2008; 8:456.
36. Nieuwenhuizen L, Verzijlbergen FJ, Wiltink E, Grutters JC, Biesma DH. A possible role of 18F-FDG PET scanning in the early detection of rituximab-induced pneumonitis in patients with non-Hodgkin’s lymphoma. Haematologica 2008; 93:1267-9.
37. Judson MA, Baughman RP, Costabel U, Flavin S, Lo KH, Kavuru MS, Drent M; Centocor T48 Sarcoidosis Investigators. Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomised trial. Eur Respir J 2008;31(6):1189-96.
38. Veltkamp M, Grutters JC, Rijkers GT, van Moorsel CHM, Ruven HJT, Drent M, van den Bosch JMM. CD14 genetics in sarcoidosis patients; who’s in control? Sarcoidosis Vasc Diffuse Lung Dis 2007; 24:154-5.
39. Carbonnelle S, Bernard A, Grutters J, Francaux M. Fractional exhaled NO and serum pneumoproteins after swimming in a chlorinated pool. Med Sci Sports Exerc 2008; 40:1472-1476.
40. Darquennes K, van den Bogart M, van Swieten HA, Duurkens VAM, Grutters JC. A rare cause of spontaneous pneumothorax after life-saving pneumonectomy in a patient with sarcoidosis Sarcoidosis. Vasc Diffuse Lung Dis 2007; 24:77-78.
41. Ricci A, Graziano P, Bronzetti E, Saltini C, Sciacchitano S, Cherubini E, Renzoni E, du Bois RM, Grutters JC, Mariotta S. Increased pulmonary neurotrophin protein expression in interstitial pneumonias. Sarcoidosis Vasc Diffuse Lung Dis 2007; 24:13-23.
42. Mrazek F, Kvezereli M, Garr E, Kubistova Z, Kriegova E, Fillerova R, Arakelyan A, Ruven HJT, Drabek J, van den Bosch JMM, Kolek V, , Welsh KI, Grutters JC, du Bois RM, Petrek M. Complement Receptor 1 Single Nucleotide Polymorphisms in Czech and Dutch Patients with Sarcoidosis. Tissue Antigens 2008; 71(1):77-80.
43. Post MC, Grutters JC, Verzijlbergen JF, Biesma DH. PET scintigraphy of etoposide-induced pulmonary toxicity. Clin Nucl Med 2007; 32:683-4.
44. Spagnolo P, Sato H, Grutters JC, Renzoni EA, Marshall SE, Ruven HJ, Wells AU, Tzouvelekis A, van Moorsel CH, van den Bosch JM, du Bois RM, Welsh KI. Analysis of BTNL2 genetic polymorphisms in British and Dutch patients with sarcoidosis. Tissue Antigens 2007; 70:219-27.
45. Heron M, Claessen AME, Grutters JC. Invariant natural killer T-cells in sarcoidosis and healthy controls. New Engl J Med 2007; 357:194.
46. Veltkamp M, Wijnen PA, van Moorsel CM, Rijkers GT, Ruven HJ, Heron M, Bekers O, Claessen AM, Drent M, van den Bosch JM, Grutters JC. Linkage between Toll-like receptor (TLR) 2 promotor and intron polymorphisms; functional effects and relevance to sarcoidosis. Clin Exp Immunol 2007; 149(3): 453-62.
47. Grutters JC, van den Bosch JMM. Corticosteroid treatment in sarcoidosis. Eur Respir J 2006; 28(3):627-36.
48. Kruit A, Grutters JC, Gerritsen WB, Kos S, Wodzig WK, van den Bosch JM, Ruven HJ. ACE I/D-corrected Z-scores to identify normal and elevated ACE activity in sarcoidosis. Respir Med 2007; 101(3):510-5.
49. Veltkamp M, Grutters JC, van Moorsel CHM, van den Bosch JMM. Toll-like receptor (TLR) 4 polymorphism Asp299Gly is not associated with disease course in Dutch sarcoidosis patients. Clin Exp Immunol 2006; 145(2):215-8.
50. Kruit A, Grutters JC, Ruven HJT, van Moorsel CHM, Weiskirchen R, Mengsteab S, van den Bosch JMM. Transforming growth factor-b gene polymorphisms in sarcoidosis patients with and without fibrosis. Chest 2006; 129: 1584-91.
51. Wasfi YS, Rose CS, Murphy JR, Silveira LJ, Luna B, Grutters JC, Inoue Y, Judson MA, Maier LA. A New Tool to Assess Sarcoidosis Disease Severity. Chest 2006; 129; 1234-45.
52. Janssen R, Kruit A, Grutters JC, van den Bosch JMM. Interleukin-18 –607 promoter polymorphism in sarcoidosis: ignoring ‘negative’ results. Am J Respir Crit Care Med 2006; 173: 814.
53. Van der Lee I, Zanen P, Grutters JC, Snijder RJ, van den Bosch JMM. Diffusing capacity for nitric oxide and carbon monoxide in patients with diffuse parenchymal lung disease and pulmonary arterial hypertension. Chest 2006; 129(2): 378-83.
54. Kruit A, Grutters JC, Ruven HJ, Sato H, Izumi T, Nagai S, Welsh KI, du Bois RM, van den Bosch JMM. Chymase gene (CMA1) polymorphisms in Dutch and Japanese sarcoidosis patients. Respiration 2006; 73(5):623-33.
55. Janssen R, Kruit A, Grutters JC, Ruven HJ, Gerritsen WB, van den Bosch JM. The mucin-1 568 adenosine to guanine polymorphism influences serum Krebs von der Lungen-6 levels. Am J Cell Mol Biol 2006; 34: 496-9.
56. Kruit A, Ruven HJ, Grutters JC, van den Bosch JM. Angiotensin-converting enzyme 2 (ACE2) haplotypes are associated with pulmonary disease phenotypes in sarcoidosis patients. Sarcoidosis Vasc Diffuse Lung Dis 2005; 22:195-203.
57. Janssen R, Kruit A, Grutters JC, Ruven HJT, van Moorsel CMH, van den Bosch JMM. TIMP-3 promoter gene polymorphisms in bird fanciers’ lung. Thorax 2005; 60: 974.
58. Spagnolo P, Renzoni EA, Wells AU, Copley SJ, Desai SR, Sato H, Grutters JC, Abdallah A, Taegtmeyer A, du Bois RM, Welsh KI. C-C chemokine receptor 5 gene variants in relation to lung disease in sarcoidosis. Am J Respir Crit Care Med 2005; 172: 721-8.
50. Grutters JC. Genetics of sarcoidosis: role of co-stimulatory genes? Respiration 2005; 72: 227-8.
59. Janssen R, Grutters JC, Sato H, van Velzen-Blad H, Zanen P, Kohno N, Welsh KI, du Bois RM, van den Bosch JMM. Analysis of KL-6 and SP-D as disease markers in bird fancier’s lung. Sarcoidosis Vasc Diffuse Lung Dis 2005; 22: 51-57.
60. Grutters JC, du Bois RM. Genetics of fibrosing lung diseases. Eur Respir J 2005; 25: 915-27.
61. Van Boven WJP, Gerritsen WBM, Zanen P, Grutters JC, van Dongen HPA, Bernard A, Aarts LPHJ. Pneumoproteins as lung specific biomarkers of alveolar permeability in conventional on pump CABG versus mini-ECC, a pilot study. Chest 2005; 127(4): 1190-5.
62. Janssen R, Sato H, Grutters JC, Ruven HJ, Du Bois RM, Matsuura R, Yamazaki M, Kunimaru S, Izumi T, Welsh KI, Nagai S, Van Den Bosch JM. The Clara cell 10 adenine38guanine polymorphism and sarcoidosis susceptibility in Dutch and Japanese subjects. Am J Respir Crit Care Med 2004; 170(11):1185-7.
63. Janssen R, Grutters JC, Ruven HJ, Zanen P, Sato H, Welsh KI, du Bois RM, van den Bosch JM.No association between interleukin-18 gene polymorphisms and haplotypes in Dutch sarcoidosis patients. Tissue Antigens 2004; 63(6):578-583.
64. Janssen R, Sato H, Grutters JC, Bernard A, van Velzen-Blad H, du Bois RM, van den Bosch JM. Study of Clara cell 16, KL-6, and surfactant protein-D in serum as disease markers in pulmonary sarcoidosis. Chest 2003; 124:2119-2125.
65. Grutters JC, Sato H, Welsh KI, du Bois RM. The importance of sarcoidosis genotype to lung phenotype. Am J Respir Cell Mol Biol 2003; 29:S59-S62.
66. Abdallah A, Sato H, Grutters JC, Veeraraghavan S, Lympany PA, Ruven HJT, van den Bosch JM, Wells AU, du Bois RM, Welsh KI. Inhibitor kappa B-alpha (IB-) promoter polymorphisms in UK and Dutch sarcoidosis. Genes Immun 2003; 4:450-454.
67. Spagnolo P, Renzoni EA, Wells AU, Sato H, Grutters JC, Sestini P, Abdallah A, Gramiccioni E, Ruven HJ, du Bois RM, Welsh KI. C-C chemokine receptor 2 and sarcoidosis: association with Löfgren’s syndrome. Am J Respir Crit Care Med 2003; 168:1162-1166.
68. Grutters JC, Fellrath JM, Mulder L, Janssen R, van den Bosch JM and Velzen-Blad H. Serum soluble interleukin-2 receptor measurement in patients with sarcoidosis: a clinical evaluation. Chest 2003; 124:186-195.
69. Grutters JC, Sato H, Pantelidis P, Ruven HJ, McGrath DS, Wells AU, van den Bosch JM, Welsh KI and du Bois RM. Analysis of IL6 and IL1A gene polymorphisms in UK and Dutch patients with sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20:20-27.
70. Sato H, Grutters JC, Pantelidis P, Mizzon AN, Ahmad T, Van Houte AJ, Lammers JW, van den Bosch JM, Welsh KI and du Bois RM. HLA-DQB1*0201: A Marker for Good Prognosis in British and Dutch Patients with Sarcoidosis. Am J Respir Cell Mol Biol 2002; 27:406-412.
71. Grutters JC, Sato H, Pantelidis P, Lagan AL, McGrath DS, Lammers JW, van den Bosch JM, Wells AU, du Bois RM and Welsh KI. Increased frequency of the uncommon tumor necrosis factor -857T allele in British and Dutch patients with sarcoidosis. Am J Respir Crit Care Med 2002; 165:1119-1124.
72. Grutters JC, ten Berg JM, van der ZJ, Jaarsma W, Ernst JM and Westermann CJ.Patent foramen ovale causing position-dependent shunting in a patient, when laying down her corset. Eur Respir J 2001; 18:731-733.
73. Grutters JC, Brinkman L, Aslander MM, van den Bosch JM, Koenderman L and Lammers JW. Asthma therapy modulates priming-associated blood eosinophil responsiveness in allergic asthmatics. Eur Respir J 1999; 14:915-922.
74. Grutters JC, Drent M, Velzen-Blad H and van den Bosch JM. Inverse association between sarcoidosis and atopic asthma. Sarcoidosis Vasc Diffuse Lung Dis 1998; 15:193-194.
75. Grutters JC, Hermus AR, de Mulder PH and Beex LV. Long-term follow up of breast cancer patients treated for hypercalcaemia with aminohydroxypropylidene bisphosphate (APD). Breast Cancer Res Treat 1993; 25:277-281.
76. Drent M, Grutters JC, Mulder PG, Velzen-Blad H, Wouters EF and van den Bosch JM. Is the different T helper cell activity in sarcoidosis and extrinsic allergic alveolitis also reflected by the cellular bronchoalveolar lavage fluid profile? Sarcoidosis Vasc Diffuse Lung Dis 1997; 14:31-38.
Peer-reviewed articles (others)
1. Drent M, Dekhuijzen PNR, Grutters JC, Bresser P, van der Bij W, Bast A. Antioxidant moet vergoed blijven. Medisch Contact 2010; 65: 30-33.
2. Barlo N, van Moorsel CHM, van den Bosch JMM, van de Graaf E, Kwakkel-van Erp JM, Grutters JC. Idiopathische pulmonale fibrose; beschrijving van een Nederlands cohort. Ned Tijdsch Geneesk 2009; 153:B425.
3. Grutters JC. Systeemziekten en de long. ILD care today, jaargang 02, nr 01 april/mei 2009.
4. Sarcoïdose: een update voor de clinicus practicus. Grutters JC, Drent M. Pulmo-Didact, 11e jaargang – 2008 – nr. 3.
5. Surfactant proteine C mutaties in families met idiopathische pulmonale fibrose. Van Moorsel CHM, van Oosterhout MFM, van den Bosch JMM, Ruven HJT, Grutters JC. Ned Tijdsch Klin Chemie 2007; 32: 263-65.
6. Idiopathische pulmonale fibrose. Van den Bosch JMM, Grutters JC. Pulmo-Didact, 10e jaargang – 2007 – nr. 2.
7. Wat is ‘alveolar damage’ en welke oorzaken zijn hier van bekend? Janssen R, Grutters JC. Longartsen Vademecum, jaargang 10, nr 10 – 14 mei 2007.
8. Drent M, Grutters JC, Jansen TLThA, van der Heijde D. Sarcoïdose: ontwikkelingen in de medicamenteuze behandeling. Ned Tijdschrift v Allergie 2007; 7:82-90.
9. Collard SM, Grutters JC, Rensing BJWM, Verzijlbergen FJ, Seldenrijk CA, de Bruin PC, Cramer MJM, van den Bosch JMM. Cardiale sarcoïdose, een kardinale diagnose. Hart bulletin 2007; 38:39-44.
10. Grutters JC. Klinische aspecten van sarcoïdose en mogelijke wisselwerkingen met allergisch astma. Ned Tijdschrift v Allergie 2005; 5:97-101.
Book chapters1. Grutters JC, Drent M, van den Bosch JMM. Sarcoidosis. European Respiratory
Monograph 46, 2009; 126-1542. Grutters JC, van den Bosch JMM: Pulmonary manifestations of systemic conditions.
Connective tissue disorders. Clinical Respiratory Medicine, 3rd ed., Philadelphia: Mosby Elsevier; 2008.
3. Grutters JC, Wells AU, Wuyts W, Schenk P, Leroy S, Dawson JK, Lauwerys B, Denton C, Spruit MA, Verleden G, Westhoven R, Demedts M. Evaluation and treatment of interstitial lung involvement in connective tissue diseases: a clinical update. European Respiratory Monograph; Vol 10; Monograph 34, Dec 2005; 27-49.
4. Westhovens R, de Keyser F, van den Hoogen F, Hellmich B, Kallenberg CG, Lauwerys B, Schenk P, Abraham DJ, Lambrecht BN, Grutters JC, Demedts M. The clinical spectrum, classification and pathogenetic mechanisms of pulmonary manifestations in connective tissue diseases. European Respiratory Monograph 2005; Vol 10; Monograph 34, Dec 2005; 1-26.
Program Director/Principal Investigator (Last, First, Middle):
PHS 398/2590 (Rev. 06/09) Page Biographical Sketch Format Page
BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
NAME
Prasse, Antje POSITION TITLE
Professor
eRA COMMONS USER NAME (credential, e.g., agency login)
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.)
INSTITUTION AND LOCATION DEGREE
(if applicable) MM/YY FIELD OF STUDY
Albert-Ludwigs University of Freiburg Germany Albert-Ludwigs University of Freiburg Germany
MD Bachelor
1988 – 1995 1992
Medicine Philosophy
University Medical Center Freiburg, Germany Dr. med 2003 Medicine
University Medical Center Freiburg, Germany
Assistant Professor
2008 Medicine
Positions Held: 1995 - 2001 Residency, Dept. of Internal Medicine, University Medical Center Freiburg, Germany 2002 Head of ILD Clinic, University Medical Center Freiburg, Germany 2008 Assistant Professor, University Medical Center Freiburg, Germany Professional Recognition/ Honors 2009 Sponsorship Award, German Society of Pneumology 2005 Young Investigator Award, German Society of Pneumology ONGOING RESEARCH SUPPORT (Selected) “Center of Chronic Immunodeficiency (CCI)“. tandem project: "Function, regulation and
generation of regulatory T cells in patients following stem cell transplantation and lung GvHD. BMBF: 106000 €
“German Network for Diffuse Parenchymal Lung Diseases-GOLD.net":. Teilprojekt 2: Role of Toll-Like receptor (TLR) Ligands in Granuloma Formation in Sarcoidosis. BMBF 01GM0859: 202380 € "German Network for Diffuse Parenchymal Lung Diseases-GOLD.net": project 3: Alternatively Activated Macrophages in Fibrotic Lung Diseases. BMBF 01GM0859: 202380 € SFB620 (“Immunodeficiency clinic and animal models”: project C8N: “Defining defects in pulmonary immunoregulation in patients with CVID and sarcoidosis.” DFG 307600 € SFB620 (“Immunodeficiency clinic and animal models”): Gerok-position: 88000 €
Pechkovsky DV, Prasse A, Kollert F, Engel KM, Dentler J, Luttmann W, FriedrichK, Muller-Quernheim J, Zissel G. Alternatively activated alveolar macrophages in pulmonary fibrosis-mediator production and intracellular signal transduction.Clin Immunol. 2010 Oct;137(1):89-101. Epub 2010 Jul 31. PubMed PMID: 20674506.
Prasse A, Pechkovsky DV, Toews GB, Jungraithmayr W, Kollert F, Goldmann T,Vollmer E, Muller-Quernheim J, Zissel G. A vicious circle of alveolar macrophagesand fibroblasts perpetuates pulmonary fibrosis via CCL18. Am J Respir Crit CareMed. 2006 Apr 1;173(7):781-92. Epub 2006 Jan 13. PubMed PMID: 16415274.
Prasse A, Probst C, Bargagli E, Zissel G, Toews GB, Flaherty KR, OlschewskiM, Rottoli P, Muller-Quernheim J. Serum CC-chemokine ligand 18 concentrationpredicts outcome in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med.2009 Apr 15;179(8):717-23. Epub 2009 Jan 29. PubMed PMID: 19179488.
Prasse A, Germann M, Pechkovsky DV, Markert A, Verres T, Stahl M, Melchers I,Luttmann W, Muller-Quernheim J, Zissel G. IL-10-producing monocytes differentiateto alternatively activated macrophages and are increased in atopic patients. JAllergy Clin Immunol. 2007 Feb;119(2):464-71. Epub 2006 Nov 2. PubMed PMID:17291860.
Prasse A, Muller KM, Kurz C, Hamm H, Virchow JC Jr. Does interferon-gammaimprove pulmonary function in idiopathic pulmonary fibrosis? Eur Respir J. 2003Dec;22(6):906-11. PubMed PMID: 14680077.
Prasse A, Muller-Quernheim J. Non-invasive biomarkers in pulmonary fibrosis. Respirology. 2009 Aug;14(6):788-95. Review. PubMed PMID: 19703061.
Bargagli E, Olivieri C, Nikiforakis N, Cintorino M, Magi B, Perari MG,Vagaggini C, Spina D, Prasse A, Rottoli P. Analysis of macrophage migrationinhibitory factor (MIF) in patients with idiopathic pulmonary fibrosis. RespirPhysiol Neurobiol. 2009 Jul 31;167(3):261-7. Epub 2009 May 21. PubMed PMID:19464392.
Bargagli E, Penza F, Bianchi N, Olivieri C, Bennett D, Prasse A, Rottoli P.Controversial role of RAGE in the pathogenesis of idiopathic pulmonary fibrosis. Respir Physiol Neurobiol. 2009 Feb 28;165(2-3):119-20; author reply 121-2. Epub2008 Nov 5. PubMed PMID: 19026768.
Bargagli E, Olivieri C, Bennett D, Prasse A, Muller-Quernheim J, Rottoli P.Oxidative stress in the pathogenesis of diffuse lung diseases: a review. RespirMed. 2009 Sep;103(9):1245-56. Epub 2009 May 22. Review. PubMed PMID: 19464864.
Chaudhary NI, Roth GJ, Hilberg F, Muller-Quernheim J, Prasse A, Zissel G,Schnapp A, Park JE. Inhibition of PDGF, VEGF and FGF signalling attenuatesfibrosis. Eur Respir J. 2007 May;29(5):976-85. Epub 2007 Feb 14. PubMed PMID:17301095.
Zissel G, Prasse A, Muller-Quernheim J. Immunologic response of sarcoidosis.Semin Respir Crit Care Med. 2010 Aug;31(4):390-403. Epub 2010 Jul 27. PubMedPMID: 20665389.
Prasse A, Waller C, Passlick B, Muller-Quernheim J. [Lung cancer from theperspective of internal medicine and surgery]. Radiologe. 2010 Aug;50(8):662-8.German. PubMed PMID: 20652215.
Horn J, Schlesier M, Warnatz K, Prasse A, Superti-Furga A, Peter HH, Salzer U.Fatal adult-onset antibody deficiency syndrome in a patient with cartilage hairhypoplasia. Hum Immunol. 2010 Sep;71(9):916-9. Epub 2010 Jun 9. PubMed PMID:20538026.
Prasse A, Zissel G, Lutzen N, Schupp J, Schmiedlin R, Gonzalez-Rey E,Rensing-Ehl A, Bacher G, Cavalli V, Bevec D, Delgado M, Muller-Quernheim J.Inhaled vasoactive intestinal peptide exerts immunoregulatory effects insarcoidosis. Am J Respir Crit Care Med. 2010 Aug 15;182(4):540-8. Epub 2010 May4. PubMed PMID: 20442436.
Bargagli E, Olivieri C, Cintorino M, Refini RM, Bianchi N, Prasse A, RottoliP. Calgranulin B (S100A9/MRP14): A Key Molecule in Idiopathic Pulmonary Fibrosis?Inflammation. 2010 Apr 27. [Epub ahead of print] PubMed PMID: 20422274.
Prasse A, Kayser G. [Rare cystic lung diseases: lymphangioleiomyomatosis,pulmonary langerhans' cell histiocytosis and lymphocytic interstitial pneumonia].Dtsch Med Wochenschr. 2010 Mar;135(10):461-5. Epub 2010 Mar 2. Review. German.PubMed PMID: 20198543.
Bargagli E, Olivieri C, Margollicci M, Bennett D, Luddi A, Perrone M,Maggiorelli C, Prasse A, Rottoli P. Serum chitotriosidase levels in patients withallergic and non-allergic asthma. Respiration. 2010;79(5):437-8. Epub 2010 Jan21. PubMed PMID: 20090309.
Woodruff PG, Wolff M, Hohlfeld JM, Krug N, Dransfield MT, Sutherland ER,Criner GJ, Kim V, Prasse A, Nivens MC, Tetzlaff K, Heilker R, Fahy JV. Safety andefficacy of an inhaled epidermal growth factor receptor inhibitor (BIBW 2948 BS) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010 Mar1;181(5):438-45. Epub 2009 Dec 10. PubMed PMID: 20007923.
Prasse A, Holle JU, Muller-Quernheim J. [Pulmonary fibrosis]. Internist(Berl). 2010 Jan;51(1):6-13. German. PubMed PMID: 19956919.
Rakhmanov M, Keller B, Gutenberger S, Foerster C, Hoenig M, Driessen G, vander Burg M, van Dongen JJ, Wiech E, Visentini M, Quinti I, Prasse A, Voelxen N,Salzer U, Goldacker S, Fisch P, Eibel H, Schwarz K, Peter HH, Warnatz K.Circulating CD21low B cells in common variable immunodeficiency resemble tissuehoming, innate-like B cells. Proc Natl Acad Sci U S A. 2009 Aug11;106(32):13451-6. Epub 2009 Jul 29. PubMed PMID: 19666505; PubMed CentralPMCID: PMC2726348.
Bargagli E, Mazzi A, Mezzasalma F, Perrone A, Olivieri C, Prasse A, BianchiN, Pieroni MG, Rottoli P. The analysis of tryptase in serum of sarcoidosispatients. Inflammation. 2009 Oct;32(5):310-4. PubMed PMID: 19582562.
Prasse A, Muller-Quernheim J. [Sarcoidosis]. Internist (Berl). 2009May;50(5):581-90. Review. German. PubMed PMID: 19367373.
Prasse A, Stahl M, Schulz G, Kayser G, Wang L, Ask K, Yalcintepe J,Kirschbaum A, Bargagli E, Zissel G, Kolb M, Muller-Quernheim J, Weiss JM, RenklAC. Essential role of osteopontin in smoking-related interstitial lung diseases. Am J Pathol. 2009 May;174(5):1683-91. Epub 2009 Apr 9. PubMed PMID: 19359522;PubMed Central PMCID: PMC2671257.
Kollert F, Probst C, Muller-Quernheim J, Zissel G, Prasse A. CCL18 productionis decreased in alveolar macrophages from cigarette smokers. Inflammation. 2009Jun;32(3):163-8. PubMed PMID: 19357939.
Muller-Quernheim J, Schurmann M, Hofmann S, Gaede KI, Fischer A, Prasse A,Zissel G, Schreiber S. [Genetics of sarcoidosis: a key to understanding itspathogenesis]. Pneumologie. 2009 Mar;63(3):166-75. Review. German. PubMed PMID:19271290.
Bargagli E, Olivieri C, Prasse A, Bianchi N, Magi B, Cianti R, Bini L,Rottoli P. Calgranulin B (S100A9) levels in bronchoalveolar lavage fluid ofpatients with interstitial lung diseases. Inflammation. 2008 Oct;31(5):351-4.PubMed PMID: 18784990.
Jungraithmayr W, Frings C, Zissel G, Prasse A, Passlick B, Stoelben E.Inflammatory markers in exhaled breath condensate following lung resection forbronchial carcinoma. Respirology. 2008 Nov;13(7):1022-7. Epub 2008 Aug 26. PubMedPMID: 18764914.
Bargagli E, Madioni C, Prasse A, Fossi A, Filippi R, Bianchi N, Voltolini L, Muller-Quernheim J, Rottoli P. Eosinophilic cationic protein in bronchoalveolarlavage fluid of lung transplant patients. Clin Chem Lab Med. 2008;46(4):563-4.PubMed PMID: 18605937.
Muller-Quernheim J, Schurmann M, Hofmann S, Gaede KI, Fischer A, Prasse A,Zissel G, Schreiber S. Genetics of sarcoidosis. Clin Chest Med. 2008Sep;29(3):391-414, viii. Review. PubMed PMID: 18539234.
Prasse A, Katic C, Germann M, Buchwald A, Zissel G, Muller-Quernheim J.Phenotyping sarcoidosis from a pulmonary perspective. Am J Respir Crit Care Med. 2008 Feb 1;177(3):330-6. Epub 2007 Nov 1. PubMed PMID: 17975200.
Prasse A, Pechkovsky DV, Toews GB, Schäfer M, Eggeling S, Ludwig C, GermannM, Kollert F, Zissel G, Muller-Quernheim J. CCL18 as an indicator of pulmonaryfibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis.Arthritis Rheum. 2007 May;56(5):1685-93. PubMed PMID: 17469163.
Zissel G, Prasse A, Muller-Quernheim J. Sarcoidosis--immunopathogeneticconcepts. Semin Respir Crit Care Med. 2007 Feb;28(1):3-14. Review. PubMed PMID:17330188.
Muller-Quernheim J, Gaede KI, Prasse A, Zissel G. [Chronic berylliosis].Pneumologie. 2007 Feb;61(2):109-16. Review. German. PubMed PMID: 17290317.
Prasse A, Muller-Quernheim J. [Therapy for idiopathic interstitialpneumonias: steroids--and what else?]. Internist (Berl). 2006 Dec;47(12):1258-62.Review. German. PubMed PMID: 17102999.
Pechkovsky DV, Goldmann T, Ludwig C, Prasse A, Vollmer E, Muller-Quernheim J,Zissel G. CCR2 and CXCR3 agonistic chemokines are differently expressed andregulated in human alveolar epithelial cells type II. Respir Res. 2005 Jul20;6:75. PubMed PMID: 16033640; PubMed Central PMCID: PMC1185567.
Prasse A, Georges CG, Biller H, Hamm H, Matthys H, Luttmann W, Virchow JC Jr.Th1 cytokine pattern in sarcoidosis is expressed by bronchoalveolar CD4+ and CD8+T cells. Clin Exp Immunol. 2000 Nov;122(2):241-8. PubMed PMID: 11091281; PubMedCentral PMCID: PMC1905777.
Virchow JC Jr, Prasse A, Naya I, Summerton L, Harris A. Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Am JRespir Crit Care Med. 2000 Aug;162(2 Pt 1):578-85. PubMed PMID: 10934090.
