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Abstract
A recently developed in vitro system for antigen-stimulated primary and secondary
murine IgE antibody responses has been used to define (a) the relative participation
of the Th1 and Th2 cell-derived lymphokines IFN-gamma and IL-4, respectively, in such
responses, and (b) the role of antigen concentration in determining functional helper
T cell activity. These studies confirm that IL-4 and IFN-gamma exert regulatory effects
on IgE synthesis, but the nature and extent of their respective effects on primary
and secondary IgE responses differ. Thus, primary IgE responses are considerably more
sensitive to and dependent on IL-4 than are secondary IgE responses since (1) anti-IL-4
monoclonal antibody totally inhibited primary IgE responses, but only partially affected
secondary responses; and (2) exogenously added IL-4 could stimulate primary IgE responses
to optimal antigen concentrations, but had no effect on secondary IgE production.
Likewise, antigen-stimulated primary IgE responses are about eightfold more sensitive
than are secondary responses to the inhibitory effects of IFN-gamma. Studying the
effect of antigen dose on the quantity of IgE antibody produced revealed that although
IFN-gamma could be detected by ELISA in cultures exhibiting high-dose antigen-dependent
diminution of IgE production, anti-IFN-gamma monoclonal antibody could not reverse
this phenomenon. Thus, IFN-gamma is not solely responsible for decreased IgE synthesis
associated with high-dose antigen exposure. IL-4 activity was detected in the fluid
from cultures stimulated with low, but not high, levels of antigen. Moreover, addition
of exogenous IL-4 restored IgE production to normal levels in cultures exposed to
high antigen concentrations. Therefore, it appears that high levels of antigen result
in selective stimulation of Th1 cells which produce IFN-gamma, and diminished activation
of IL-4-producing Th2 cells. These results help explain observations regarding the
influence of antigen dose on the generation of experimental and clinical IgE antibody
responses in vivo.