The influence of initial exposure timing to β-lactoglobulin on oral tolerance induction

Background: Although a number of studies have investigated the induction of oral tolerance to several proteins, relatively little is known about the induction of oral tolerance to beta-lactoglobulin, one of the major antigenic proteins in milk. Objective: We investigated the influence of the timing of the initial beta-lactoglobulin exposure on oral tolerance induction and examined some characteristics of the tolerogenic immune response. Methods: BALB/c mice were given beta-lactoglobulin prenatally or from the third or fifth postnatal week, bred for 17 weeks, and compared with unexposed control mice. Specific plasma anti-beta-lactoglobulin antibodies (total IgG, IgG subclasses, IgM, and IgE), antigen-specific splenocyte responses, frequencies of antibody-producing cells, and cytokine production by splenocytes, intestinal mucosal lymphocytes, and Peyer's patches were analyzed. Results: Differences were observed among the 4 groups of mice in changes of plasma anti-beta-lactoglobulin antibody titers, antigen-specific T-cell proliferation, and Frequencies of antibody-producing splenocytes, intestinal mucosal lymphocytes, and Peyer's patch cells after the first exposure to beta-lactoglobulin, The onset and duration of the immunologic responses were found to be dependent on the timing of antigen exposure. Prenatal exposure to antigen facilitated the induction of oral tolerance to beta-lactoglobulin, whereas delayed antigen exposure retarded tolerance. The induction of oral tolerance was associated with increased IL-4 and/or IL-10 production and decreased IL-12 production. Conclusion: Our results suggest that the timing of initial antigen exposure greatly influences the induction of oral tolerance to beta-lactoglobulin and that altered secretion of regulatory cytokines may be responsible for the differences in antibody production and oral tolerance induction.