Viable germs and non-viable parts of microbial organisms are ubiquitous in nature. These microbial products such as endotoxin are recognized by the innate immune system early in life and may direct the maturation of a child’s immune responses in a way enabling tolerance of components of the natural environment such as tree and grass pollen, or animal dander. We assessed a child’s exposure to endotoxin in a multicentre cross-sectional survey in rural, partly farming areas and investigated its association with clinical symptoms of allergy. Endotoxin levels in mattress dust were strongly inversely related to the occurrence of hay fever, atopic asthma and atopic sensitisation. The aim of the study is to determine if a subject’s environmental exposure to microbial products may play a crucial role for the development of tolerance towards ubiquitous allergens found in natural environments. The project started in 1998 and was funded by the Bayerische Staatsministerium für Umwelt, Gesundheit und Verbraucherschutz (Bavarian State Department for Environment, Health and Consumer Protection)

> Erika.Von.Mutius@med.uni-muenchen.de
www.lgl.bayern.de/publikationen/doc/umwelt6_allergien.pdf

The project aims are to determine the relationship between environmental factors relating to the early development and severity of atopy and early indications of the development of an asthmatic phenotype. The objective is to create an intelligence-based strategy for primary prevention in relation to atopy and asthma in children. Participants in this EC funded study are Imperial College of Science, Technology and Medicine, London; Institut Municipal d’Assistencia Sanitaria, Barcelona; Instituto Nacional de la Salud, Madrid; National Public Health Institute, Helsinki; General Peripheral Hospital of Heraklion, Heraklion; Wroclav Medical University, Wroclav and Munich university Children’s Hospital , Munich. Coordinator: Professor Paul Cullinan, National Heart and Lung Institute, Dep. Occupational and Environmental Medicine, London.

> p.cullinan@imperial.ac.uk
ajrccm.atsjournals.org/cgi/reprint/200310-1348OCv1.pdf

Funded by Dutch Lung Foundation "Longfonds"
Duration: 2017 - 2022
Co-ordinator: Dr. Hermelijn H. Smits, Leiden, NL
Partners: Prof. Pieter S. Hiemstra, Leiden, NL
Prof. Christian Taube, Leiden, NL
Prof. Erika von Mutius, Munich, GE
Prof. Markus Ege, Munich, GE
Prof. Bart Lambrecht, Ghent, BE
Prof. Hamida Hammad, Ghent, BE
Prof. Ben Marsland, Epalinges, CH
Prof. Rick Maizels, Glasgow, UK
Dr. Henry McSorley, Edinburgh, UK


Project Summary:
Asthma is the most common chronic paediatric disorder in Westernized countries. Symptoms
are cough, wheeze, difficulty to breath, and exacerbations in response to viral infections and
allergens. Asthma is characterized by lung inflammation, barrier lining damage and airway
remodelling. There is neither prevention nor cure, only treatments that alleviate symptoms.
Our overarching aim is to mimic nature’s approach of preventing asthma, which has
been deranged by changes in our western life-style.
Protection against asthma is linked to environmental microbial exposure in early life. Examples
are provided by farming, helminth parasites and diet-mediated microbial richness. Farmrelated
protection is independently explained by farm-milk consumption and air-borne
microbial exposure during early life. Chronic helminth infections protect via active immune
regulation of allergic responsiveness, as a side-effect necessary for parasite survival. A rich commensal flora is essential for the maturation of the neonatal immune system. The microbial composition is influenced by our diet and farm-milk may promote its richness. Many studies have pointed out that these microbes can profoundly modify host immune responses at different levels, and in parallel influence the lung barrier and their responsiveness to external triggers.
Asthma is a complex syndrome and we anticipate that not one but rather several prevention strategies might be needed to successfully intervene on a population level. Therefore, we aim to target several pivotal mechanisms to restore crucial interactions between diet, microbiome, immune system and lung barrier in early life. First, we will investigate whether farm-milk protects against asthma in a placebo-controlled intervention study in infants. The preventive role of fiber consumption, farm-dust exposure and recombinant helminth proteins against allergen sensitization and viral respiratory infections will be investigated in (pre-)clinical models. Changes in global gene expression, metabolome and microbiome will be included in both approaches and used to predict which children will benefit most from additional treatments by farm-dust and/or recombinant helminth proteins.
With this multi-pronged approach, we will take a step towards preventing asthma in children. We aim to restore the highly protective and long lasting mechanisms that evolution has developed to avoid overt reactions to allergens and environmental triggers in chronic reactive airway disease.

Funded by German Federal Ministry of Education and Research (BMBF)
Duration: 2017-2021
Coordinator: Prof. Bianca Schaub, Munich, GE
Partners: Prof. Erika von Mutius, Munich, GE
Prof. Wolfgang Greiner, Bielefeld, GE
Prof. Kirsten Beyer, Berlin, GE
Prof. Eckart Hamelmann, Bielefeld, GE
Prof. Michael Kabesch, Regensburg, GE
Prof. Gesine Hansen, Hannover, GE

Project Summary:
The CHAMP Consortium aims to investigate the determinants of different allergic diseases (food allergy, atopic dermatitis, asthma, hay fever) across the whole pediatric age range. Particular attention will be given to factors determining primary tolerance (no onset of disease) and acquired tolerance (remission of existing disease). We will identify clinically relevant biomarkers predicting early onset, progression and remission. As main results, we aim to define a molecular allergy score early in life predicting subsequent allergy risk, to identify predictors of natural tolerance of food allergy and to assess underlying mechanisms in murine models of allergy development with focus on early tolerance induction. We aim to predict mild versus severe allergic diseases, to identify relevant biomarkers and to predict remission of asthma and hay fever. Finally, we expect to HRQoL of patients and quality of life (QoL) of their parents across different allergic diseases, different disease stages and various age groups.
Importantly, this consortium has the unique opportunity to assess the development and remission of childhood allergies at all stages of childhood immune and organ development. In summary, adding novel insight to the puzzle of early onset, natural tolerance and remission of different allergic diseases from birth to adolescence will lay the ground for future development of preventive strategies and shall in the long term contribute to opening up novel avenues for therapeutic options. This will clearly make an impact on the life of our patients and their families.

In terms of disease incidence and mortality, lung diseases are ranked second in the world and are directly or indirectly responsible for every fifth death. The annual cost of lung diseases amounts to 102 billion euros alone for Western Europe. It is expected that the number of patients and thus also the costs will continue to rise in the coming years. To date, there are no cures for most respiratory diseases – just symptomatic treatments. For these reasons it is even more important to conduct research to develop new approaches and options for prevention, diagnosis and therapy. In the German Center for Lung Research (DZL), the leading German research institutes have therefore joined together to combat the most important lung diseases through translational research.

http://www.dzl.de/

The aim of the DIABIMMUNE project is to assess the role of the hygiene hypothesis in the development of immune-mediated diseases, T1D in particular, and to define the mechanisms behind the potential protective effect conferred by microbial agents. The study design comprises two cohorts: a birth cohort and a cohort comprising young children. The objective is to study 2000 children at the age of 3 and 5 years and to observe 320 newborn infants with increased genetic risk for autoimmune disease from birth up to the age of 3 years. The estimated number of study subjects will altogether be approximately 7000 with Finland, Russian Karelia and Estonia each contributing have 2320 subjects. The children are tested for organ-specific autoantibodies, allergies, infections, gut microflora, and for nutritional factors. The recruitment for the birth cohort started in September 2008. The project is funded by the European Commission (7 th Framework Programme, project 202063).

> mikael.knip@hus.fi
http://www.diabimmune.org/

The highly inter-disciplinary EFRAIM project will prospectively investigate the main protective factors in early life influencing thedevelopment of allergies in birth cohorts conducted in allergy protective environments in five European countries. These birth cohorts have been enrolling over 1,000 children and have collected detailed information on the onset of allergic illnesses, objective measures of allergies and a vast amount of information about a number of environmental exposures. Large biobanks with a variety of biological samples have been established. In the EFRAIM project particular attention will be given to the potential role of dietary exposures, lifestyle and other environmental (e.g. microbial) exposures early in life which are causal determinants rather than triggers of the illness. The mechanisms mediating these protective exposures such as the maturation of immune responses, gut colonisation, the mucosal barrier function and the genetic and epigenetic factors interacting with the environmental exposures will be investigated. The knowledge about protective exposures early in life can be turned into the development of preventive strategies. The EFRAIM project will actively address two routes of preventive interventions in animal models and in vitro studies: the development of an allergy protective milk formula and the development of an allergy vaccine. Both approaches are based on knowledge gained in the human studies. The EFRAIM project is expected to produce ground-breaking new insights on protective agents and their mechanisms that can be used to prevent the further development of allergies.

> Erika.Von.Mutius@med.lmu.de
http://www.efraim-online.com/

The aim of the FORALLVENT project is the creation of a forum for the development of strategies enabling to close the gap between the science on allergic disease and the practical application of its results in prevention, clinical treatment and in the formulation of specialized foods. Future research in the most promising avenues for the development of innovative preventive strategies shall be prepared. To this end knowledge from different disciplines and experience gained in various previous experimental and epidemiological studies in the 5th and 6th framework programme and other research in Europe will be reviewed and synthesised. An interdisciplinary expert group will brainstorm on the most promising innovative strategies for the development of preventive and therapeutic approaches involving science and industry. Particular attention will be paid to the development of allergy protective milk formula. Furthermore an in vivo test system will be prepared by securing the possibility to reassess children enrolled in a birth cohort study in an environment rich in microbial exposures at age 6 years. Hypotheses formulated in the expert groups can then be confirmed or refuted in vivo. The FORALLVENT study will finally help prepare the shaping and structuring of the 7th frame work programme of the European Commission.

> www.forallvent.info

GA2len objectives in asthma and allergy are:
- to enhance the quality and relevance of research and to address all aspects of the disease.
- to create a permanent and durable structure that will maximize the scientific contribution of Europe to this area.
- to accelerate the application of research results to clinical practice, patients’ needs and policy development.
- to promote training and integration between the public and private sector.
- to eventually decrease the burden of allergy and asthma throughout Europe.

The network will examine events occurring during intra-uterine life with special focus on the foeto-maternal interface, early life events in the development of allergic sensitisation, the translation of allergic sensitisation and the persistence and aggravation of allergic diseases and asthma. The duration of the project chaired by Professor Paul van Cauwenberge, University of Ghent, is 5 years. Approximately 500 researchers are involved. GA2len, a consortium of leading European research teams is a EU FP6 funded network.

> www.ga2len.net

The GABRIEL project, funded through an EC Framework 6 grant, involves over 150 scientists from 14 European countries, using the latest research across a variety of disciplines, including genetics, epidemiology and immunology, to identify key factors in the development of asthma. Professor Bill Cookson, from Imperial College London, and co-ordinator of the study, said: “Asthma is the major chronic childhood illness in Europe costing the European Community more than Euro three billion each year. Although effective therapies for mild asthma exist, the 10 percent of children with severe disease account for 60 percent of this expense, and even when treatment is effective it is not able to cure the disease.” Asthma is caused by a combination of genetic and environmental effects, and despite being rare a hundred years ago, it has become increasingly common in developed societies across the world. Scientists believe rural environments are strongly protective against the disease, and increasing urbanisation may be contributing to the rise in the numbers affected. Professor Cookson added: “We hope this study will help us identify just how genes and the environment cause the development of asthma, identifying both risk and protective factors, with the long-term aim of preventing the illness.” Professor Erika von Mutius from Munich University and co-leader of the project added: “Previous studies have shown the causes of asthma are diverse with many genetic and environmental factors all potentially having an impact. Traditionally it has been hard to analyse all the genetic and environmental information but the latest developments in areas such as genomics and bioinformatics now allow us to make sense of huge and complicated datasets.” As well as looking at genetic and environmental interactions, GABRIEL will study the molecular basis for environmental factors which can increase the risk of industrial asthma. It will also identify the agents which protect strongly against asthma in rural and farming communities and use genetics, genomics and proteomics to discover novel genetic and microbial factors that cause or protect against asthma. The project will test genetic factors in over 40,000 subjects with childhood or adult asthma, with data from environmental factors such as tobacco smoke, air pollution, nutrition, allergen exposure and industrial agents. Professor von Mutius added: “One particular area we will be looking at is the  ‘hygiene hypothesis’, a theory which argues a lack of exposure to microbes in early childhood may cause an increased risk of developing asthma and allergies. Earlier work has indicated this may be the case, but we hope the scale of GABRIEL will allow us to properly test the hypothesis and to identify the responsible agents.” GABRIEL will also develop model systems to investigate the molecular basis of genetic and environmental interactions which influence asthma, and use these model systems to translate novel findings into means of prevention and treatment for asthma. Professor von Mutius added: “This type of very large-scale study can only be carried out with International co-operation. We are most fortunate that we are able to carry out the GABRIEL project within Europe, with its wide diversity of environments and genes and its shared scientific heritage.” Professor Cookson added: “GABRIEL would not be possible without European Community funding. It allows us to draw on the best of asthma and genetic research from many countries. The protective effect of a rural childhood indicates that asthma is a potentially preventable illness. We hope that GABRIEL will lead us to a clearer idea of what we may be able to use to prevent the disease from appearing”.


http://gabriel.web.med.uni-muenchen.de

GALTRAIN partners already have links with each other. Most GALTRAIN fellows will register for a PhD within the institute of a GALTRAIN Partner, and then, following creation of a detailed plan of training units, spend periods within the laboratory of other Partners. The scope of training that GALTRAIN can offer is exceptional, and includes epidemiology, immunology, structural chemistry, animal and human models of allergy and clinical trial design.

> http://www.nottingham.ac.uk/biology/galtrain/

The objectives of this research project were

1. to assess the inflammatory and toxicological potential of ambient suspended particles (collected at places across Europe with contrasts in traffic intensity) in comparison with diesel and gasoline engine particles.

2. to relate this to the previously demonstrated effects of exhaust on human airways.

3. to relate this to epidemiological findings of adverse health effects of ambient particles.

4. to overall assess toxicity in-vitro and in-vivo in animals and in humans, as well as health effects in epidemiological studies in relation to the physico-chemical characteristics of PM.

> www.uni-ulm.de/epidemiologie

Asthma and allergies are chronic conditions affecting billions of Europeans. These complex diseases are
determined by interplay of genetic and environmental factors. Treatments can control symptoms, but cannot cure or prevent the diseases. I, and my team, have shown that children are strongly protected from asthma and allergies when growing up in a farming environment rich in microbial exposures: the prevalence of asthma and hay fever is reduced over 5 fold. We have shown that environmental exposure to microbial compounds is inversely related to asthma and allergies. We have isolated microbes from animal sheds which protect mice from allergic airway inflammation. My team is now at a critical point to move this work forward to the next step, which is to systematically identify the microbes and their immuno-stimulatory compounds that protect from asthma and allergies. We have key resources in hand. In previous population based studies large numbers of environmental samples from farm and non farm children with and without asthma and allergies have been stored in biobanks. Genome wide genotyping data have also been gathered. The HERA project aims at applying the latest innovative high throughput sequencing techniques to comprehensively characterise the microbial ecology of these environmental samples. New methods for assessing microbial immuno-stimulatory substances will be used. These innovations will allow the HERA team to identify distinct asthma and allergy protective microbial exposures taking each individual’s genetic susceptibility into account. Once protective microbial exposures have been identified, the responsible substances can be isolated. These substances can be developed into novel and effective prevention
strategies to combat the asthma and allergy epidemic.

ISAAC, the International Study of Asthma and Allergies in Childhood, is a unique , multinational collaborative project investigating variations in childhood asthma by standardization methodology. Aims of this three-phase project are:

1. to describe the prevalence and severity of asthma, rhinitis and eczema in children living in different countries and to compare data obtained between participating centres.

2. To estimate to what extent the variation the variation in the prevalence and severity of asthma and allergies in children between centres can be explained by differences in known or suspected risk factors or by differences of disease management.

3. to examine variations in time trends of asthma, allergic rhinitis and atopic eczema worldwide and assess the relationship between patterns found and environmental data, and to investigate in which directions asthma and allergies are developing.

In ISAAC Phase One 156 centres worldwide used standardized questionnaires to collect data from 721,601 children from different age groups. In Phase Two Professor Stephan Weiland in 1998 began to compare this data from selected populations with supplementary objective parameter (lung function testing, atopic sensibilisation) to obtain more details of risk factors for these diseases.

Phase Two (German ISAAC Phase Two Study)

Partners in this national research program, integrated in the worldwide International Study of Asthma and Allergies in Childhood – ISAAC – were the Universities of Ulm, Dresden, Münster and Munich. Data collection started in 1995 and was completed in1997. a cross-sectional study was performed in two East German cities (Dresden and Leipzig) and one West German city (Munich) with 3000 first grade and 3000 fouth grade pupils with questionnaires and lung function testing with bronchial provocation, prick test and determination of immunological blood parameter.

Phase Three examines variations in time trends of asthma, allergic rhinoconjunctivitis and atopic eczema worldwide and assesses the relationship between patterns found and environmental data. ISAAC Phase Three uses the same research design as Phase One with a brief additional written questionnaire to assess environmental factors.

http://isaac.auckland.ac.nz/
www.uni-ulm.de/epidemiologie

A multicentre study aimed at identifying relevant polymorphisms in candidate genes causing asthma and atopy. These data are compared with controls derived from the German ISAAC II population. It is a multicentre project involving the University Children’s Hospital Munich, University of Ulm, Children’s Hospital Wesel and Children’s University Hospital at Charité, Berlin. A special funding program by the German Federal Department for Research (Functional human genomic research) enabled the participating centres to conduct this study. The main results have been recently published as part of the GABRIEL Study in Nature (Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, Depner M, von Berg A, Bufe A, Rietschel E, Heinzmann A, Simma B, Frischer T, Willis-Owen SA, Wong KC, Illig T, Vogelberg C, Weiland SK, con Mutius E, Abecasis GR, Farrall M, Gut IG, Lathrop GM, Cookson WO. Genetic variants rgulating ORMDL3 expressio contribute to the risk of childhood asthma. Nature. 2007 Jul 26;448(7152):470-3. Epub 2007 Jul 4).

http://www.lrz-muenchen.de/~u7r11dy/webserver/webdata/pdf/Magics%20Studienprotokoll.pdf

This multi-centre study was financed under the EC Framework V programme Quality of Life and Management of Living Resources and coordinated by Göran Pershagen, Karolinska Institutet, Institute of Environmental Medicine, Stockholm.

The aim of the project is to strengthen the basis for effective prevention of allergy in children, which has reached epidemic proportions in Europe and elsewhere in recent decades. PARSIFAL focuses on children of farmers and anthroposophic children, two groups with a low prevalence of atopic diseases and sensitisation, but for which specific protective factors have not yet been clearly identified. Specific objectives include assessments of the role of certain environmental and lifestyle factors that affect the development of allergy in children, such as diet, vaccinations, infections and animal contact. In addition, the influence by indoor microbial contaminants and the intestinal microflora is studied. The study focuses on children of farmers and anthroposophic children for reason of efficiency to obtain suitable distributions of exposure. Identification of important protective determinants in these groups will have relevance also for the general population.

> Göran.Pershagen@imm.ki.se

This birth cohort study is funded by the European Commission (5th Framework) and aims to assess lifestyle factors via standardized questionnaires and venous blood samples to measure atopy and extract DNA in a population of 400 farmers’ and 400 non-farmers’ pregnant women living in rural areas of five European countries (Germany, Switzerland, Austria, France and Finland). After birth, interviewers will assess exposure of the child to microbial products in stables, milk and indoor. The objective of this interdisciplinary birth cohort is to allow a better understanding of mechanisms involved in conferring protection from the development of childhood asthma and allergies. The results of this study will guide the further development of preventive strategies in Europe using microbial products in subjects with genetically determined responsiveness.

> Erika.Von.Mutius@med.uni-muenchen.de

http://www.allergie-lunge.de/