SUMMARYOral tolerance has been characterized as an immunological hyporesponsiveness to fed antigen. Previous studies have suggested that high-dose oral tolerance involves the preferential interaction of B7 with CTLA-4 on the T cell. To determine whether similar mechanisms are involved in the induction of lowdose oral tolerance, mice were treated with anti-CTLA-4 monoclonal antibody (MoAb), with or without IL-12, at the time of feeding. Results showed that anti-CTLA-4 MoAb alone failed to restore cellular proliferation, antibody titres and IFN-g levels; however, IL-4 cytokine levels in OVA-fed mice were partially restored. In contrast, administration of IL-12 along with anti-CTLA-4 MoAb to mice during feeding completely prevented the suppression of Th1 immune responses, as shown by increased serum IgG2a titres, IFN-g production and cell proliferation. These results suggest that blocking B7-CTLA-4 interactions in the presence of IL-12 prevents the induction of low-dose oral tolerance at the Th1 cell level.