Induction of IgE class-restricted tolerance was studied in high IgE-responder (BALB/c X SJL)F1 mice, of which the parental BALB/c and SJL mice are high and low IgE-responder mice, respectively. 2,4-Dinitrophenyl (DNP)-specific monoclonal IgE was administered to (BALB/c X SJL)F1 mice neonatally in two forms: soluble IgE at 250 micrograms per injection, or 10-100 ng of IgE coupled to 25-50 X 10(6) syngeneic splenocytes by binding to the chemically reactive hapten trinitrobenzene sulfonate (TNBS) or directly conjugated via a heterobifunctional reagent, N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP). Polyclonal induction of IgE class-restricted tolerance was observed in (BALB/c X SJL)F1 mice, neonatally treated with soluble IgE or IgE-conjugated syngeneic splenocytes. Thus these mice failed to mount IgE antibody responses to either keyhole limpet hemocyanin or ovalbumin challenge, assessed by the passive cutaneous anaphylaxis reaction. The IgG antibody responses to these same antigens, however, were not affected by this treatment. The IgE class-restricted tolerance induced by both forms of IgE persisted up to at least 6 mo with repeated antigenic challenges. IgE coupled to syngeneic cells by TNBS or the SPDP method induced prolonged tolerance up to 9 mo. The induction of polyclonal IgE class-restricted tolerance was achieved only by monoclonal IgE, whereas DNP-specific monoclonal IgG1 plus IgG2b coupled to syngeneic splenocytes by the SPDP method failed to modulate either IgE or IgG antibody responses. In contrast, (BALB/c X A/J)F1 mice, of which both parental strains are high IgE responders, developed IgE class-restricted tolerance upon repeated neonatal injection of soluble IgE, but not IgE-conjugated syngeneic splenocytes, indicating that gene products of the low IgE-responder mice contributed to the effective presentation and/or recognition of epsilon heavy chain of the IgE molecules. Taken collectively, these results demonstrated that non-antigen-specific, isotype-restricted tolerance can be induced in the IgE antibody system. The differential induction of IgE class-restricted tolerance by different forms of tolerogen in the strains studied perhaps distinguishes two underlying cellular mechanisms for IgE class-restricted tolerance.
The mechanisms of genetic control of IgE responses are exercised at different immuno-physiological levels. This study centered upon the development of IgE lineage-specific regulatory T cells. Herein, we demonstrate the following points: (a) perinatal administration of soluble self IgE molecule or self IgE complexed with foreign antigen induces IgE tolerance as manifested by antigen-specific IgE unresponsiveness and a generalized IgE immunodeficiency, and the induction of IgE tolerance does not affect antigen-specific IgG1, IgG, and IgA responses; (b) inducibility of perinatal IgE tolerance is correlated with complete absence of endogenously secreted IgE in the neonates; and the state of persistent IgE tolerance also does not correlate with the presence of high levels of circulating anti-IgE autoantibodies; (c) The lesions induced during the ontogeny of IgE antibody system do not appear to result from an imbalance of production of interleukin 4 and interferon-gamma by T helper Th2 and Th1 cells in antigen-stimulated cultures; the dual immunoregulatory lesions in T cell subsets are demonstrated: clonal anergy/deletion of CD4+ IgE Th cells and the presence of CD8+ IgE suppressor cells induced by perinatal IgE treatment. We propose that antigen/interleukin 4 activated B cells are controlled by IgE lineage-specific regulatory T cells which recognize self IgE determinant(s) on IgE committed B cells. Life-long IgE tolerance ensues as a result of a new steady state of IgE lineage-specific CD4+ and CD8+ T cell subsets.
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