Interleukin 4 receptor targeted cytotoxicity: genetic construction and in vivo immunosuppressive activity of a diphtheria toxin-related murine interleukin 4 fusion protein.
The interleukin 4 (IL 4) receptor is expressed on various cells of the immune system, including T and B lymphocytes, macrophages and mast cells. We have constructed a recombinant protein, DAB389-mIL 4, that is composed of the enzymatically active and membrane translocation domains of diphtheria toxin fused to murine IL 4. We demonstrate that this fusion toxin selectively inhibits protein synsthesis in eukaryotic cells which express the murine IL 4 receptor. The cytotoxic potency of this fusion toxin is shown to be directly proportional to the reported number of IL 4 receptors on the surface of target cells. Since the action of DAB389-mIL 4 can be blocked with either excess mIL 4 or antibody to mIL 4, we conclude that its entry into target cells is mediated through the mIL 4 receptor. A mutant form of DAB389-mIL 4, DA(197)B389-mIL 4, in which the fragment A-associated ADP-ribosyltransferase is inactive, is not cytotoxic to murine IL 4 receptor-bearing cells. Finally, we demonstrate that DAB389-mIL 4 administered subcutaneously to DBA/2 mice results in suppression of delayed-type hypersensitivity (DTH); whereas, the non-toxic DA(197)B389-mIL 4 fails to dampen the DTH response.
Evans Department of Clinical Research, University Hospital, Boston, MA 02118.
F
F
Lakkis
A
A
Steele
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A
Pacheco-Silva
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V
Rubin-Kelley
T B
TB
Strom
J R
JR
Murphy
D000818:Animals; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004167:Diphtheria Toxin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D006968:Hypersensitivity, Delayed / Q000188:drug therapy; D007108:Immune Tolerance / Q000187:drug effects*; D000922:Immunotoxins / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D010957:Plasmids / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D011993:Recombinant Fusion Proteins / Q000494:pharmacology
C054780:DAB(486)-interleukin 2; D004167:Diphtheria Toxin; D000922:Immunotoxins; D007376:Interleukin-2; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D011993:Recombinant Fusion Proteins