Inhibition of CD23 processing correlates with inhibition of IL-4-stimulated IgE production in human PBL and hu-PBL-reconstituted SCID mice.
BACKGROUND
CD23, the low affinity serum immunoglobulin E (IgE) receptor, is upregulated on B cells following interleukin (IL)-4 stimulation and is concomitantly cleaved to generate soluble CD23 (sCD23) fragments with cytokine-like activity.


OBJECTIVE
Compounds that selectively inhibit the proteolytic release of CD23 to generate sCD23 were assessed for their ability to inhibit IgE production in order to evaluate the contribution of sCD23 in the production of human IgE as well as the ability of such compounds to block IgE production.


METHODS
IgE production was measured in IL-4-stimulated human peripheral blood lymphocytes (PBL) and PBL-reconstituted SCID mice in the presence of a broad-spectrum matrix metalloprotease (MMP) inhibitor, a compound selective for inhibition of CD23 processing over MMPs and an anti-CD23 mAb, MHM6.


RESULTS
The two compounds were equipotent in inhibiting IgE production without inhibition of IgG production by IL-4/anti-CD40-stimulated PBL. Soluble CD23 release was also shown to precede IgE accumulation in the cell-free medium. Addition of compound at later times other than day 0 in the 14 day assay resulted in progressively less inhibition of both IgE and sCD23, and exactly paralleled the effect of an anti-CD23 mAb, MHM6 on IgE levels. Both compounds also inhibited the release of CD23 from human RPMI 8866 cells adoptively transferred i. p. to mice. Doses required for inhibition of CD23 correlated well with the doses required for inhibition of IgE production in IL-4-challenged hu-PBL-SCID mice. IgE was selectively inhibited over total IgG in the SCID mice as well.


CONCLUSIONS
Inhibition of CD23 processing alone is sufficient to inhibit IL-4-stimulated IgE production both in vitro and in vivo.
Mayer
R J
RJ
Department of Immunology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
Bolognese
B J
BJ
Al-Mahdi
N
N
Cook
R M
RM
Flamberg
P L
PL
Hansbury
M J
MJ
Khandekar
S
S
Appelbaum
E
E
Faller
A
A
Marshall
L A
LA
D000818:Animals; D002678:Chimera; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D017710:Lymphocyte Transfusion; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D016513:Mice, SCID; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000276:immunology*; D017455:Receptors, IgE / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D061965:Matrix Metalloproteinase Inhibitors; D010446:Peptide Fragments; D017455:Receptors, IgE; D015847:Interleukin-4; D007073:Immunoglobulin E