Tolerance induction during ontogeny. III. Carrier recognition by the immature and adult immune system determines tolerogenicity of hapten-carrier conjugates.

Hapten-specific B-cell tolerance may be induced by nonimmunogenic hapten derivatives of carboxylmethylcellulose or methylcellulose (MC) in adult, neonatal, or irradiated fetal liver reconstituted mice. Such tolerance was shown to occur independent of T cells, and a receptor blockade has been ruled out as a causative mechanism. Oxidation and subsequent reduction of the vicinal hydroxyl groups of both carriers significantly reduces their tolerogenic potential in adult mice, yet their hapten derivatives remain nonimmunogenic. Such chemical modification of the carrier does not affect the molecular weight and not only does not reduce the binding avidity but increases it for either free antibody- or antigen-binding cells. We have examined the ability of the immature immune system to functionally discriminate between the nominal and the chemically modified hapten conjugate. Like adult mice, the immunologically immature animals were invariably capable of distinguishing between the tolerogenic and the nontolerogenic carrier. Mice treated during ontogenic development with 2,4-dinitrophenyl (DNP)-MC were found to be hapten specifically tolerant when challenged at 4 weeks of age with the TI-2 antigen DNP-Ficoll (F) but not when challenged with the polyclonal activator lipopolysaccharide (LPS) or the TI-1 antigen DNP-Brucella. Moreover, neonatal mice treated for 8 weeks with 2,4,6-trinitrophenyl-ovalbumin (TNP-OVA) were hapten specifically tolerant when challenged with TNP-OVA or the TI-1 antigen TNP-LPS but responded to a challenge with the TI-2 antigen TNP-F. These data suggest that B-cell tolerance in adult as well as in immunologically immature mice is not only carrier dependent but, in addition, that the carrier selects the B subpopulation to be rendered unresponsive. The most popular version of the clonal abortion hypothesis puts no constraints upon the nature of the antigen as long as the B cell is ontogenically "predisposed" toward being rendered unresponsive upon contact with a ligand of sufficiently high binding avidity. Our data are at variance with this prediction.