Subproject 8 - Priming of tolerance and allergy: To assess underlying mechanisms in murine models of allergy development with focus on early tolerance induction

Assessment of immune mechanisms of early tolerance development against allergens in experimental models of allergic diseases

Allergic diseases like asthma, atopic dermatitis and food allergy affect about every 4th child in industrial countries. Epidemiologic studies support the hypothesis that early environmental influences during pregnancy and/or after birth affect the infantile immune system and shape the individual risk to develop allergy or tolerance. A better understanding of the immune mechanisms of early tolerance induction is important to exploit this information for the development of preventive approaches to combat the allergy epidemic.

Primary goal of the SP8 is, in close collaboration to SP3, SP4, and SP7, the identification and functional analysis of immunological mechanisms in early tolerance induction using a murine tolerance model.

We hypothesize that tolerance induction between different atopic diseases are regulated by shared mechanisms, and that the understanding of these mechanisms will lead to new preventative strategies.

Aim 1:  Identification of immunological mechanisms, which play a central role in perinatal tolerance development and protection against diverse atopic diseases by using a murine tolerance induction model. Focus will be the molecular analysis of perinatal tolerance development and the identification of shared mechanisms and key players in different allergic diseases. Special attention will be drawn to the inflammasome NLRP3 which is a major regulator of innate immunity and is therefore interesting especially for the naïve and developing immune system of young children. NLRP3 has been found in a birth cohort as a risk factor for allergy and airway inflammation (see also SP3) suggesting a role in perinatal immune priming. The role of NLRP3 in adaptive immunity is so far poorly understood, and we hypothesis that it could serve as a promising target to elucidate the interface between innate and adaptive processes of tolerance.

Aim 2:  The microbiome of an organism is an important key factor in the development and regulation of the immune system. As shown before in human cohorts the microbiome and the exposure to bacterial endotoxins crucially influence the induction of antigen specific tolerance. However, the underlying mechanisms are not well understood. In collaboration with SP7 we aim to analyze the relevance of specific microbiome components in perinatal tolerance induction.

Aim 3:  Finally this project will serve as an overarching platform to systematically address the mechanisms and function of specific immunological patterns, novel factors, as well as signaling pathways identified in the cohorts of SP3, SP4, and SP7 in regard to perinatal tolerance induction.

As the main result the identification of an immunological signature associated with perinatal tolerance development with the objection to the development of primary prevention strategies is pursued.

The team around principal investigator Prof. Dr. med. Gesine Hansen is an interdisciplinary research group composed of pediatricians specialized in pulmonology and allergy, as well as of biologists and immunologists with long-term experience with human cohort studies as well as experimental allergy studies.

     - Post-doctoral fellow in the Allergy & Tolerance Research Group, Medical School Hannover
     - Major research interests: Perinatal immune priming with focus on B cell development