Human IgE receptor alpha-chain IgG chimera blocks passive cutaneous anaphylaxis reaction in vivo.
Cross-linking of the high affinity IgE receptor (Fc epsilon RI) expressed on mast cells and basophils is essential for triggering anaphylaxis in vivo. Previously, other investigators have tried to produce competitive inhibitors using IgE peptide analogues and anti-IgE antibodies with limited success. To create a novel specific inhibitor of IgE that can block binding of IgE to Fc epsilon RI without the capacity to stimulate degranulation, we made an Fc epsilon RI-IgG immunoadhesin. The Fc epsilon RI-IgG was constructed by gene fusion of the extracellular portion of the human alpha-chain of Fc epsilon RI, which contains the high affinity binding site for IgE, with a truncated human IgG1 H chain C region. The Fc epsilon RI-IgG recognizes both human and murine IgE. Coincubation of Fc epsilon RI-IgG with murine IgE prevented sensitization of RBL-2H3 cells and the subsequent histamine release in response to anti-IgE. Similarly, when the Fc epsilon RI-IgG was preincubated with equimolar concentrations of either hyperimmune mouse sera or purified mouse IgE, it completely blocked the passive cutaneous anaphylaxis reaction in rats. Furthermore, i.v. administration of Fc epsilon RI-IgG following intracutaneous injection of serum from DNP-immunized mice was able to block the passive cutaneous anaphylaxis reaction in a time-dependent fashion. These results demonstrate that Fc epsilon RI-IgG is a potent inhibitor of IgE binding to intracutaneous mast cells in vivo and may prove clinically useful for the treatment of IgE-mediated disease.
Haak-Frendscho
M
M
Department of Immunology, Genentech, Inc., South San Francisco, CA 94080.
Ridgway
J
J
Shields
R
R
Robbins
K
K
Gorman
C
C
Jardieu
P
P
D000595:Amino Acid Sequence; D000818:Animals; D001491:Basophils / Q000378:metabolism; D002460:Cell Line; D006636:Histamine Release; D007073:Immunoglobulin E / Q000378:metabolism* / Q000494:pharmacology; D007074:Immunoglobulin G / Q000737:chemistry*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010323:Passive Cutaneous Anaphylaxis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017455:Receptors, IgE / Q000737:chemistry*; D011993:Recombinant Fusion Proteins
D007074:Immunoglobulin G; D017455:Receptors, IgE; D011993:Recombinant Fusion Proteins; D007073:Immunoglobulin E