The immune system in early life is characterized by a preponderance of Th2 cytokines and immature activation and function of immune cells, which appear to prone newborns for severe infections as well as allergic diseases. Immunomodulation represents a promising therapeutic strategy against those diseases and may have in the future implication also in early life. In the current thesis, we focused on two immunomodulatory substance classes, Toll like receptor (TLR) ligands and sphingolipids. Both, TLRs and sphingolipid receptors have a very distinct distribution pattern and function on immune cells. Therefore, they can both modulate and enhance the immune response towards a Th1 environment, which might be beneficial particularly for the immature immunological situation in early life.
In the first part of this thesis, we aimed to investigate the potential of the TLR9 ligand CpG to induce a strong inflammatory immune response of plasmacytoid dendritic cells (pDCs), which are important in defense against many viral and bacterial pathogens. We found similar pDC numbers and TLR9 surface expression in cord blood of term and preterm newborns compared with adult peripheral blood, while the production of IFN by these cells was impaired in preterm babies. Therefore, TLR9 ligands may not be as promising as immunomodulatory substance against Th2 biased diseases in preterm babies as expected but need to be focus of further mechanistic investigations in depth. The second part of this PhD thesis deals with the investigation of the effect of the immunomodulatory substance class, sphingolipids, on food allergy being another frequent Th2 biased immune disorder in early life.
In order to investigate this second issue, we established a mouse food allergy model, which is based on allergen feedings under anti-ulcer medication. Hindering the gastric digestion of food proteins results in the induction of allergen specific IgE, elevated Th2 cytokines and a decrease of body temperature after oral allergen provocation indicating anaphylactic reactions. Using this sensitization protocol, we then investigated the impact of endogenous sphingosine-1 phosphate (S1P) production on food allergy induction. We could show that deletion of both sphingosine kinases, SphK1 and SphK2, which are responsible for intracellular S1P production, inhibits the development of allergen specific IgE and impairs the effector phase of food allergy. These results have led to the assumption that the S1P homeostasis is of importance in Th2 driven food allergic responses with major impact also in early life.