Food allergy in mice is modulated through the thymic stromal lymphopoietin pathway.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is involved in the pathogenesis of allergic reactions in the skin and the lung. Nevertheless, data on the role of TSLP in food allergy are scarce. We explored the role of TSLP in a mouse model with oral sensitization and oral challenge eliciting food allergy. METHODS: TSLP receptor (TSLPR)-/- mice and wild type mice were orally sensitized to ß-lactoglobulin in presence of cholera toxin (CT) or CT alone. The elicited immune response was characterized in vitro and the mice were subsequently challenged with the antigen. Lymphocytes from various locations in the gut were activated either by the antigen or by CT and assayed for cytokine secretion. RESULTS: Here we report that TSLPR-/- are less prone to generate food-induced reactions in conjunction with a decreased antigen-specific IgG1, but not IgE response. In addition, mesenteric lymphnode lymphocytes of TSLPR-/- mice were secreting lower quantities of IL-4, IL-5 and IL-10 after in vivo Ag activation, whereas higher numbers of IL-17 secreting cells were observed. Similarly, activation by the Th2-type adjuvant cholera toxin resulted in an increased frequency of IL-12 and IL-17 secreting lamina propria and mesenteric lymphocytes, together with increased production of IL-12 by activated dendritic cells in TSLPR-/- mice. CONCLUSIONS: TSLP can be considered as an essential, but not exclusive, mediator for elicitation of food allergy in mice, as well as a potential target for future therapeutic interventions.

Effects of an interleukin-15 antagonist on systemic and skeletal alterations in mice with DSS-induced colitis.

Inflammatory bowel diseases are commonly complicated by weight and bone loss. We hypothesized that IL-15, a pro-inflammatory cytokine expressed in colitis and an osteoclastogenic factor, could play a central role in systemic and skeletal complications of inflammatory bowel diseases. We evaluated the effects of an IL-15 antagonist, CRB-15, in mice with chronic colitis induced by oral 2% dextran sulfate sodium for 1 week, followed by another 1% for 2 weeks. During the last 2 weeks, mice were treated daily with CRB-15 or an IgG2a control antibody. Intestinal inflammation, disease severity, and bone parameters were evaluated at days 14 and 21. CRB-15 improved survival, early weight loss, and colitis clinical score, although colon damage and inflammation were prevented in only half the survivors. CRB-15 also delayed loss of femur bone mineral density and trabecular microarchitecture. Bone loss was characterized by decreased bone formation, but increased bone marrow osteoclast progenitors and osteoclast numbers on bone surfaces. CRB-15 prevented the suppression of osteoblastic markers of bone formation, and reduced osteoclast progenitors at day 14, but not later. However, by day 21, CRB-15 decreased tumor necrosis factor α and increased IL-10 expression in bone, paralleling a reduction of osteoclasts. These results delineate the role of IL-15 on the systemic and skeletal manifestations of chronic colitis and provide a proof-of-concept for future therapeutic developments.

The role of IL-10 in preventing food-induced anaphylaxis.

BACKGROUND: Food allergy is a common condition resulting in a much impaired quality of life. So far, no clearly effective preventive and therapeutic strategies have been established. However, several options have been tested with promising results. OBJECTIVE: This review examines the potential of various strategies involving an IL-10-mediated effect for tolerance induction to food antigens, mostly for preventing food allergy. METHODS: In addition to a review of the literature, we describe and comment on experiments involving a Lactoccocus lactis strain transfected to secrete murine IL-10 directly into the gut. RESULTS/CONCLUSION: This strain was efficient at preventing subsequent sensitization with a common food allergen. There appears to be a potential for such strategies for the prevention of human food allergy but further investigations will be needed to explore them.

APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa.

The bone marrow constitutes a favorable environment for long-lived antibody-secreting plasma cells, providing blood-circulating antibody. Plasma cells are also present in mucosa-associated lymphoid tissue (MALT) to mediate local frontline immunity, but how plasma cell survival there is regulated is not known. Here we report that a proliferation-inducing ligand (APRIL) promoted survival of human upper and lower MALT plasma cells by upregulating expression of the antiapoptotic proteins bcl-2, bcl-xL, and mcl-1. The in situ localization of APRIL was consistent with such a prosurvival role in MALT. In upper MALT, tonsillar epithelium produced APRIL. Upon infection, APRIL production increased considerably when APRIL-secreting neutrophils recruited from the blood infiltrated the crypt epithelium. Heparan sulfate proteoglycans (HSPGs) retained secreted APRIL in the subepithelium of the infected zone to create APRIL-rich niches, wherein IgG-producing plasma cells accumulated. In lower MALT, neutrophils were the unique source of APRIL, giving rise to similar niches for IgA-producing plasmocytes in villi of lamina propria. Furthermore, we found that mucosal humoral immunity in APRIL-deficient mice is less persistent than in WT mice. Hence, production of APRIL by inflammation-recruited neutrophils may create plasma cell niches in MALT to sustain a local antibody production.

Oral administration of an IL-10-secreting Lactococcus lactis strain prevents food-induced IgE sensitization.

BACKGROUND: Because tolerance to food is potentially modulated by IL-10, strategies to prevent food allergy should favor an increased delivery of IL-10 to the gut. OBJECTIVES: We hypothesized that administration of a Lactococcus lactis transfected to secrete murine IL-10 could prevent sensitization in a mouse model of food allergy. METHODS: Before each oral sensitization with beta-lactoglobulin in the presence of cholera toxin, young mice were administered the transfected Lactococcus lactis. Antigen-induced anaphylaxis after oral challenge assessed clinical protection achieved by the pretreatment. Serum and feces antigen-specific antibody concentrations were sequentially measured. Antibody titers were correlated with antibody and IL-10-secreting cell numbers in the spleen and in Peyer patches. RESULTS: Pretreatment with transfected Lactococcus lactis contributed to diminish anaphylaxis significantly, and inhibit antigen-specific serum IgE and IgG(1) production strongly. In addition, transfected Lactococcus lactis increased the production of antigen-specific IgA in the gut. Variations of antibody levels in the serum and the gut correlated with the numbers of antibody-producing cells. In addition, the presence of exogenous IL-10 in the gut by transfected Lactococcus lactis induced IL-10 secretion by Peyer patches cells. Increased IL-10 titers were also measured in the plasma. CONCLUSION: These results suggest that a microorganism bioengineered to deliver IL-10 in the gut can decrease food-induced anaphylaxis and provide an option to prevent IgE-type sensitization to common food allergens. CLINICAL IMPLICATIONS: Nonpathogenic IL-10-producing microorganisms in the gut could have a potential to prevent systemic food-induced anaphylaxis.

Antigen-specific secretory IgA antibodies in the gut are decreased in a mouse model of food allergy.

BACKGROUND: A large body of evidence implicates IgA antibodies in the immune response to pathogens present in the gut. Whether IgA antibodies play a similar role in food allergy remains to be determined. OBJECTIVE: We sought to characterize beta-lactoglobulin (BLG)-specific serum and secretory IgA antibody production in the gut and to define the role of antigen-induced cytokines in IgA production in a murine model of food allergy. METHODS: BLG-specific IgA antibodies were measured in the sera and feces of mice anaphylactic or tolerant to BLG. The number of antibody-secreting cells in the spleen and Peyer's patches was determined by means of ELISPOT. Mesenteric lymph node cells and Peyer's patch T cells were transferred to naive mice, and antibody production in the sera and feces in recipient mice, as well as antibody-secreting cell numbers, were measured. RESULTS: Serum IgA antibody titers were strongly increased in anaphylactic mice. In contrast, BLG-specific IgA antibody titers were increased in feces but not in sera from tolerant mice. These results were correlated with an increased number of BLG-specific IgA-secreting cells in Peyer's patches from tolerant mice. The adoptive transfer of Peyer's patch CD3+ cells from tolerant mice induced an increased number of IgA-secreting cells preferentially in the Peyer's patches of naive recipient mice. Furthermore, an increase of BLG-induced IL-10 and TGF-beta levels was found at IgA production sites. CONCLUSIONS: These results suggest a role for secretory IgA in tolerance mechanisms to foods. Peyer's patch CD3+ cells are primarily involved by favoring IgA production through the release of IL-10 and TGF-beta.

Lymphocytes in Peyer patches regulate clinical tolerance in a murine model of food allergy.

BACKGROUND: Food allergy can lead to severe, potentially life-threatening anaphylactic reactions. To generate efficient strategies aimed at an active cure, a better understanding of the pathogenic mechanisms is strongly needed. OBJECTIVE: To investigate T-cell-related mechanisms of food allergy and tolerance to beta-lactoglobulin (BLG) in gut-associated lymphoid structures. METHODS: Beta-lactoglobulin-specific IgG1, IgG2a, and IgE in serum from mice anaphylactic to BLG were analyzed by ELISA and compared with those obtained in mice actively tolerized to BLG. The number of Ab-secreting cells in the spleen and in Peyer patches was determined by ELISPOT. The numbers of cytokine-producing cells after antigen-specific activation were measured by the same method. Furthermore, mesenteric lymph node cells and Peyer patches cells were transferred to naive mice, and Ab production as well as Ab-secreting cells were measured. RESULTS: Serum IgG1 and IgE Ab titers as well as IL-4-producing cell numbers were strongly increased in anaphylactic mice. IL-10 was found in Peyer patch cells from tolerant mice after BLG activation but not in anaphylactic mice. Peyer patch cells, in contrast to mesenteric lymph node cells, proliferated weakly in anaphylactic mice after antigen activation, and activation of Peyer patches was partially inhibited by tolerization. CONCLUSIONS: Our data suggest a specific role for lymphocytes in Peyer patches in tolerance to BLG. Low IL-10 production in Peyer patches may favor symptoms of food allergy.

Efficient induction of CD8 T-associated immune protection by vaccination with mRNA transfected dendritic cells.

Dendritic cells are excellent targets for antigen-specific immune intervention. Here we attempted to introduce a CD8 T cell-dependent epitope into dendritic cells for presentation on major histocompatibility complex class I and induction of immunity. Murine bone-marrow-derived dendritic cells were subjected to electroporation with mRNA transcribed in vitro from a plasmid encoding lymphocytic choriomeningitis virus glycoprotein or enhanced green fluorescent protein under the control of a T7 promotor. The transfection efficiency of dendritic cells was 22 to 40%. Maturation was not inhibited by the electroporation. Dendritic cells electroporated with the appropriate antigen induced cell number-dependent in vitro proliferation in CD8 T cells expressing a transgenic receptor recognizing the 33 to 41 sequence of lymphocytic choriomeningitis virus glycoprotein in association with H-2Kb/Db, indicating correct synthesis, processing, and presentation of the epitope. Naive C57BL/6 mice vaccinated with electroporated dendritic cells and challenged with lymphocytic choriomeningitis virus were protected. Vaccination induced epitope-specific T cells as assessed by tetramer staining in blood and spleen. These results indicate that targeting dendritic cells with antigen-encoding mRNA can induce antigen-specific CD8 T cell responses as well as protective anti-viral immunity in vivo. Targeting dendritic cells with antigen-encoding mRNA may find wider application for immune intervention in disorders such as autoimmunity and cancer.

The T lymphocyte in food-allergy disorders.

PURPOSE OF REVIEW: While much attention is focused upon the role of IgE antibodies in food-allergy disorders, the T cell remains central to all forms, both IgE and non-IgE-mediated, of food-hypersensitivity responses. This review considers the central role of the T cell in this group of disorders and provides a comprehensive overview of recent studies that elucidate our understanding of the mechanisms involved in the pathogenesis of food allergy in regard to the role of the T cell. RECENT FINDINGS: Recent studies have defined a dynamic process involving T cell homing receptors (e.g. cutaneous lymphocyte antigen) and activation markers in food-hypersensitivity disorders. Modulation of the T-cell responses occurs through the recognition of dominant allergenic epitopes, the elaboration of regulatory cytokines (e.g. transforming growth factor-beta, IL-4, IL-5, tumor necrosis factor-alpha) and the influence of immunomodulatory microbial and environmental agents. The resulting disorders reflect T-cell dysregulation. SUMMARY: Significant recent advances in our understanding of the role of the T cell in food hypersensitivity have been made and will probably contribute to improved diagnostic and treatment methods in the near future.