SummaryOral tolerance is an active process that starts with sampling of luminal antigens by the intestinal epithelial cells (IEC), followed by processing and assembly with major histocompatibility complex class II and subsequently a release of tolerogenic exosomes (tolerosomes) from the IEC. We have previously shown that tolerosomes can be isolated from serum shortly after an antigen feed, and will potently transfer antigen-specific tolerance to naive recipients. Here we study the capacity of the tolerosomes to protect against allergic sensitization in a mouse model of allergic asthma. Serum or isolated serum exosomes from tolerized BALB/c donor mice were transferred to syngeneic recipients followed by sensitization and intranasal exposure to ovalbumin (OVA). Blood, bronchoalveolar lavage (BAL) and lymph nodes were sampled 24 hr after the final exposure. The number of eosinophils was counted in BAL fluid and the levels of immunoglobulin E (IgE) and OVA-specific IgE were measured in serum. Mediastinal and coeliac lymph nodes were analysed by flow cytometry. The animals receiving serum from OVA-fed mice displayed significantly lower numbers of airway eosinophils and lower serum levels of total IgE as well as of OVA-specific IgE compared with controls. Moreover, the tolerant animals showed a significantly higher frequency of activated T cells with a regulatory phenotype in both mediastinal and coeliac lymph nodes. The results show that serum or isolated serum exosomes obtained from OVA-fed mice and administered intraperitoneally to naive recipient mice abrogated allergic sensitization in the recipients.
SummaryStudies have shown that atopic individuals have decreased serum levels of n-3 fatty acids. Indicating these compounds may have a protective effect against allergic reaction and/or are consumed during inflammation. This study investigated whether fish (n-3) or sunflower (n-6) oil supplementation affected T helper type 1 (Th1)-and Th2-mediated hypersensitivity in the skin and airways, respectively, and whether the fatty acid serum profile changed during the inflammatory response. Mice were fed regular chow, chow + 10% fish oil or chow + 10% sunflower oil. Mice were immunized with ovalbumin (OVA) resolved in Th1 or Th2 adjuvant. For Th1 hypersensitivity, mice were challenged with OVA in the footpad. Footpad swelling, OVA-induced lymphocyte proliferation and cytokine production in the draining lymph node were evaluated. In the airway hypersensitivity model (Th2), mice were challenged intranasally with OVA and the resulting serum immunoglobulin (Ig)E and eosinophilic lung infiltration were measured. In the Th1 model, OVA-specific T cells proliferated less and produced less interferon (IFN)-g, tumour necrosis factor (TNF) and interleukin (IL)-6 in fish oil-fed mice versus controls. Footpad swelling was reduced marginally. In contrast, mice fed fish oil in the Th2 model produced more OVA-specific IgE and had slightly higher proportions of eosinophils in lung infiltrate. A significant fall in serum levels of long-chain n-3 fatty acids accompanied challenge and Th2-mediated inflammation in Th2 model. Fish oil supplementation affects Th1 and Th2 immune responses conversely; significant consumption of n-3 fatty acids occurs during Th2-driven inflammation. The latter observation may explain the association between Th2-mediated inflammation and low serum levels of n-3 fatty acids.
The hygiene hypothesis suggests that lack of microbial stimulation in early infancy may lead to allergy, but it has been difficult to identify particular protective microbial exposures. We have observed that infants colonised in the first week(s) of life with Staphylococcus aureus have lower risk of developing food allergy. As many S. aureus strains produce superantigens with T-cell stimulating properties, we here investigate whether neonatal mucosal exposure to superantigen could influence the capacity to develop oral tolerance and reduce sensitisation and allergy. BALB/c mice were exposed to staphylococcal enterotoxin A (SEA) as neonates and fed with OVA as adults, prior to sensitisation and i.n. OVA challenge. Our results show that SEA pre-treated mice are more efficiently tolerised by OVA feeding, as shown by lower lung-cell infiltration and antigen-specific IgE response in the SEA pre-treated mice, compared with sham-treated mice. This was not due to deletion or anergy of lymphocytes by SEA treatment, because the SEA pre-treated mice that were fed with PBS showed similar inflammatory response as the sham-treated PBS-fed mice. Our results suggest that strong T-cell activation in infancy conditions the mucosal immune system and promotes development of oral tolerance.Key words: Allergic sensitisation . Mucosal immunity . Staphylococcal enterotoxin A . Tolerance Supporting Information available online IntroductionAllergies have increased markedly in Western industrialised countries, where they now afflict every third child. Allergies are linked to wealth, good education and small families, observations that have given rise to the hygiene hypothesis, according to which the developing immune system should be exposed to appropriate microbial stimulation in early childhood in order to mature correctly and for allergies to be avoided [1,2]. The hygiene hypothesis is also supported by experimental data. Germ-free animals are less prone to develop oral à These author contributed equally to this work. Eur. J. Immunol. 2009. 39: 447-456 DOI 10.1002 Immunomodulation 447 tolerance than animals reared conventionally [3,4]. Oral tolerance is induced by passage of antigens over the gut mucosa, prevents against both Th1-and Th2-dominated immune responses [5] and includes development of Treg [6,7]. Natural thymic-dependent Treg (CD4 1 CD25 hi FoxP3 1 ) are fundamental in protection against autoimmunity, gut inflammation and IgE responses. This cell subset has reduced functional capacity in germ-free animals [8].The strongest T-cell activators known are the ''superantigens'', exotoxins produced by certain pathogenic bacteria such as Staphylococcus aureus. These include staphylococcal enterotoxin A, B, C, D and E, as well as toxic shock syndrome toxin-1. The superantigen binds to the variable part of the TCR and to the MHC class II molecule, thereby ''mimicking'' antigen recognition, which leads to T-cell activation [9][10][11][12]. As many as 10-30% of all T cells can become activated by a certain superantigen compared with o0...
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