Apoptosis-inducing human-origin Fcepsilon-Bak chimeric proteins for targeted elimination of mast cells and basophils: a new approach for allergy treatment.
During the past few years, many chimeric proteins have been developed to specifically target and kill cells expressing specific surface molecules. Generally these molecules carry a bacterial or plant toxin to destroy the unwanted cells. The major obstacle regarding these molecules in their clinical application is the immunogenicity and nonspecific toxicity associated with bacterial or plant toxins. We lately reported a new approach for construction of chimeric proteins: we successfully replaced bacterial or plant toxins with human apoptosis-inducing proteins. The resulting chimeras were shown to specifically induce apoptosis in the target cells. Taking advantage of the human apoptosis inducing proteins Bak and Bax as novel killing components, we have now constructed new chimeric proteins targeted against the human FcepsilonRI, expressed mainly on mast cells and basophils. These cells are the main effectors of the allergic response. Treatment of the target cells with the new chimeric proteins, termed Fcepsilon-Bak/Bax, had a dramatic effect on cell survival, causing apoptosis. The effect was specific to cells expressing the FcepsilonRI of both human and, very unexpectedly, also of mouse origin. Moreover, interaction of the chimeric proteins with the mast cells did not cause degranulation. Fcepsilon-Bak/Bax are new chimeric proteins of human origin and, as such, are expected to be both less immunogenic and less toxic and, thus, may be specific and efficient reagents for the treatment of allergic diseases.
Belostotsky
R
R
Department of Cellular Biochemistry and Human Genetics, Hebrew University, Hadassah Medical School, Jerusalem, Israel.
Lorberboum-Galski
H
H
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001491:Basophils / Q000187:drug effects*; D015550:Cell Degranulation / Q000187:drug effects; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D006967:Hypersensitivity / Q000628:therapy; D007073:Immunoglobulin E / Q000235:genetics / Q000494:pharmacology; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects*; D008565:Membrane Proteins / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D017455:Receptors, IgE; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D050998:bcl-2 Homologous Antagonist-Killer Protein
D018926:Anti-Allergic Agents; C494772:BAK1 protein, human; C494773:Bak1 protein, mouse; D007141:Immunoglobulin Fc Fragments; D008565:Membrane Proteins; D017455:Receptors, IgE; D011993:Recombinant Fusion Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D007073:Immunoglobulin E