Mechanism of neonatally induced idiotype suppression and its relevance for the acquisition of self-tolerance.

We present an analysis of the elimination of a monoclonal anti-idiotope antibody injected into C57BL/6 mice on the day of birth. During the first 4 weeks of life the antibody is eliminated from the circulation with a slow half-life, ranging from 15-18 days. This finding makes sense biologically as the animals depend at that time on maternally transmitted antibodies. After 4 weeks elimination speeds up considerably. The rate of elimination appears to be the same for a 1 microgram and a 100 microgram dose. The elimination data and previous results on the specificity, duration and cellular basis of idiotype suppression induced by the monoclonal anti-idiotope fit into the following model of idiotype suppression, which is in good accord with other experimental evidence on idiotype and allotype suppression in the literature: suppression depends strictly on the concentration of anti-idiotope in the cellular environment. As long as it is in the microgram range, the generation of idiotope-bearing B cells from pre-B cells is prevented. The system recovers quickly from this type of suppression, as soon as the concentration of anti-idiotope falls below that range. A second type of suppression is also induced in the anti-idiotope-treated animals. It is long-lived (8-10 weeks longer that the first type), has a peculiar specificity in that it affects, in our particular case, only a certain subset of the antibodies bearing the target idiotope, and involves regulatory T (and possibly B) cells which prevent the functional maturation of B cells expressing those antibodies in the animal. Suppression of this type also depends strictly on anti-idiotope concentration and is induced either at the time when the generation of idiotope-bearing B cells from pre-B cells is still inhibited or just thereafter, when such cells begin to appear in the system and the anti-idiotope concentration is still at a few hundred nanograms per ml. Experimental evidence indicates that in the induction of suppression, the primary target of the anti-idiotope are idiotope-bearing antibodies variable regions. We assume that those variable regions, complexed by anti-idiotope are the inducers of regulatory (suppressive) T cells. Idiotype suppression may also be induced upon interaction of antibody variable regions (and possibly other receptors) with ligands other than anti-idiotypic antibodies. We, therefore, think that idiotype suppression not only establishes self-tolerance within the antibody system, but is a mechanism of self-tolerance in general.