SUPPRESSION OF IN-VIVO IGE AND TISSUE IL-4 MESSENGER-RNA INDUCTION BYSDZ 280.636, A SYNTHETIC MURAMYL DIPEPTIDE DERIVATIVE

Modulation of IgE isotype expression on B cells is one of the numerous effects of muramyl peptides on the regulation of the immune system. A non toxic diacyl glycerol derivative of muramyl dipeptide (MDP), in w hich the L-alanine is replaced by L-threonine (MDP-Threo-GDP; SDZ 280. 636), is currently under investigation as lead compound for the develo pment of an anti-allergic drug. In this report, the modulatory effect of orally administered SDZ 280.636 in a murine model on polyclonally i nduced IgE levels is described. In this model, mice are injected i.v. with goat anti mouse IgD (GAMD) and challenged three to four weeks lat er with goat IgG (GIG). Both the primary and secondary immune response s lead to an increase of serum IgE levels. We demonstrate the efficacy of this muramyl dipeptide derivative in selectively inhibiting a poly clonal IgE response in GAMD-primed, GIG challenged mice without affect ing the levels of other immunoglobulin classes. It is further shown th at the induction of interleukin 4 (IL-4) gene transcript levels in lym phoid organs, which is observed as a consequence of boosting GAMD pret reated mice with GIG, is selectively suppressed in gut associated lymp hoid tissues (GALT) and mesenteric lymph nodes hut not in spleen. In c ontrast, interleukin 13 (IL-13) mRNA levels are not affected by SDZ 28 0.636. The findings that SDZ 280.636 inhibits polyclonal IgE responses and suppresses IL-4, but not IL-13 mRNA expression point towards diff erences in the regulatory pathways of IL-4 and IL-13 gene transcriptio n in lymphoid organs. Thus the mechanism of action appears to involve a specific suppression of IL-4 gene transcription in cells occurring i n Peyer's patches and mesenteric lymph nodes which are among the first constituents of the immune system encountered by an orally administer ed drug.