CD4(+) CD25(+) T regulatory cells do not transfer oral tolerance to peanut allergens in a mouse model of peanut allergy.

BACKGROUND: Recent studies have implicated CD4(+) CD25(+) regulatory T cells (nTregs) in the maintenance of tolerance to oral antigens and in the regulation of the food allergic IgE response. OBJECTIVE: The objective was to assess if nTregs can transfer allergen-specific oral tolerance to naïve, non-TCR transgenic mice and regulate peanut extract (PE)-specific hypersensitivity responses. Additionally, the role of the regulatory cytokines IL-10 and TGF-ß in the modulation of peanut-allergic sensitization was studied. METHODS: CD25-enriched T cells from PE-tolerant mice were adoptively transferred to recipient mice, which were subsequently sensitized to PE. Depletion of CD25(+) cells and neutralization of IL-10 and TGF-ß were compared in a CH3/HeOuJ mouse model of peanut-allergic sensitization. RESULTS: Transfer of CD25(+) Tregs-enriched cell populations did not affect the PE-specific cytokine production or PE-specific antibody levels compared with control mice but interestingly resulted in a decrease of mast cell responsiveness. On the contrary, transfer of CD25(+) Tregs-depleted cells caused an increase in non-specific cytokine production, in the absence of changes in PE-specific responses. TGF-ß neutralization resulted even in a larger increase in spontaneous release of all cytokines measured (IL-4, IL-5, IL-10, IL-13, and IFN-γ), but surprisingly also to a higher PE-specific Th2-associated (IL-4, IL-5, IL-13) cytokine production compared with depletion of CD25 cells or neutralization of IL-10. Similarly, depletion of CD25 cells and TGF-ß neutralization but not of IL-10 neutralization lead to an increase in PE-specific antibody levels and elevated mast cell degranulation following a PE challenge. CONCLUSIONS AND CLINICAL RELEVANCE: We conclude that CD4(+) CD25(+) Tregs from non-transgenic-tolerant mice cannot transfer specific oral tolerance of exogenous antigens to naïve mice and are more involved in general immune suppressive mechanisms. However, we found evidence that TGF-ß secreting Tregs (Th3) may play an important role.

Regulation by intestinal γδ T cells during establishment of food allergic sensitization in mice.

BACKGROUND: Food allergy affects approximately 5% of children and is the leading cause of hospitalization for anaphylactic reactions in westernized countries. The mucosal adjuvant cholera toxin induces allergic sensitization to co-administered proteins in mice, while feeding the protein alone induces oral tolerance. Intestinal γδ T cells could be of importance in the induction of oral tolerance. This study aims to investigate whether γδ T cells have functional relevance in food allergic sensitization. METHODS: Changes in γδ T cells on days 1, 2, 3, and 7 after initiation of food allergy were evaluated using flowcytometry. Furthermore, the anti-γδ T-cell receptor (TCR) antibody UC7 was used to block the γδ TCR in mice in vivo, followed by sensitization to peanut. After 4 weeks, peanut-specific antibodies in serum and cytokine production in spleen were measured. RESULTS: Induction of food allergy resulted in a profound decrease in the percentage of γδ T cells in intestinal tissues and Peyer's Patches, but not in mesenteric lymph nodes or spleen. This decrease could be detected from days 1 to 2 after the initiation of food allergy and the number of γδ T cells returned to normal on day 7. Blockade of the γδ TCR resulted in elevated food allergic responses upon sensitization with peanut characterized by increased IgE and Th2 cytokine production in splenocytes. CONCLUSION: These results demonstrate a unique regulatory role of γδ T cells, suggesting that targeting γδ T cells in the intestine may contribute to strategies to prevent and possibly treat food allergy.

Diclofenac enhances allergic responses in a mouse peanut allergy model.

BACKGROUND: Diclofenac and other non-steroidal anti-inflammatory drugs (NSAIDs) interfere with cyclo-oxygenase-mediated synthesis of prostaglandins, resulting in the inhibition of inflammatory immune responses. In contrast, it is known that NSAIDs are able to induce gastrointestinal damage. OBJECTIVE: Our aim was to investigate whether NSAIDs are able to enhance sensitization or abrogate tolerance to food antigens. METHODS: Mice were exposed to diclofenac and sensitized to peanut using cholera toxin as a mucosal adjuvant. In a tolerance model, oral tolerance was induced via feeding of peanut 3 weeks before sensitization with peanut. Diclofenac was administered before peanut feeding. After 4 weeks, peanut-specific antibodies in the serum and cytokine production in the spleen were measured. Induction of intestinal damage after oral exposure with diclofenac and peanut + cholera toxin was examined microscopically. RESULTS: Diclofenac-exposed animals showed increased levels of peanut-specific IgG1, IgG2a and IgE in the serum compared with vehicle-treated animals. Furthermore, peanut-induced cytokine production in the spleen was elevated upon diclofenac treatment. Importantly, diclofenac did not induce peanut-allergic responses in the absence of the cholera toxin, although exposure to diclofenac and peanut + cholera toxin resulted in intestinal epithelial damage. Reduced peanut-specific antibody production in the case of oral tolerance was not reversed after diclofenac exposure. However, oral tolerance, as measured by inhibition of peanut-specific cytokine responses, was reverted by diclofenac. CONCLUSIONS: These data point towards an increased risk for induction of food-allergic responses by diclofenac, when other circumstances are also in favour of induction of allergy.