Immune Responses to Fed Protein Antigens in Mice

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Immune Responses to Fed Protein Antigens in Mice. 3. Systemic Tolerance or Priming Is

Related to Age at Which Antigen Is First Encountered.(1)

Tolerance is very readily introduced in neonatal animals when antigen is given by routes other than via the gut. In view of this relative ease of tolerance induction in the neonatal period, it might be expected that oral tolerance would normally be even more profound and complete in neonates than in adults.

% Suppression = (1 – response of antigen fed mice/response of saline fed mice) x100

Animals fed OVA between 1 and 7 d after birth did not develop oral tolerance. Indeed, mice fed 1 d after birth exhibited, repeatedly and consistently, signs of priming both for antibody responses and CM. Feeding OVA on the first day of life led to qualitatively similar priming effects for both systemic antibody and CMI responses, in repeated experiments with CBA and BALB/c mouse strains.

When mice were weaned at age 21 d, and given an OVA feed on that day, they showed no subsequent oral tolerance for antibody responses, and less than usual suppression of CMI responses. On the other hand, littermates weaned 3 d after feeding or fed OVA 3 d after weaning showed significant oral tolerance both for humoral and CMI responses. Intravenous OVA injection, in amounts similar to those used for intra-amniotic antigen administration, did not enhance immune reactivity in the pups. Systemic tolerance induction, produced by feeding OVA at the age of 28 d, was identical in the pups of saline- and OVA-injected mothers.

Multiple daily feeds of OVA are more effective than a single feed of the same total amount in suppression of delayed type hypersensitivity responses.

Primed antibody responses were found to be partially suppressable by an OVA feed only 2 wk after the initial priming dose and they were indistinguishable from those of tolerant animals when retoleri- sation was performed 4 wk after the initial treatment. On the other hand, CMI responses exhibited a striking disparity and retolerisation was not accomplished before 14 wk.

Animals that had been exposed to ovalbumin by intra-amniotic injection demonstrated oral tolerance for serum antibody responses when retolerisation was attempted by feeding OVA 4 wk after birth.

The development of the small intestine in baby mice occurs in stages with a rapid series of changes around the time of weaning in the 3rd wk of life. At weaning there is not only exposure to many new dietary antigens, but also withdrawal of maternal milk and changes in gut flora. The permeability of the neonatal gut to macromolecules is increased, as, for example, demonstrated by high concentrations of serum antigen after feeding. Gut-processed fragments of OVA circulate in the serum 60 min after feeding of OVA to adult mice, and these can induce tolerance for CMI in adult recipients of such serum.

1. S. Strobel, A. Ferguson, Immune responses to fed protein antigens in mice. 3. Systemic tolerance or priming is related to age at which antigen is first encountered. Pediatr. Res. 18, 588–594 (1984).

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