Inhibition of orally-induced immune tolerance in mice by prefeeding an endopeptidase inhibitor

Intragastric feeding of T-dependent protein antigens to mice induces substantial systemic tolerance in specific antibody and cell-mediated immune responses. To evaluate the role of gastrointestinal digestion in this phenomenon, the trypsin inhibitor aprotinin was fed to adult BDF₁ mice prior to tolerogenic feedings of ovalbumin or human gamma globulin. As assessed by measurement of protein-specific antibody responses, aprotinin significantly reduced tolerance induced by feeding carrier protein, but not tolerance induced by parenteral antigen injection. Aprotinin also reduced oral tolerance to ovalbumin as measured by delayed-type hypersensitivity and T cell proliferative responses. However, aprotinin did not alter antibody tolerance to a carrier-associated hapten in the same animals. Feeding of human gamma globulin concomitantly with aprotinin induced specific antibody responses without further immunization, and reduced subsequent tolerance. Aprotinin also increased the level of immunologically detectable ovalbumin found in the serum following antigen feeding. The data support the hypothesis that aprotinin indirectly mediated changes in specific stimuli available to the lymphoid system as a result of alterations in gastrointestinal processing of fed antigens rather than to direct effects of aprotinin upon systemic immune responses.