Effect of multiple antigenic exposures in the gut on oral tolerance and induction of antibacterial systemic immunity

We have analyzed oral tolerance of microbial antigens in an experimental mo del in which mice are treated orally with a single small dose of soluble an tigen and challenged systemically with the antigen in complete Freund's adj uvant. We found that, while oral administration of sonicated extracts of ei ther Leishmania major, Leishmania donovani, or Staphylococcus aureus was to lerogenic, as was administration of the nominal antigen ovalbumin or conalb umin, oral administration of Escherichia coli or Salmonella typhimurium son icated extract was not. Since E. coli is an enteric commensal that colonize s the intestine soon after birth, these data suggested that lack of demonst rable oral tolerance may be related to the frequency of oral exposure to an antigen. In support of this, we found that multiple oral doses of ovalbumi n or S. aureus or L. donovani antigens did not increase systemic hyporespon siveness beyond that achieved with a single oral dose. We have also tested the ability of mice fed with sonicates of the tolerogenic S. aureus or the nontolerogenic S. typhimurium to clear a subsequent systemic infection with the homologous bacteria and found that, while clearance of S. aureus was u naffected by prior feeding, clearance of S. typhimurium was actually enhanc ed. The data suggest that frequent oral antigenic exposure may eventually l ead to induction of systemic immunity in tolerant mice.