A CHIMERIC PROTEIN COMPRISED OF IL-4 AND PSEUDOMONAS EXOTOXIN IS CYTOTOXIC FOR ACTIVATED HUMAN-LYMPHOCYTES

IL4-Pseudomonas exotoxin (IL4-PE4E) is a chimeric molecule in which hu man IL-4 is genetically fused to the mutated binding domain of Pseudom onas exotoxin. This molecule binds specifically to human IL-4 receptor -bearing cells. IL4-PE4E was extremely cytotoxic to highly purified an ti-CD3-activated CD8(+) T lymphocytes. The cytotoxic activity of this molecule was dependent on the activation state of CD8(+) T cells: 3- a nd 4-day activated T cells were very susceptible to the cytotoxic acti vity of IL4-PE4E compared with 0- to 2-day activated cells. PHA-activa ted lymphocytes and PBL activated in mixed lymphocyte reaction were al so highly sensitive to IL4-PE4E. CD16(+) and/or CD56(+) highly purifie d NK cells or highly purified, Ii-a-activated NK cells were also very sensitive to the cytotoxic effect of IL4-PE4E. IL-2-activated LAK cell s had little susceptibility after 1 day but were very sensitive to IL4 -PE4E after 3 days. The cytotoxic effects of IL4-PE4E were mediated th rough a ligand receptor interaction because excess rIL-4 abrogated the se effects as did a neutralizing Ab to human IL-4. A chimeric mutant p rotein that can bind to IL-4 receptors but lacks the ability to inhibi t protein synthesis was not cytotoxic to activated lymphocytes. The IL 4-PE4E-mediated cytotoxicity of activated T cells correlated with the level of expression of IL-4 receptors on these cells. CD8+ T cells act ivated for 3 days expressed the highest density of IL-4 receptors comp ared with 1- or 2-day activated cells. Among two chimeric toxins teste d only IL4-PE4E was cytotoxic to 2-day anti-CD3-activated CD8+ T lymph ocytes, whereas IL6-PE4E was not active at all. These studies suggest that human IL4 toxin could be a potent agent for the elimination of ac tivated lymphocytes in allograft rejection, some autoimmune diseases, or treatment of lymphomas and leukemias.