The
anti-asthmatic agent andolast is thought to inhibit the release of allergic mediators, but its mechanism of action is not fully understood. We investigated whether the compound inhibits
immunoglobulin E (
IgE) synthesis and tested the hypothesis that
andolast affects immunoglobulin class switching.
Interleukin (IL)-4 and the interaction of CD40 expressed on B cells with its
ligand on T cells are necessary for
IgE synthesis. Thus, peripheral blood mononuclear cells (PBMCs) from 40 asthmatic, 16 non-asthmatic allergic, and 9 normal donors were stimulated with
IL-4 and/or anti-CD40 antibody. T cells from 9 additional allergic donors were activated with anti-CD3/CD28
antibodies to express
IL-4 mRNA. After incubation in the absence or presence of test compounds,
immunoglobulin concentrations were measured by
enzyme immunoassay, and
mRNA levels were analyzed by RT-PCR.
Andolast significantly inhibited
IgE synthesis by stimulated PBMCs from both
asthma patients and combined allergic/normal donors. In mechanistic studies,
andolast was found to act at different cellular levels. Firstly, it reduced by about 45 percent (p<0.05) the levels of
IL-4 mRNA in T cells stimulated with anti-CD3/CD28. Secondly,
andolast reduced by about 36 percent (p<0.05) the expression of epsilon germline transcripts in PBMCs stimulated with IL-4/anti-CD40. Thirdly, the effect of
andolast on
immunoglobulin synthesis was selective in that the production of
IgG4 antibodies was not significantly inhibited. Our findings, while supporting the evidence that
andolast is effective for the treatment of
asthma, provide new insights into its mechanism of action.