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A chimeric protein comprised of IL-4 and Pseudomonas exotoxin is cytotoxic for activated human lymphocytes.

R K Puri, P T Mehrotra, P Leland, R J Kreitman, J P Siegel and I Pastan
J Immunol April 1, 1994, 152 (7) 3693-3700;
R K Puri
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P T Mehrotra
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P Leland
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R J Kreitman
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J P Siegel
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I Pastan
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Abstract

IL4-Pseudomonas exotoxin (IL4-PE4E) is a chimeric molecule in which human IL-4 is genetically fused to the mutated binding domain of Pseudomonas exotoxin. This molecule binds specifically to human IL-4 receptor-bearing cells. IL4-PE4E was extremely cytotoxic to highly purified anti-CD3-activated CD8+ T lymphocytes. The cytotoxic activity of this molecule was dependent on the activation state of CD8+ T cells: 3- and 4-day activated T cells were very susceptible to the cytotoxic activity of IL4-PE4E compared with 0- to 2-day activated cells. PHA-activated lymphocytes and PBL activated in mixed lymphocyte reaction were also highly sensitive to IL4-PE4E. CD16+ and/or CD56+ highly purified NK cells or highly purified, IL-2-activated NK cells were also very sensitive to the cytotoxic effect of IL4-PE4E. IL-2-activated LAK cells had little susceptibility after 1 day but were very sensitive to IL4-PE4E after 3 days. The cytotoxic effects of IL4-PE4E were mediated through a ligand receptor interaction because excess rIL-4 abrogated these effects as did a neutralizing Ab to human IL-4. A chimeric mutant protein that can bind to IL-4 receptors but lacks the ability to inhibit protein synthesis was not cytotoxic to activated lymphocytes. The IL4-PE4E-mediated cytotoxicity of activated T cells correlated with the level of expression of IL-4 receptors on these cells. CD8+ T cells activated for 3 days expressed the highest density of IL-4 receptors compared with 1- or 2-day activated cells. Among two chimeric toxins tested only IL4-PE4E was cytotoxic to 2-day anti-CD3-activated CD8+ T lymphocytes, whereas IL6-PE4E was not active at all. These studies suggest that human IL4 toxin could be a potent agent for the elimination of activated lymphocytes in allograft rejection, some autoimmune diseases, or treatment of lymphomas and leukemias.

  • Copyright © 1994 by American Association of Immunologists

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The Journal of Immunology
Vol. 152, Issue 7
1 Apr 1994
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A chimeric protein comprised of IL-4 and Pseudomonas exotoxin is cytotoxic for activated human lymphocytes.
R K Puri, P T Mehrotra, P Leland, R J Kreitman, J P Siegel, I Pastan
The Journal of Immunology April 1, 1994, 152 (7) 3693-3700;

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A chimeric protein comprised of IL-4 and Pseudomonas exotoxin is cytotoxic for activated human lymphocytes.
R K Puri, P T Mehrotra, P Leland, R J Kreitman, J P Siegel, I Pastan
The Journal of Immunology April 1, 1994, 152 (7) 3693-3700;
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Print ISSN 0022-1767        Online ISSN 1550-6606