We propose that immunologic tolerance to self-antigens is due to the production of specific antibody against the antigen combining sites in the receptors of self-reactive lymphoid cells. Generation of this suppressive antibody is dependent upon an early auto-aggressive response in which proliferation of self-reactive lymphoid clones quantitatively favors presentation of their receptors as antigens. Combining sites are qualitatively good antigens in the pretolerant animal because they are associated with antigens that can serve as recognition sites for those thymic lymphocytes that are necessary to trigger the production of antibody. Thus, self-antigens adjacent to combining sites can serve as carriers to promote antibody responses against the combining sites. Antibody generated against the self-reactive combining sites in this early interval suppresses the selfreactive cells and establishes tolerance.
We postulate that, after tolerance has been established, the immune response is regulated primarily by the interactions between receptors, foreign antigen, and antigen-specific antibody. This theory on the generation of tolerance by production of antibody to combining sites would explain a number of observations on graft-versus-host disease, neonatal chimeric tolerance, establishment of new transplantation tolerance in adult radiation chimeras, and the failure of young animals to produce significant amounts of antibody against foreign antigens.