Hyperreactivity of adult BALB/c mice tolerized at birth with TNP-ovalbumin.

BALB/c mice injected with 0.2 mg TNP-ovalbumin (OA) within 24 hours after birth showed reduced levels of functionally active TNP-specific B cells and, accordingly, of plaque-forming cells (PFC) after challenge with carrier-bound TNP until the age of 8 weeks. Yet, when B cells of tolerized mice were cultured in the absence of antigen, a significant number of anti-TNP PFC were detected. Challenge of neonatally tolerized mice at older age with T-dependent or T-independent antigens led to a continuously increasing response towards TNP, which was dominated by IgG-producing B cells. At the age of 8 months, a five-fold augmentation of TNP-specific B cells and of anti-TNP antibodies (AB), as compared to animals treated accordingly as adults, was observed. Clonal analysis of regulatory cells revealed 2 populations of helper (Th1 and Th2) and suppressor (Ts1 and Ts2) T cells in spleen cells (SC) of tolerized mice. In SC of mice immunized as adults, Th1 and Th2, but only one Ts populations were observed. The frequencies of Th1 and Ts1 were in the same range in animals immunized neonatally or as adults. After challenge, frequencies of regulatory cells remained constant in animals immunized as adults. But, in neonatally tolerized mice, challenge resulted in increased frequencies of Th1 and Th2; Ts1 remained constant, and concomitantly the frequency of Ts2 declined significantly. The data are interpreted as newborn tolerance being due to transient B cell anergy via receptor blockade as well as inactivation of AB-producing cells. Neither deficiency in TNP-specific help nor dominance of TNP-specific suppression is involved in maintainance of tolerance, but tolerance appears to be sustained by interference of TNP-specific regulatory cells with anti-idiotypic regulatory cells (Th2, Ts2). Supposing a system of circular network interactions, activation of anti-idiotypic clones will be counterregulated/balanced by activation of antigen-specific clones. Thus, decreasing idiotypic connectivity during life may result in overshooting reactivity of neonatally tolerized mice at older age.