Reducing or deviating xenogeneic immune response prior to xenotransplantation may enhance the efficacy of conventional immunosuppressive therapies in prolonging xenograft survival. The potential to suppress or steer immune responses by oral administration of xenoantigens was evaluated. Based on knowledge of oral tolerance, hypotheses tested were that feeding xenoantigens would inhibit cell-mediated immune response (CMIR) and production of antibodies associated with graft rejection and induce bystander suppression. DA and LEW rats, high and low responders to xenoantigens, respectively, were fed dead porcine blood mononuclear cells (PBMC) and subsequently received live PBMC and hen egg-white lysozyme (HEWL, a third-party antigen) by subcutaneous injection. Delayed-type hypersensitivity (DTH) to PBMC was an indicator of CMIR. Quantification of T(H)1 (IgG(2b)) and T(H)2 (IgG(1))-associated antibodies and their ratio measured magnitude and bias of the antibody-mediated response to PBMC and HEWL. Feeding PBMC reduced IgG(2b) antibody production by 90% (DA) and 71% (LEW) and increased IgG(1) antibodies by 116% in DA but not LEW rats (p<or=0.05). DTH was unaffected (DA) or increased (LEW) in antigen-fed rats. Bystander suppression was demonstrated by inhibition of antibodies to HEWL in DA rats. LEW rats did not respond to HEWL. Evaluation of tertiary immune response to PBMC revealed DTH and antibodies to xenoantigens was inhibited. These data demonstrated orally-induced immune deviation and bystander suppression in rats given PBMC that may favor discordant xenograft survival and suggests a method to suppress xenogeneic immunity in high responders by repeated immunization with xenoantigens.