The systemic immune response and tolerance induced by oral administration of various doses of bovine alpha s1-casein were examined, focusing on cytokine responses in this study. Spleen cells from mice fed low doses of antigen secreted interferon-gamma and interleukin-2 in response to in vitro antigen stimulation, indicating that a Th1-type response was induced. In these mice, the Th1 responses after subsequent immunization and boosting with the antigen were diminished. In the case of mice fed high doses of the antigen, secretion of Th1 cytokines was minimal, but systemic responses after subsequent immunization and boosting with the antigen were strongly inhibited. Active suppression was not observed at any dose. The results indicate that, in this system, low-dose feeding induced activation of Th1 cells followed by tolerization, while high-dose feeding induced profound tolerance without prior activation. Our results have implications for clinical application of oral tolerance to allergy and autoimmune disease.