Regulation of interleukin-2 induced interleukin-5 and interleukin-13 production in human peripheral blood mononuclear cells.
Adjuvant interleukin (IL)-2 immunotherapy has been used for many years for a variety of malignant and nonmalignant entities. In many cases, a dose escalation might have seemed desirable, but was prevented by the rather severe adverse effects of systemic IL-2 application. Only recently has the regulation of IL-2 induced cytotoxicity been understood better, so that now efforts can be aimed at the design of cytokine cocktails that would selectively induce cytotoxicity but result in as few adverse effects as possible. Previously, induction of IL-5 under systemic IL-2 therapy has been described, and a number of the side-effects have been attributed to this event. We therefore investigated the regulation of IL-2 induced production of IL-5 and IL-13 (which, similarly to IL-5, is a mediator of allergy-like symptoms). At the same time, the effects of regulatory cytokines, such as IL-4, IL-10 and IL-12, on interferon-gamma (IFN-gamma), the major cytotoxic mediator of IL-2 therapy, were studied. All three have been discussed as antitumour immunotherapeutics, either alone or in combination with IL-2. In anti-CD3-treated peripheral blood mononuclear cells, IL-2 induced IL-5 and IL-13 alongside IFN-gamma, IL-10 and IL-12. In the presence of IL-2, inhibition of endogenous IL-12 production further enhanced the IL-5 and IL-13 responses, while IFN-gamma and IL-10 were markedly suppressed. Co-incubation with IL-2 and IL-12 suppressed IL-5/IL-13 below, but enhanced IFN-gamma and IL-10 above, levels induced by IL-2 alone. IL-10 was suppressive on all the investigated cytokines, while IL-4 interfered with IL-2 induced IFN-gamma and IL-12 production, but was additive to IL-2 in its effect on IL-5 and IL-13. These data suggest that the combination of IL-12 with IL-2 would enhance the cytotoxic activity of this regimen, but might reduce its adverse effects.
Verheyen
J
J
Department of Pediatric Hematology and Oncology, Center of Child Health, Heinrich-Heine University Medical Center, Düsseldorf, Germany.
Bönig
H
H
Kim
Y M
YM
Banning
U
U
Mauz-Körholz
C
C
Kramm
C
C
Körholz
D
D
D017252:CD3 Complex / Q000097:blood; D023201:CD40 Ligand; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007167:Immunotherapy; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood; D018793:Interleukin-13 / Q000096:biosynthesis* / Q000097:blood; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015847:Interleukin-4 / Q000494:pharmacology; D015848:Interleukin-5 / Q000096:biosynthesis* / Q000097:blood; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000097:blood; D009500:Neutralization Tests
D017252:CD3 Complex; D018793:Interleukin-13; D007376:Interleukin-2; D015848:Interleukin-5; D008562:Membrane Glycoproteins; D016753:Interleukin-10; D023201:CD40 Ligand; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma