Fraunhofer Institute for Toxicology and Experimental Medicine
Fraunhofer Institute for Toxicology and Experimental Medicine

Challenge models

Challenge tests with allergens, endotoxin, ozone, hypoxia, methacholine, and AMP

Allergen challenges

Fraunhofer ITEM is equipped with three special challenge chambers, the Fraunhofer Allergen Challenge Chambers, in which pollen and other allergens can be dispersed in the air under controlled conditions.
© Fraunhofer ITEM
Fraunhofer ITEM is equipped with three special challenge chambers, the Fraunhofer Allergen Challenge Chambers, in which pollen and other allergens can be dispersed in the air under controlled conditions.

Allergen challenge chambers

Allergen challenge chambers (ACCs) are an excellent tool for testing allergy treatments in early-phase clinical trials. Their particular advantages are controlled temperature, humidity and, especially, allergen concentrations, resulting in improved signal-to-noise ratios. As a result, they greatly reduce the number of participants needed to demonstrate significant treatment effects compared to standard field studies.

Fraunhofer ITEM is equipped with three special challenge chambers in which pollen and other allergens can be dispersed in the air under controlled conditions. These chambers, known as Fraunhofer Allergen Challenge Chambers (or Fraunhofer ACCs for short), each are 47 square meters in size and can accommodate 18 test subjects at a time. The Fraunhofer ACC model was validated for natural grass pollen in 2001 and for natural birch pollen in 2014. It has been used in numerous clinical trials to test the efficacy, duration, and onset of action of allergy treatments.

In 2008, Fraunhofer ITEM patented a process in which a commercially available allergen solution is mixed with lactose. The resulting solution is spray-dried to create particles of a defined size, which are then dispersed in a Fraunhofer ACC. This approach makes it possible to use the Fraunhofer ACC to test treatments for a wide range of allergens, including some that are difficult to aerosolize, such as cat dander and house dust mite. In addition, the ability to define the particle size permits targeted challenging of the nose or lungs.

But use of the Fraunhofer ACC is not limited to testing allergy treatments; it is also an excellent means of studying how allergic rhinitis symptoms affect the absorption of intranasal drug formulations by combining ACC exposures with pharmacokinetic studies.

Please see below for recent publications.

Models of allergen challenge

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The Fraunhofer Allergen Challenge Chambers
© Fraunhofer ITEM
The Fraunhofer Allergen Challenge Chambers can be used for challenge tests with antiallergic drugs, but also for pharmacokinetic studies.

In the past few years, we have used inhaled allergen challenges in numerous trials. The induction of early and late-phase asthmatic reactions in patients with asthma by means of inhaled allergen challenge enables efficacy testing of novel asthma treatments. A German multicenter network with identical operating procedures and the same high quality level across all participating sites is available for expedited recruitment.

Nasal allergen challenges are not only useful to assess the efficacy of novel anti-allergic treatments. They are also an excellent tool to collect nasal biomarkers via nasal lavages and nasal filter paper samplings. We have long-standing experience with the collection and validated analysis of nasal biomarkers in our immunological lab.

We have long-standing experience in bronchial segmental allergen challenges via bronchoscopy. Segmental allergen challenges facilitate the collection of sample material (bronchoalveolar lavage, brushings, biopsies) after challenges. Additionally, this method is equally effective for testing the efficacy of new medications.

Challenge chambers at Fraunhofer ITEM

© Fraunhofer ITEM, Felix Schmitt

Hypoxia challenge chamber

Newly established at Fraunhofer ITEM is a hypoxia chamber that can simulate a normobaric height of up to 5000 meters. At this altitude a physiologic constriction of the pulmonary blood vessels is induced, mimicking pulmonary arterial hypertension (PAH). This model can be used to test the efficacy of new medications for PAH treatment in healthy volunteers.

Segmental endotoxin challenge

Segmental instillation of an endotoxin such as LPS (lipopolysaccharide) via bronchoscopy induces a local inflammation for about 48 hours. During this local inflammation process, an increase in cytokines and chemokines and an influx of neutrophils and monocytes, as typically seen in COPD patients, take place in the lungs of the study participants . By collection of bronchial samples such as bronchoalveolar lavage (BAL), biopsies, and bronchial brushings, this model allows the efficacy of anti-inflammatory drugs to be tested in proof-of-concept studies. We have used segmental endotoxin challenges in many clinical trials to test the efficacy of novel anti-inflammatory medications for COPD treatment.

Inhaled endotoxin challenge

Less invasive than the segmental endotoxin challenge, we have established an inhaled endotoxin challenge with LPS (lipopolysaccharide). By using a special inhalation device we are able to considerably reduce the amount of LPS needed for inhalation challenge tests.

© Fraunhofer ITEM, Felix Schmitt

Ozone challenge chamber

In our ozone challenge chamber, we can challenge up to two subjects at a time with a controlled ozone atmosphere to induce a neutrophilic inflammation in the lungs. In connection with our long-standing experience in collecting induced sputum, this model allows us to assess the degree of the inflammation after the challenge. Ozone challenge tests can be used to assess the efficacy of anti-inflammatory drugs that target neutrophilic inflammation.

Methacholine/AMP challenge tests

Methacholine challenges, and more rarely AMP challenges, are used as standard challenge tests in asthma trials. We have long-standing experience in methacholine and also AMP challenges and have used both techniques in numerous clinical trials.

Recent publications

Recent publications on the topic "allergen challenges"

Krug, N., Hohlfeld, J., Buhl, R., Renz J., Garn H., Renz H. (2017).
Blood eosinophils predict therapeutic effects of a GATA3-specific DNAzyme in asthma patients.
Journal of Allergy and Clinical Immunology.
Volume 140, Issue 2, August 2017, Pages 625-628.e5.

Badorrek, P., Müller, M., Koch, W., Hohlfeld, J., Krug, N. (2017).
Specificity and reproducibility of nasal biomarkers in patients with allergic rhinitis after allergen challenge chamber exposure.
Annals of Allergy, Asthma & Immunology.
Volume 118, Issue 3, March 2017, Pages 290-297.

Krug, N., Hohlfeld, J., Kirsten, A., Kornmann, O., Beeh, K., Kappeler, D., Korn, S., Ignatenko, S., Timmer, W., Rogon, C., Zeitvogel, J., Zhang, N., Bille, J., Homburg, U., Turowska, A., Bachert, C., Werfel, T., Buhl, R., Renz, J., Garn, H., Renz, H. (2015).
Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme.
N Engl J Med 2015; 372:1987-1995
DOI: 10.1056/NEJMoa1411776

Dijkstra, D., Hennig, C., Hansen, G., Biller, H., Krug, N., Hohlfeld, J. (2014).
Identification and quantification of basophils in the airways of asthmatics following segmental allergen challenge.
Cytometry Part A. Journal of Quantitative Cell Science
2014 Jul;85(7):580-7. 

Winkler, C., Witte, L., Moraw, N., Faulenbach, C., Müller, M., Holz, O., Schaumann, F., Hohlfeld, J. (2014).
Impact of endobronchial allergen provocation on macrophage phenotype in asthmatics.
BMC Immunol. 2014; 15: 12.
Published online 2014 Mar 10. doi:  10.1186/1471-2172-15-12

Vogel-Claussen, J., Renne, J., Hinrichs, J., Schönfeld, C., Gutberlet, M., Schaumann, F., Winkler, C., Faulenbach, C., Krug, N., Wacker, F., Hohlfeld, J. (2014). 
Quantification of Pulmonary Inflammation after Segmental Allergen Challenge Using Turbo-Inversion Recovery-Magnitude Magnetic Resonance Imaging.
American Journal of Respiratory and Critical Care Medicine
Vol. 189, No. 6 | Mar 15, 2014.

Nicholson, G., Kariyawasam, H., Tan, A., Hohlfeld, J., Quinn, D., Walker, C., Rodman, D., Westwick, J., Jurcevic, S., Kon, O.M., Barnes, P., Krug, N., Hansel, T. (2011). 
The effects of an anti–IL-13 mAb on cytokine levels and nasal symptoms following nasal allergen challenge.
J Allergy Clin Immunol. 2011 Oct;128(4):800-807.

Zoerner, A., Stichtenoth, D., Engeli, S., Batkai, S., Winkler, C., Schaumann, F., Janke, J., Holz, O., Krug, N., Tsikas, D., Jordan, J., Hohlfeld, J. (2011).
Allergen Challenge Increases Anandamide in Bronchoalveolar Fluid of Patients With Allergic Asthma. 
Clinical Pharmacology & Therapeutics. 2011 Sep;90(3):388-91.

Atochina-Vasserman, E., Winkler, C., Abramova, H., Schaumann, F., Krug, N., Gow, A., Beers, M., Hohlfeld, J. (2011).
Segmental Allergen Challenge Alters Multimeric Structure and Function of Surfactant Protein D in Humans.
American Journal of Respiratory and Critical Care Medicine.
Vol. 183, No. 7 | Apr 01, 2011.

Recent publications on the topic "endotoxin challenges"

Holz, O., Tan, L., Schaumann, F., Müller, M., Scholl, D., Hidi, R., McLeod, A., Krugm N., Hohlfeld, J. (2015).
Inter- and intrasubject variability of the inflammatory response to segmental endotoxin challenge in healthy volunteers.
Pulmonary Pharmacology & Therapeutics
Volume 35, December 2015, Pages 50-59

Janssen, O., Schaumann, F., Holz, O., Lavae-Mokhtari, B., Welker, L., Winkler, C., Biller,  H., Krug, N., Hohlfeld, J. (2013). 
Low-dose endotoxin inhalation in healthy volunteers - a challenge model for early clinical drug development.
BMC Pulm Med. 2013 Mar 28;13:19.

Hohlfeld, J., Schoenfeld, K., Lavae-Mokhtari, M., Schaumann, F., Mueller, M., Bredenbroeker, D., Krug, N., Hermann, R. (2008).
Roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: A randomized placebo-controlled trial.
Pulmonary Pharmacology & Therapeutics.
Volume 21, Issue 4, August 2008, Pages 616-623.

Schaumann, F., Muller, M., Braun, A., Luettig, B., Peden, D., Hohlfeld, J., Krug, N. (2008).
Endotoxin Augments Myeloid Dendritic Cell Influx into the Airways in Allergic Asthma Patients. Am J Respir Crit Care Med. 2008;177(12):1307-13.

Recent publications on the topic "ozone challenge chamber"

Holz, O., Heusser, K., Müller, M., Windt, H., Schwarz, K., Schindler, C. Tank, J., Hohlfeld, J., Jordan, J. (2018).
Airway and systemic inflammatory responses to ultrafine carbon black particles and ozone in older healthy subjects.
J Toxicol Environ Health A. 2018;81(13):576-588.

Holz, O., Biller, H., Mueller, M., Kane, K., Rosano, M., Hanrahan, J., Hava, D., Hohlfeld, J. (2015).
Efficacy and safety of inhaled calcium lactate PUR118 in the ozone challenge model - a clinical trial.
BMC Pharmacology and Toxicology 2015.

Tank, J., Biller, H., Heusser, K., Holz, O., Diedrich, A., Framke, T., Koch, A., Grosshennig, A., Koch, W., Krug, N., Jordan, J., Hohlfeld, J. (2011).
Effect of Acute Ozone Induced Airway Inflammation on Human Sympathetic Nerve Traffic: A Randomized, Placebo Controlled, Crossover Study. 
PLoS One. 2011 Apr 8;6(4):e18737.

Biller, H., Holz, O., Windt, H., Koch, W., Müller, M., Jörres, R., Krug, N., Hohlfeld, J. (2011).
Breath profiles by electronic nose correlate with systemic markers but not ozone response. 
Respiratory Medicine.
Volume 105. Issue 9, September 2011, Pages 1352-1363.

Contacts

Jens Hohlfeld

Contact Press / Media

Prof. Dr. Jens Hohlfeld

Deputy Institute Director & Division Director of Airway Research

Phone +49 511 5350-8101

Philipp Badorrek

Contact Press / Media

Dr. Philipp Badorrek

Deputy Division Director Airway Research & Head of Department of Clinical Airway Research

Phone +49 511 5350-8130