Marianne Bol-Schoenmakers

The role of intestinal dendritic cells subsets in the establishment of food allergy

Cite this as: J. J. Smit, M. Bol‐Schoenmakers, I. Hassing, D. Fiechter, L. Boon, R. Bleumink and R. H. H. Pieters, Clinical & Experimental Allergy, 2011 (41) 890–898.

Intestinal alkaline phosphatase contributes to the reduction of severe intestinal epithelial damage

Inflammatory bowel disease is characterized by chronic inflammation of the intestine and is accompanied by damage of the epithelial lining and by undesired immune responses towards enteric bacteria. It has been demonstrated that intestinal alkaline phosphatase (iAP) protects against the induction of inflammation, possibly due to dephosphorylation of lipopolysaccharide (LPS). The present study investigated the therapeutic potential of iAP in intestinal inflammation and epithelial damage. Intestinal epithelial damage was induced in C57BL/6 mice using detran sulfate sodium (DSS) and iAP was administered 4days after initial DSS exposure. Loss in body weight was significantly less in iAP-treated mice and accompanied with reduced colon damage (determined by combination of crypt loss, loss of goblet cells, oedema and infiltrations of neutrophils). Treatment with iAP was more effective in case of severe inflammation compared to situations of mild to moderate inflammation. Rectal administration of LPS into a moderate inflamed colon did not aggravate inflammation. Furthermore, soluble iAP did not lower LPS-induced nuclear factor-kappaB activation in epithelial cells in vitro but induction of cellular AP expression by butyrate resulted in decreased LPS response. In conclusion, the present study shows that oral iAP administration has beneficial effects in situations of severe intestinal epithelial damage, whereas in moderate inflammation endogenous iAP may be sufficient to counteract disease-aggravating effects of LPS. An approach including iAP treatment holds a therapeutic promise in case of severe inflammatory bowel disease.

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

To cite this article: Bol‐Schoenmakers M, Marcondes Rezende M, Bleumink R, Boon L, Man S, Hassing I, Fiechter D, Pieters RHH, Smit JJ. Regulation by intestinal γδ T cells during establishment of food allergic sensitization in mice. Allergy 2011; 66: 331–340.

Activation of the aryl hydrocarbon receptor reduces the number of precursor and effector T cells, but preserves thymic CD4+CD25+Foxp3+ regulatory T cells

Aryl hydrocarbon receptor (AhR) activation suppresses immune responses, including allergic sensitization, by increasing the percentage of regulatory (Treg) cells. Furthermore, AhR activation is known to affect thymic precursor T cells. However, the effect of AhR activation on intrathymic CD4+CD25+Foxp3+ Treg cells is unknown. Therefore, we investigated the effect of AhR activation on the percentage and number of CD4+CD25+Foxp3+ Treg cells during allergic sensitization in relevant immunological organs. C3H/HeOuJ mice were treated on day 0 with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and subsequently sensitized to peanut. On day 8, mice were sacrificed and thymus, spleen and mesenteric lymph nodes (MLN) were isolated. TCDD treatment decreased the number of CD4-CD8-, CD4+CD8+, CD4+CD8- and CD4-CD8+ precursor T cells, but not the number of thymic CD4+CD25+Foxp3+ Treg cells. TCDD treatment increased the number of splenic CD4+CD25+Foxp3+ Treg cells and decreased Th1, Th2 and cytotoxic T cells in the spleen. This appeared to be independent of allergic sensitization. In MLN, TCDD treatment suppressed the increase of the number of CD4+CD25+Foxp3+ Treg cells, Th1, Th2 and cytotoxic T cells induced by peanut sensitization. Together, TCDD treatment preserves thymic CD4+CD25+Foxp3+ Treg cells and decreases peripheral T helper and cytotoxic T cells. This effect of TCDD may contribute to the increased influence of CD4+CD25+Foxp3+ Treg cells on immune mediated responses and to the understanding of how AhR activation modulates immune mediated diseases, including food allergy.

Non-dioxin-like AhR Ligands in a Mouse Peanut Allergy Model

Recently, we have shown that AhR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses sensitization to peanut at least in part by inducing a functional shift toward CD4(+)CD25(+)Foxp3(+) T cells. Next to TCDD, numerous other AhR ligands have been described. In this study, we investigated the effect of three structurally different non-dioxin-like AhR ligands, e.g., 6-formylindolo[3,2-b]carbazole (FICZ), β-naphthoflavone (β-NF), and 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF), on peanut sensitization. Female C57BL/6 mice were sensitized by administering peanut extract (PE) by gavage in the presence of cholera toxin. Before and during peanut sensitization, mice were treated with FICZ, β-NF, or 6-MCDF. AhR gene transcription in duodenum and liver was investigated on day 5, even as the effect of these AhR ligands on CD4(+)CD25(+)Foxp3(+) T(reg) cells in spleen and mesenteric lymph nodes (MLNs). Mice treated with TCDD were included as a positive control. Furthermore, the murine reporter cell line H1G1.1c3 (CAFLUX) was used to investigate the possible role of metabolism of TCDD, FICZ, β-NF, and 6-MCDF on AhR activation in vitro. TCDD, but not FICZ, β-NF, and 6-MCDF, suppressed sensitization to peanut (measured by PE-specific IgE, IgG1, IgG2a and PE-induced interleukin (IL)-5, IL-10, IL-13, IL-17a, IL-22, and interferon-γ). In addition, FICZ, β-NF, and 6-MCDF treatments less effectively induced AhR gene transcription (measured by gene expression of AhR, AhRR, CYP1A1, CYP1A2, CYP1B1) compared with TCDD-treated mice. Furthermore, FICZ, β-NF and 6-MCDF did not increase the percentage of CD4(+)CD25(+)Foxp3(+) T(reg) cells in spleen and mesenteric lymph nodes compared with PE-sensitized mice, in contrast to TCDD. Inhibition of metabolism in vitro increased AhR activation. Together, these data shows that TCDD, but not FICZ, β-NF, and 6-MCDF suppresses sensitization to peanut. Differences in metabolism, AhR binding and subsequent gene transcription might explain these findings and warrant further studies to investigate the role of the AhR in food allergic responses.

Aryl hydrocarbon receptor activation affects the dendritic cell phenotype and function during allergic sensitization

Aryl hydrocarbon receptor (AhR) activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses peanut sensitization by affecting T cell subsets. However, effects of AhR activation on dendritic cells (DC) in an allergic setting were not investigated yet. Therefore, we analysed the effects of AhR activation on DC phenotype in vivo, as well as their ex vivo potency to stimulate allergen-specific splenic T cells and to induce CD4+CD25+Foxp3+ regulatory (T(reg)) cells. C3H/HeOuJ mice were treated with TCDD by gavage and subsequently sensitized to peanut extract (PE). After eight days, mice were sacrificed and DC in spleen and mesenteric lymph nodes (MLN) were characterized or cocultured with PE-specific CD4+ T cells. AhR activation almost doubled the absolute number of CD11c+CD103+ DC, while not affecting CD11b+ DC, the absolute number of DC, the expression of the activation makers MHCII, CD86, CD80, CD40, CD54 and CD8 on CD11c+ and the activation status of CD11c+CD103+ DC in the spleen. In the MLN, TCDD decreased the absolute number of DC and CD103+ DC, while not affecting CD11b+ DC and the expression of activation markers on DC. PE-pulsed splenic DC from TCDD-treated mice suppressed IL-5, IL-13 and IFN-γ production by PE-specific T cells, but did not induce CD4+CD25+Foxp3+ T(reg) cells. This suppression of cytokine production was not mediated by the TCDD-induced increase in CD103+ DC in the spleen. Combined, these results indicate that AhR activation suppresses the initiation of food allergic responses by affecting DC and their interaction with effector T cells.

Diclofenac enhances allergic responses in a mouse peanut allergy model

Cite this as: M. Bol‐Schoenmakers, R. Bleumink, M. Marcondes Rezende, E. Mouser, I. Hassing, I. Ludwig, J. J. Smit and R. H. H. Pieters, Clinical & Experimental Allergy, 2011 (41) 424–433.

Cellular interactions of organotin compounds in relation to their antitumor activity

From numerous studies it is evident now that some organotin compounds exhibit antitumor activity as was tested in particular against the P388 lymphocytic leukemia in mice (see for review, Crowe 1987). Special attention has been paid at first to the dialkyl-and diaryl-substituted organotin compounds, with dihalide or dipseudohalide complexes as anionic residues (Crowe et al 1980; 1984). More recently these anioic residues were replaced by organic molecules attached to the tin by either Sn-O, Sn-N or Sn-S bonds (Barbieri et al 1982; Saxena and Tandon 1983; Haiduc et al 1983; Huber et al 1985; Ruisi et al 1985; Gielen et al 1986a; 1986b). The structure activity relationships of the various diorganotin compounds tested revealed that in vivo the diethyl-and diphenyl-derivatives were the most promising (Crowe 1987). In the murine P388 prescreening test the best T/C values obtained did not reach values higher than 200 (Crowe et al 1987), values which are still lower than those of 200-300 observed with platinum derivatives in the same tumor system (Rosenberg et al 1969; Rosenberg 1979). In solid tymor systems only limited data are available on the effects of organotins. Crowe (1984) reported that many of the organotin complexes which were active towards P388 were found to be inactive in some solid tumor systems tested. In contrast, Cardarelli (1984a, 1984b), Arakawa (in press) and Penninks (1986) reported some activity of organotins towards solid tumors, although different tumor systems and/or routes of administration were used.

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.

The mycotoxin deoxynivalenol facilitates allergic sensitization to whey in mice

Intestinal epithelial stress or damage may contribute to allergic sensitization against certain food antigens. Hence, the present study investigated whether impairment of intestinal barrier integrity by the mycotoxin deoxynivalenol (DON) contributes to the development of whey-induced food allergy in a murine model. C3H/HeOuJ mice, orally exposed to DON plus whey once a week for 5 consecutive weeks, showed whey-specific IgG1 and IgE in serum and an acute allergic skin response upon intradermal whey challenge, although early initiating mechanisms of sensitization in the intestine appeared to be different compared with the widely used mucosal adjuvant cholera toxin (CT). Notably, DON exposure modulated tight-junction mRNA and protein levels, and caused an early increase in IL-33, whereas CT exposure affected intestinal γδ T cells. On the other hand, both DON- and CT-sensitized mice induced a time-dependent increase in the soluble IL-33 receptor ST2 (IL-1R1) in serum, and enhanced local innate lymphoid cells type 2 cell numbers. Together, these results demonstrate that DON facilitates allergic sensitization to food proteins and that development of sensitization can be induced by different molecular mechanisms and local immune responses. Our data illustrate the possible contribution of food contaminants in allergic sensitization in humans.