Commensals and immune modulation Group

Project 1: 'Helminths'

Helminths, such as schistosomes, are the master regulators of the host immune system; they can survive up to 10 years in the human body. Their excretory/secretory (ES) products contain many molecules, of which some actively influence the immune system and drive the tolerogenic arm of the immune system. These processes may have a positive bystander effect, as chronic helminth infections are associated with lower incidences of allergies in endemic areas and protect against allergic airway inflammation in mouse models of asthma.

This project entails a number of activities:

• Characterization of immune responses from people living in endemic areas (together with Yazdanbakhsh) and in mouse models to define dominant responses that can protect against allergic airway inflammation (e.g. Breg and Treg cells).
• Triad interaction between helminths, existing microbiota and the host immune system (in collaboration with MacDonald, University of Manchester, UK).
• Identification and characterization of active immunomodulatory fractions of ES, including extracellular vesicles (together with Hokke).
• Investigate the immunomodulatory function of recombinantly expressed schistosome-derived molecules in vitro and in vivo. We use culture models of human immune cells (e.g. dendritic cells, macrophages, B-cells; together with Guigas & Everts) either or not in co-culture with respiratory epithelial cells (together with Hiemstra, Pulmonology) and in mouse models of human asthma (in collaboration with McSorley, University of Dundee, UK & Maizels, University of Glasgow, UK). This work is part of the AWWA-consortium.

This line of research is funded in part by the Netherlands Lung Foundation and by ZonMW.  

Project 2: 'Exposure to microbes''

At birth the immune system is still immature and needs to rapidly develop to protect the newborn baby against invading pathogens, but at the same time develop tolerance against innocent microbes and harmless allogenic antigens. Exposure to microbes/commensals or conditions that promote the colonization of commensals may enhance immune maturation and prevent the development of allergic airway diseases in children – one of the first exaggerated inflammatory conditions, that can be recognized in children from birth onwards.

In this project, we are involved in several clinical intervention trials in neonates:

• MARTHA (PI Erika von Mutius, Munich). Minimally processed cow’s milk is given to full-term born children (between 6-12 month) for 2 years. This trial is part of the AWWA consortium.
• PROTEA (PI Strander, Franciscus Hospital, Rotterdam). Bacterial lysates are given orally to late pre-term babies (6 weeks) for 1 year.

Before, during and after the placebo-controlled interventions, nasal srapes/swabs/nasorption and venous blood is collected for extensive immunophenotyping by mass- and spectral flow to monitor immune deviations in comparison to clinical parameters, such as allergic sensitization and the incidence/severity of respiratory infections over time.

This line of research is co-funded by the Netherlands Lung Foundation.   

Project 3: 'Inflammatory diseases'

A large variety of inflammatory diseases can be recognized that either differ in the type of inflammation (e.g. auto-immunity is caused by type 1 inflammation, allergies are characterized by type 2 inflammation while cancer is characterized by a dominant immune suppression), or the location or tissues involved (e.g. the skin, lungs, gut or brain). To allow tailored or personalized  immunomodulatory treatments for these immune disorders, extensive immunophenoptying is mandatory, not only in blood but also in the affected (mucosal) tissues.

In this project, we make use of novel single-cell platforms, including mass-and spectral flowcytometry, combined with sc-transcriptomics (10x).

• Characterization of upper airway inflammation in response to allergens (allergic rhinitis and/or asthma patients) and/or viral infections (e.g. SARS-CoV2 in COVID-19 patients).
• Disease-overarching approach to gain insight in central immune hubs that form a switch towards either too much inflammation or too much immune suppression. Immunophenotyping of blood samples from patients with inflammatory diseases or with cancer, receiving dendritic cell- driven immunotherapy, before, during and after the treatment by mass- and spectral flow cytometry.

This work is co-funded by Health Holland and SGF (Samenwerkende GezondheidsFondsen).

Project 4: 'Respiratory infections'

Severe viral respiratory infections, though uncommon in healthy adults, often occur in immunocompromised patients, leading to hospitalization and even death. There is no effective medication.

Gut commensals profoundly impact host immunity. They generate bioactive molecules – commensal immune modulators (CIM) – that promote gut integrity and antimicrobial activity in immune cells, but without tissue-damaging inflammation.

In this project, CIMs are investigated for their potential to enforce mucosal immunity in risk groups and prevent severe respiratory infections.

• Nasal mucosal responses should prevent pathogens from spreading to the lower airways. By administration of CIMs directly to the nose (in collaboration with Roestenberg, LUCID, and van Gelder, Academic Pharma), their immune bolstering effects on mucosal immunity will be investigated using innovative single-cell analysis platforms (see project 3).
• The role of CIMs in modulating mucosal immunity and reducing rhinovirus infections in vitro, is studied using epithelial 3D-organoids, epithelial/immune co-cultures from minimally invasive nasal (micro-)biopsies (in collaboration with Hiemstra and van der Does, Pulmonology, see project 1).

This work is supported by the Bontius Stichting and by ZonMW.