INTERLEUKIN-4 RECEPTOR EXPRESSION BY HUMAN B-CELLS - FUNCTIONAL-ANALYSIS WITH A HUMAN INTERLEUKIN-4 TOXIN, DAB(389)IL-4

Background: Studies of hyman IgE-secreting B cells have proven difficu lt because of the small size of this population. We have used an inter leukin-4 (IL-4) fusion toxin to detect functionally IL-4 receptor (IL- 4R) expression on B cells involved in IgE synthesis. Methods: In dipht heria toxin IL-4 (DAB(389)IL-4) the receptor-binding domain of diphthe ria toxin has been replaced with human IL-4. DAB(389)IL-4 cytotoxicity depends on IL-4R binding and internalization. Results: Addition of DA B(389)IL-4 inhibited IgE synthesis induced by IL-4(+) anti-CD40 monocl onal antibody or hydrocortisone. IgE inhibition resulted from DAB(389) IL-4 B-cell cytotoxicity because DAB(389)IL-4 inhibited IL-4-independe nt B-cell proliferation. Thus induction of human IgE synthesis involve s IL-4R(+) cells. In contrast, terminally differentiated, IgE-producin g B cells no longer express functional IL-4R because DAB(389)IL-4 only modestly inhibited ongoing IgE synthesis by B cells from patients wit h hyper-IgE states and only minimally affected IL-4-induced IgE synthe sis in normal B cells when the toxin was added at day 7. Pokeweed mito gen-induced IgM synthesis was sensitive to early but not to late addit ion of DAB(389)IL-4. Thus the loss of functional IL-4R immunoglobulin- secreting B cells is independent of isotype switching. Conclusions: Ig E-secreting B cells no longer express functional IL-4R. Therapies for allergic disease that target the IL-4R would not affect IgE-secreting B cells but may block the recruitment of B cells into the IgE-secretin g pool. For optimal benefits this approach may be combined with therap ies that target IL-4R-, IgE-secreting B cells.