Specificity, duration and mechanism of idiotype suppression induced by neonatal injection of monoclonal anti-idiotope antibodies into mice.

Monoclonal antibodies detecting idiotopes on the germ line-encoded anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) antibody B1-8 were injected at various doses into newborn mice and the expression of B1-8 idiotopes was measured in anti-NP responses in later life. Suppression was long lasting, and a 100-fold increase in the dose of anti-idiotope delayed recovery from suppression by 5-6 weeks. Upon injection of a single anti-idiotope, suppression was observed for all B1-8 idiotopes to various degrees. Certain idiotopically defined antibody phenotypes were much more efficiently suppressed, and later recovered from suppression, than others. This specificity pattern was observed at the level of both B and T cells from the manipulated animals, as demonstrated in cell transfer experiments in which such cells were mixed with normal T and B cells. In these experiments, there was evidence for suppression mediated by regulatory T (and possibly also B) cells. Whereas the B cells from the manipulated animals were idiotypically unresponsive in a T cell-dependent adoptive primary response, the frequency of lipopolysaccharide-reactive B cells expressing the target idiotype was only slightly reduced in these animals as compared to control mice. Together with data on the elimination of anti-idiotope antibody from the neonatally injected animals these results are interpreted in the following way: idiotype suppression is induced through the reaction of anti-idiotope with idiotopes expressed on the surface of newly generated B cells, at microgram concentrations of anti-idiotope. When the concentration of anti-idiotope fall below that level, recovery from suppression sets in. Two types of suppression are induced. The first, namely, direct blockade of B cell maturation, is short-lived. The second involves the induction of regulatory cells, perhaps through idiotope-bearing antibody V regions complexed by anti-idiotope. This type of suppression is long-lived and its specificity depends upon the distribution of the target idiotope in the antibody repertoire and/or peculiarities of the T cell receptor repertoire. It impinges on the selection of the B cell repertoire in the animal as expressed in T cell-dependent (and possibly other) responses and is thus hardly seen at the level of lipopolysaccharide-reactive (immature) cells. Idiotype suppression by regulatory cells may be perpetuated by antigen interacting with idiotypic antibodies on the B cell surface and may therefore play a role in establishing tolerance not only for the expressed antibody repertoire, but for self antigens in general.