No abstract

The recognition of allergen by cord blood cells indicates that allergen priming must occur prenatally. The relevance for subsequent sensitization is unclear.

Human milk contains large amounts of free oligosaccharides (HMOs). HMOs have been shown to exert antiinflammatory properties, and evidence for their immunomodulatory effects is increasing. The purpose of this study was to evaluate influences of two human breast milk-derived oligosaccharide samples (neutral and acidic oligosaccharides), and of a low-molecularweight fucoidan on cytokine production and activation of cord blood mononuclear cells. Cord blood mononuclear cells from randomly chosen healthy newborns were co-cultured with the oligosaccharide samples. By means of flow cytometry, intracellular cytokine production (d 20) and surface marker expression of T cells (d 5) were measured. In vitro-induced Ig levels were quantified nephelometrically (total IgG1) and by ELISA (total IgE) in the supernatant of cell cultures. The acidic oligosaccharide fraction increased the percentage of interferon-␥ producing CD3ϩCD4ϩ and CD3ϩCD8ϩ cells (p Ͻ 0.05) and the IL-13 production in CD3ϩCD8ϩ cells (p Ͻ 0.05). In acidic oligosaccharide cultures, CD25ϩ expression on CD3ϩCD4ϩ cells was significantly elevated (p Ͻ 0.05). Low-molecular-weight fucoidan induced IL-4 production in CD3ϩCD4ϩ T cells (p Ͻ 0.05) and IL-13 production in CD3ϩCD8ϩ T cells (p Ͻ 0.05), whereas interferon-␥ production remained unaffected in both T-cell populations. Ig production (total IgE and total IgG1) remained unaffected. Human milk-derived oligosaccharides and plant-derived oligosaccharides affect the cytokine production and activation of cord blood derived T cells in vitro. Therefore, oligosaccharides and, in particular, acidic oligosaccharides may influence lymphocyte maturation in breast-fed newborns. The postnatal period is a crucial time for the maturation of the immune system. At birth, T-lymphocytes exhibit a Th2-profile, characterized by a limited ability to produce cytokines. Throughout the first months after birth these Th2-skewed responses are modified into low-level immunity, predominantly expressing Th1-cytokines and IgG-antibodies, particularly of the IgG1 subclass (1,2).Human milk is a biologic fluid containing large amounts of free oligosaccharides. HMOs represent the third largest solid component (after lactose and lipids) in breast milk, occurring at a concentration of 20 -23 g/L in colostrum and 12-14 g/L in mature milk (3). HMOs are very resistant to enzymatic hydrolysis (4,5), indicating that these oligosaccharides must display essential nonnutritive functions.Throughout the last decade, numerous studies demonstrated the ability of HMOs to inhibit pathogens acting as receptors for microbes (6,7). Only a few reports on direct effects on immune function have been published so far. Human milk oligosaccharide structures like lacto-N-fucopentaose III (LNFPIII) and lacto-N-neotetraose (LNneoT) showed an effect on murine IL-10 production (8). It is further discussed that human milk is involved in the generation of antiinflammatory mediators that suppress Th1-type and inflammatory responses in mice (9). 0031-3998/04/5604-0536 PEDIATRIC RES...

(M.P., M.W.) Human naive CD4 ϩ T helper (Th) and CD8 ϩ cytotoxic (Tc) T cells, which only produce IL-2, may differentiate into Th1/Tc1-or Th2/Tc2-like lymphocytes, characterized by their cytokine production profile. 1␣,25-dihydroxyvitamin D 3 (1␣,25(OH) 2 D 3 ) has been reported to inhibit Th1/Tc1-related, but increase Th2/ Tc2-associated cytokines in T cells from adults. In industrialized countries, vitamin D supplementation for prevention of rickets is initiated within the first days of life and continued throughout the entire first year. Epidemiologic studies suggest an association of vitamin D exposure in newborns with the incidence of allergic diseases in later life. This study addresses the effects of 1␣,25(OH) 2 D 3 on Th1/Tc1 versus Th2/Tc2 differentiation in long term cell cultures of (naive) cord blood T lymphocytes. Our results show that in CD4 ϩ as well as CD8 ϩ cord blood cells, 1␣,25(OH) 2 D 3 inhibits not only IL-12-generated IFN-␥ production, but also suppresses IL-4 and IL Human naive T cells, which produce only IL-2, can differentiate into at least two functionally distinct subsets of memory or effector T cells, which can be distinguished by their cytokine profile (1, 2): CD4 ϩ Th1 cells on one hand producing predominantly IFN-␥, IL-2, and lymphotoxin, and CD4 ϩ Th2 cells on the other hand, which are the main source of IL-4 and IL-5, represent two extremely polarized phenotypes of a continuous spectrum of cytokine-producing T lymphocytes. Similar subpopulations (i.e. Tc1 and Tc2) exist in the CD8 ϩ T cell population (3, 4). Th1-and Th2-associated immune responses have been implicated in the pathogenesis of infectious, allergic, and autoimmune diseases (3).The local cytokine environment plays an important role in the differentiation of naive T cells along the Th1/Tc1 or Th2/Tc2 pathway (5, 6). For example, in vitro priming of naive T cells in the presence of IL-4 generates IL-4-producing Th2 effector cells (7-10). Similarly, IL-12, secreted by monocytes and dendritic cells, induces the capacity to produce IFN-␥ in neonatal T cells (11).Furthermore, the arachidonic acid metabolite prostaglandin E2 (12, 13), and several members of the steroid hormone family, such as progesterone (14, 15), glucocorticoids (16), and 1␣,25-dihydroxyvitamin D 3 (1␣,25(OH) 2 D 3 ) (17) have been reported to influence Th and Tc subset generation. 1␣,25(OH) 2 D 3 is not only required for normal mineral homeostasis but also regulates differentiation, growth, and function of different cell types such as hematopoietic and immune cells as well as a variety of normal and malignant epithelial cells (18 -20). The discovery of the high affinity receptor for 1␣,25(OH) 2 D 3 in monocytes and activated lymphocytes (21) suggested that this steroid acts as an immunoregulatory hormone (22,23). Interference with cytokine production of monocytes and lymphocytes seems to be a key mechanism by which 1␣,25(OH) 2 D 3 interacts with the immune system. Suppression of mitogen-induced proliferation (24) and inhibition of secretion of IL-1, ...

Allergen-specific cord blood reactivity may be attributed to low levels of allergens crossing the human placenta and providing the fetus with the necessary stimulus for T cell priming.

We could not find any early systemic immunologic changes during the first 8 weeks of clinically effective SLIT to inhalant allergens in paediatric patients with allergic rhinoconjunctivitis and/or asthma.

An ideal vaccine for allergen-specific immunotherapy of type I allergies should display reduced mediator-releasing capacity, induce maturation of APC, and modify the disease-eliciting Th2-dominated allergen-specific response to a more physiological response. We have previously shown that rSbsC-Bet v 1, the recombinant fusion protein of a bacterial surface (S-layer) protein of Geobacillus stearothermophilus ATCC 12980 and the major birch pollen allergen Bet v 1, exhibited reduced allergenicity and induced IFN-γ and IL-10 synthesis in Bet v 1-specific Th2 clones. In this study, we characterized the effects of rSbsC-Bet v 1 on immature monocyte-derived dendritic cells (mdDC) and the consequences for the polarization of naive CD4+ T lymphocytes isolated from the blood of birch pollen-allergic patients. mdDC responded to rSbsC-Bet v 1 with a significant up-regulation of costimulatory molecules, functional maturation, and the synthesis of IL-10 and IL-12. mdDC matured with rSbsC-Bet v 1 induced the differentiation of naive T cells into IFN-γ-producing cells. This effect was IL-12 dependent. In parallel, a substantial number of naive T cells developed into IL-10-producing CD25+Foxp3+CLTA-4+ cells capable of active suppression. Thus, rSbsC-Bet v 1 showed immune stimulatory capacity on DC, which then promoted the simultaneous differentiation of Th0/Th1 cells and regulatory T cells. These data further support that the concept of conjugating allergens to bacterial agents is a promising approach to improve vaccines for specific immunotherapy of atopic allergies.

These findings provide direct evidence for the release of tiny amounts of nutritive allergens from placental tissue indicating diaplacental allergen transfer and fetal exposure to nutritive allergens in vivo.