Mechanisms of inhibition of IgE synthesis by nedocromil sodium: nedocromil sodium inhibits deletional switch recombination in human B cells.
IgE synthesis requires IL-4 and a T cell-B cell interaction that involves the B-cell antigen CD40 and its ligand expressed on activated T cells. Nedocromil sodium (NS), an effective prophylactic agent in asthma, inhibits IgE synthesis by human B cells. In this report we examined the mechanisms of this inhibition. NS targeted the B cells because it inhibited IgE synthesis induced by anti-CD40 and IL-4 in highly purified B cells (greater than 98% CD19+). NS had no effect on the induction of epsilon-germline transcripts by IL-4 but strongly inhibited CD40-mediated S mu --> S epsilon deletional switch recombination. The effect of NS was not specific for CD40 because it inhibited IgE synthesis in B cells stimulated with hydrocortisone plus IL-4. Moreover, the effect of NS was not specific for IgE because it inhibited CD40/IL-4-driven IgG4 synthesis by B cells sorted for lack of surface expression of IgG4. NS caused only modest inhibition of spontaneous IgE synthesis by B cells from patients with hyper-IgE syndrome, suggesting that it has little effect on B cells that have already undergone isotype switching. These results strongly suggest that NS inhibits IgE isotype switching by inhibiting deletional switch recombination and that NS has a novel potential mechanism for the prevention of asthma and other allergic diseases.
Loh
R K
RK
Children's Hospital/Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Jabara
H H
HH
Geha
R S
RS
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D001483:Base Sequence; D019013:CD40 Antigens / Q000187:drug effects / Q000276:immunology / Q000494:pharmacology; D002478:Cells, Cultured; D017353:Gene Deletion; D015322:Gene Rearrangement, B-Lymphocyte / Q000187:drug effects*; D006801:Humans; D006854:Hydrocortisone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006942:Hypergammaglobulinemia / Q000235:genetics; D017578:Immunoglobulin Class Switching / Q000187:drug effects*; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000187:drug effects; D007132:Immunoglobulin Isotypes / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008969:Molecular Sequence Data; D017835:Nedocromil / Q000494:pharmacology*; D013577:Syndrome; D014158:Transcription, Genetic / Q000187:drug effects
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007132:Immunoglobulin Isotypes; D007166:Immunosuppressive Agents; D017835:Nedocromil; D015847:Interleukin-4; D007073:Immunoglobulin E; D006854:Hydrocortisone