Induction of Oral Tolerance with Micro‐Doses of Ovomucoid Depends on the Length of the Feeding Period

Abstract

Oral administration of antigen induces antigen-specific immunologic tolerance, which is known to be dose-dependent. We studied the influence of continuous oral administration of nanogram and microgram doses of antigen on oral tolerance induction. Mice were continuously exposed to varying doses (1 ngÀ1 mg/day) of ovomucoid (OM) for a minimum of 30 days and a maximum of 100 days. It was possible to induce oral tolerance measured as reduced proliferation and antibody production (immunoglobulin (Ig)G 1 , IgG 2a and total Igs) when mice were fed 1 mg of OM/day for 40 or 50 days. It was not possible to induce oral tolerance with daily doses of antigen of 10 mg or less. Feeding of 100 mg OM/day for 40 and 50 days and 1 mg OM/day for 30 days generated tolerization of Th2-dependent responses, but retained an intact response of Th1-dependent antibodies, whereas feeding of 1 mg OM/day for 40 and 50 days resulted in tolerization of both Th1-and Th2-antibody responses. The results presented here suggest that there is a threshold of microgram-doses below which oral tolerance cannot be induced, and that selective suppression of Th2 responses can be achieved by continuous microdose feeding, while an extension of the feeding dose or feeding period tolerizes both Th1-and Th2-dependent responses.

Low-Dose Oral Tolerance due to Antigen in the Diet Suppresses Differentially the Cholera Toxin-Adjuvantized IgE, IgA and IgG Response

“…At the outset of the experiments, we determined the actual KSTI exposure of the F0 mice fed the standard soy-containing diet by analyzing the KSTI content in food sample extracts using a very sensitive ELISA. The content of KSTI in different food batches was found to be at microgram levels (31 ± 14 µg/g) corresponding to a daily intake of approximately 100–200 µg KSTI for the F0 mice, which in terms of oral tolerance induction is to be considered a prolonged low dose exposure [16, 17]. …”

Effect of Maternal Dietary Cow’s Milk on the Immune Response to β-Lactoglobulin in the Offspring: A Four-Generation Study in Mice

“…In this study, it is difficult to draw firm conclusions concerning the immunological effect of small amounts of BLG (approximately 1 µg/g) in such diets as we could not compare the responses to those of mice bred on a strictly antigen-free diet. Only a few studies have focused on the effect of feeding low doses of antigens to experimental animals bred on a strictly antigen-free diet [26, 27, 28]. Applying the same experimental protocol for the detection of oral tolerance, following the administration of ovomucoid to BALB/c mice in the drinking water, we found in a previous study the threshold for tolerance induction to be in the range of 0.1 mg of ovomucoid/day for 50 days [28].…”

“…Only a few studies have focused on the effect of feeding low doses of antigens to experimental animals bred on a strictly antigen-free diet [26, 27, 28]. Applying the same experimental protocol for the detection of oral tolerance, following the administration of ovomucoid to BALB/c mice in the drinking water, we found in a previous study the threshold for tolerance induction to be in the range of 0.1 mg of ovomucoid/day for 50 days [28]. Neither tolerance nor priming were observed at lower antigen doses, supporting the present findings that ingestion of an amount of BLG of approximately 5 µg/day does not affect the immune response to BLG in mice.…”

Modulation of Oral Tolerance to Ovalbumin by Dietary Protein in Mice

“…In addition, plenty of reports have shown that digested formulas can stimulate the gut immune system towards induction of tolerance in newborns with an elevated risk of allergies (22,23). However, there have been only a few reports addressing the effect of nutritional status on oral tolerance (15, 24) and vir- ) were prepared as described in "Materials and Methods."…”