Suppression of in vivo IgE and tissue IL-4 mRNA induction by SDZ 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 which the L-alanine is replaced by L-threonine (MDP-Threo-GDP; SDZ 280.636), is currently under investigation as lead compound for the development of an anti-allergic drug. In this report, the modulatory effect of orally administered SDZ 280.636 in a murine model on polyclonally induced IgE levels is described. In this model, mice are injected i.v. with goal anti mouse IgD (GAMD) and challenged three to four weeks later with goal IgG (GIG). Both the primary and secondary immune responses lead to an increase of serum IgE levels. We demonstrate the efficacy of this muramyl dipeptide derivative in selectively inhibiting a polyclonal IgE response in GAMD-primed, GIG challenged mice without affecting the levels of other immunoglobulin classes. It is further shown that the induction of interleukin 4 (IL-4) gene transcript levels in lymphoid organs, which is observed as a consequence of boosting GAMD pretreated mice with GIG, is selectively suppressed in gut associated lymphoid tissues (GALT) and mesenteric lymph nodes but not in spleen. In contrast, interleukin 13 (IL-13) mRNA levels are not affected by SDZ 280.636. The findings that SDZ 280.636 inhibits polyclonal IgE responses and suppresses IL-4, but not IL-13 mRNA expression point towards differences in the regulatory pathways of IL-4 and IL-13 gene transcription in lymphoid organs. Thus the mechanism of action appears to involve a specific suppression of IL-4 gene transcription in cells occurring in Peyer's patches and mesenteric lymph nodes which are among the first constituents of the immune system encountered by an orally administered drug.
Kricek
F
F
Sandoz Research Institute, Vienna, Austria. kricek@al.wienvl.sandoz.com
Zunic
M
M
Ruf
C
C
De Jong
G
G
Dukor
P
P
Bahr
G M
GM
D000818:Animals; D004151:Dipeptides / Q000494:pharmacology*; D005260:Female; D006041:Goats; D007072:Immunoglobulin D / Q000494:pharmacology; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000097:blood; D007074:Immunoglobulin G / Q000494:pharmacology; D007132:Immunoglobulin Isotypes / Q000097:blood; D015847:Interleukin-4 / Q000096:biosynthesis*; D008221:Lymphoid Tissue / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000096:biosynthesis*; D014158:Transcription, Genetic
D004151:Dipeptides; D007072:Immunoglobulin D; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D012333:RNA, Messenger; C106787:SDZ 280.636; D015847:Interleukin-4; D007073:Immunoglobulin E