MECHANISMS OF DICHOTOMOUS ACTION OF IL-2-PSEUDOMONAS EXOTOXIN-40 (IL-2-PE40) ON CELL-MEDIATED AND HUMORAL IMMUNE-RESPONSE

IL-2-PE40 is a chimeric protein composed of human IL-2 genetically fus ed to the amino terminus of a modified form of Pseudomonas exotoxin la cking its cell recognition domain. The immunosuppressive efficacy of I L-2-PE40 was demonstrated in several experimental murine transplant an d autoimmune models. However, some observations suggested that IL-2-PE 40 could not inhibit the humoral response. In this report, we describe the dichotomous effects of IL-2-PE40 on humoral and cell-mediated imm une response in a simple, well characterized in vivo model. Although I L-2-PE40 inhibited the cell-mediated delayed type hypersensitivity rea ction to SRBC, it increased the humoral immune response to the same Ag . To understand the mechanism of dichotomous action of IL-2-PE40 on th e immune response, IL-2R-bearing T cells were treated with IL-2-PE40 i n vitro and the cytokine expression was studied at mRNA and protein le vel. Similar to IL-2, IL-2-PE40 promoted the expression of T helper 1- like (IFN-gamma) as well as T helper 2-like (IL-4, IL-10) cytokines. T hese in vitro studies show that IL-2-PE40 can induce signal transducti on in activated T cells through the IL-2R before exerting its cytotoxi c effect. In contrast to DTH reaction, humoral immune response require s T cell help only for a limited period. Therefore, the short-term sti mulation of T helper cells by IL-2-PE40 may be sufficient in vivo to m ediate a B cell response in the local environment, whereas the DTH rea ction and other cell-mediated immune responses are inhibited by the to xin moiety of the chimeric protein.