AN IMMUNE CELL-SELECTIVE INTERLEUKIN-4 AGONIST

Interleukin 4 (IL-4) is a pleiotropic cytokine. Og the cell types resp onsive to IL-4, T cells express one IL-4 receptor (IL-4R) type, IL-4R alpha/IL-2R gamma (class I IL-4R), whereas endothelial cells express a nother type, IL4R alpha/IL-13R alpha (class II IL-4R). It was hypothes ized that IL-4 variants could be generated that would be selective for cell types expressing the different IL-4Rs. a series of IL-4 muteins were generated that were substituted its the region of IL-4 implicated in interactions with IL-2R gamma. These muteins were evaluated in T c ell and endothelial cell assays. One of these muteins, containing the mutation Arg-121 to Glu (IL-4/R121E), exhibited complete biological se lectivity for T cells, B cells, and monocytes, but showed no activity on endothelial cells. Receptor binding steadies indicated that IL-4/R1 21E retained physical interaction with IL-2R gamma bat not IL-13R alph a; consistent with this observation, IL-4/R121E was an antagonist of I L-4-induced activity on endothelial cells. IL-4/R121E exhibits a spect rum of activities in vitro that suggest utility in the treatment of ce rtain autoimmune diseases.