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 fused to the amino terminus of a modified form of Pseudomonas exotoxin lacking its cell recognition domain. The immunosuppressive efficacy of IL-2-PE40 was demonstrated in several experimental murine transplant and autoimmune models. However, some observations suggested that IL-2-PE40 could not inhibit the humoral response. In this report, we describe the dichotomous effects of IL-2-PE40 on humoral and cell-mediated immune response in a simple, well characterized in vivo model. Although IL-2-PE40 inhibited the cell-mediated delayed type hypersensitivity reaction to SRBC, it increased the humoral immune response to the same Ag. To understand the mechanism of dichotomous action of IL-2-PE40 on the immune response, IL-2R-bearing T cells were treated with IL-2-PE40 in vitro and the cytokine expression was studied at mRNA and protein level. 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. These in vitro studies show that IL-2-PE40 can induce signal transduction in activated T cells through the IL-2R before exerting its cytotoxic effect. In contrast to DTH reaction, humoral immune response requires T cell help only for a limited period. Therefore, the short-term stimulation of T helper cells by IL-2-PE40 may be sufficient in vivo to mediate a B cell response in the local environment, whereas the DTH reaction and other cell-mediated immune responses are inhibited by the toxin moiety of the chimeric protein.
Volk
H D
HD
Institute of Medical Immunology, Charité University Clinic, Humboldt University of Berlin, Germany.
Müller
S
S
Yarkoni
S
S
Diamantstein
T
T
Lorberboum-Galski
H
H
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004912:Erythrocytes / Q000276:immunology; D005098:Exotoxins / Q000494:pharmacology*; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects*; D000922:Immunotoxins / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D011994:Recombinant Proteins; D012756:Sheep / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology*
D016207:Cytokines; D005098:Exotoxins; C057961:IL-2-PE40 chimeric protein, recombinant; D000922:Immunotoxins; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins