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Interleukin 4 receptor targeted cytotoxicity: Genetic construction and in vivo immunosuppressive activity of a diphtheria toxin‐related murine interleukin 4 fusion protein

1991; Wiley; Volume: 21; Issue: 9 Linguagem: Inglês

10.1002/eji.1830210937

1521-4141

Fadi G. Lakkis, Alan W. Steele, Álvaro Pacheco‐Silva, Vicki E. Rubin‐Kelley, Terry B. Strom, John R. Murphy,

Clostridium difficile and Clostridium perfringens research

Abstract 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, DAB 389 ‐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 DAB 389 ‐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 DAB 389 ‐mIL 4, DA(197)B 389 ‐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 DAB 389 ‐mIL 4 administered subcutaneously to DBA/2 mice results in suppression of delayed‐type hypersensitivity (DTH); whereas, the non‐toxic DA(197)B 389 ‐mIL 4 fails to dampen the DTH response.