Secondary immunization with a protein antigen (tetanus toxoid) in man. Characterization of humoral and cell-mediated regulatory events.

Abstract

Tetanus toxoid (TET) was used as an immunogen to explore regulatory events occurring after secondary immunization in man. Changes in dose-response patterns, kinetics, and frequency of antigen-reactive cells in the peripheral blood, and the serum antibody titres were studied. The most striking feature of these studies was the finding that immediately after immunization, a brief period of decreased responsiveness preceded the expected amplification of antigen-specific humoral and cell-mediated responses. One day after immunization serum antibody levels declined to approximately half their initial values before the expected increase in titre. These results could not be explained by the formation of antigen-antibody complexes. Lymphoproliferative responses were also depressed 1 day after immunization but increased in both magnitude and sensitivity from 7 to 28 days after challenge. A decrease in thymidine incorporation evident at supraoptimal antigen concentrations also became progressively more prominent during this interval. Cell mixing experiments documented the presence of a radioresistant population present 1 day after immunization capable of suppressing TET-specific lymphoproliferative responses of autologous lymphocytes obtained before immunization. These suppressors are preferentially activated at high antigen concentrations. Limiting dilution analysis revealed a 30-fold increase in TET-reactive proliferating cells by 28 days after immunization. Expansion occurred first in cells recognizing high antigen concentrations and subsequently in cells recognizing lower doses. Taken together, these findings present a consistent if somewhat counterintuitive picture of some of the regulatory processes accompanying booster immunization. The earliest detectable event appears to be the application of an active suppressor mechanism, release from which signals initiation of those processes classically associated with an anamnestic response.