Regulation of antigen-specific IgE, IgG1, and mast cell responses to ingested allergen by mucosal tolerance induction

Mucosal administration of soluble protein Ags results in profound immunologic nonresponsiveness, characterized by reduced production of Th1 and Th2 cytokines and concomitant suppressed Ig production. It has been suggested that Th2 cells are required for the induction and maintenance of this tolerogenic state. In this study, we show that oral tolerance induction abrogates subsequent Th2-driven Ag-specific IgE and IgG1 responses, while intranasal tolerance induction only blocks the production of IgE, but not IgG1. Consistent with suppressed IgE serum levels, elevated IFN-gamma production was observed in the spleens of tolerized mice. Moreover, both oral and intranasal tolerance induction were found to inhibit intestinal mast cell responses upon subsequent priming and intragastric provocation. Transfer of total splenocytes or purified CD4 , but not CD8 , T cells from intranasally tolerized mice clearly suppressed ongoing Ag-specific IgE, but not IgG1, responses in primed recipients. In addition, coadministration of IFN-gamma- neutralizing Abs completely blocked the transfer of suppression to primed recipients. These results show that Th2 cells can be subjected to tolerance induction, by inducing cross-regulatory, IFN-gamma- producing CD4 T cells. Moreover, our results point out differences in the regulation of T cell-dependent Ag-specific IgE and IgG1 responses

Regulation of antigen-specific IgE, IgG1, and mast cell responses to ingested allergen by mucosal tolerance induction

Mucosal administration of soluble protein Ags results in profound immunologic nonresponsiveness, characterized by reduced production of Th1 and Th2 cytokines and concomitant suppressed Ig production. It has been suggested that Th2 cells are required for the induction and maintenance of this tolerogenic state. In this study, we show that oral tolerance induction abrogates subsequent Th2-driven Ag-specific IgE and IgG1 responses, while intranasal tolerance induction only blocks the production of IgE, but not IgG1. Consistent with suppressed IgE serum levels, elevated IFN-gamma production was observed in the spleens of tolerized mice. Moreover, both oral and intranasal tolerance induction were found to inhibit intestinal mast cell responses upon subsequent priming and intragastric provocation. Transfer of total splenocytes or purified CD4 , but not CD8 , T cells from intranasally tolerized mice clearly suppressed ongoing Ag-specific IgE, but not IgG1, responses in primed recipients. In addition, coadministration of IFN-gamma- neutralizing Abs completely blocked the transfer of suppression to primed recipients. These results show that Th2 cells can be subjected to tolerance induction, by inducing cross-regulatory, IFN-gamma- producing CD4 T cells. Moreover, our results point out differences in the regulation of T cell-dependent Ag-specific IgE and IgG1 responses

Pre-Transplant Immune Regulation Due to Fetal and Maternal Antigen Exposure

Tumorimmunolog

Methotrexate prophylaxis prevents severe aGvHD after HLA-identical sibling transplantation for pediatric ALL without compromising relapse risk

Transplantation and immunomodulatio

Anti H-Y immunity in secondary recurrent miscarriage-immunogenetic and immunologic evidence

Transplantation and immunomodulatio

H-Y antibody titers are increased in unexplained secondary recurrent miscarriage patients and associated with low male : female ratio in subsequent live births

The birth of a boy is significantly more common than a girl prior to secondary recurrent miscarriage (SRM) and is associated with a poorer chance of a subsequent live birth. Children born after SRM are more likely to be girls. High-titer antisera specific for male antigens (H-Y) have been shown to arrest development of male bovine embryos efficiently. We consequently questioned the role of H-Y antibodies in women with SRM. Serum samples from patients with unexplained SRM (n = 84), unexplained primary recurrent miscarriage (PRM) (n = 12) and healthy women (n = 37) were obtained. The samples were taken during pregnancy (gestational weeks 4-5) for 77 (80%) of the patients. Enzyme-linked immunosorbent assay was used to detect immunoglobulin G antibodies that specifically recognized any of the five recombinant H-Y proteins (EIF1AY, RPS4Y1, ZFY, DDX3Y and UTY) and their H-X homologs. H-Y-specific antibodies were more frequent in SRM patients (46%) compared with female controls (19%, P = 0.004) and PRM patients (8%, P = 0.01). The presence of H-Y antibodies in early pregnancy was associated with a low male: female birth ratio among the subsequent live births, as only 12% of children born to H-Y antibody-positive patients were boys compared with 44% boys born to H-Y antibody negative patients (P = 0.03). The high frequency of H-Y antibody-positive SRM patients and the association between the presence of these antibodies in early pregnancy and the low number of male offspring, suggest that maternal immune responses against H-Y antigens can cause pregnancy losses. Further exploring these mechanisms may increase our understanding of unexplained SRM.Tumorimmunolog

Effects of Protein and Calorie Restriction on the Metabolism and Toxicity Profile of Irinotecan in Cancer Patients

Preclinical data suggests that protein and calorie restriction (PCR) might improve treatment tolerability without impairing antitumor efficacy. Therefore, we have studied the influence of PCR on irinotecan pharmacokinetics and toxicity. In this crossover trial, patients with liver metastases of solid tumors were included and randomized to treatment with irinotecan preceded by 5 days of PCR (~ 30% caloric and ~ 70% protein restriction) during the first cycle and a second cycle preceded by a normal diet or vice versa. Pharmacokinetic blood sampling and biopsies of both healthy liver and liver metastases were performed. The primary end point was the relative difference in geometric means for the active metabolite SN-38 concentration in healthy liver analyzed by a linear mixed model. No significant differences were seen in irinotecan (+ 16.8%, P = 0.22) and SN-38 (+ 9.8%, P = 0.48) concentrations between PCR and normal diet in healthy liver, as well as in liver metastases (irinotecan: −38.8%, P = 0.05 and SN-38: −13.8%, P = 0.50). PCR increased irinotecan plasma area under the curve from zero to 24 hours (AUC0–24h) with 7.1% (P = 0.04) compared with normal diet, whereas the SN-38 plasma AUC0–24h increased with 50.3% (P < 0.001). Grade ≥ 3 toxicity was not increased during PCR vs. normal diet (P = 0.69). No difference was seen in neutropenia grade ≥ 3 (47% vs. 32% P = 0.38), diarrhea grade ≥ 3 (5% vs. 21% P = 0.25), and febrile neutropenia (5% vs. 16% P = 0.50) during PCR vs. normal diet. In conclusion, plasma SN-38 exposure increased dramatically after PCR, whereas toxicity did not change. PCR did not alter the irinotecan and SN-38 exposure in healthy liver and liver metastases. PCR might therefore potentially improve the therapeutic window in patients treated with irinotecan