title: Subcutaneous injection of interleukin 12 induces systemic inflammatory responses in humans: implications for the use of IL-12 as vaccine adjuvant.
abstract: Interleukin 12 (IL-12) is a cytokine with important regulatory functions bridging innate and adaptive immunity. It has been proposed as an immune adjuvant for vaccination therapy of infectious diseases and malignancies. The inflammatory properties of IL-12 play an important role in the adjuvant effect. We studied the effect of s.c. injections of recombinant human IL-12 (rHuIL-12) in 26 patients with renal cell cancer and demonstrated dose-dependent systemic activation of multiple inflammatory mediator systems in humans. rHuIL-12 at a dose of 0.5 microg/kg induced degranulation of neutrophils with a significant increase in the plasma levels of elastase (p < 0.05) and lactoferrin (p = 0.01) at 24 h. Additionally, rHuIL-12 injection mediated the release of lipid mediators, as demonstrated by a sharp increase in the plasma secretory phospholipase A2 (sPLA2) level (p = 0.003). rHuIL-12, when administered at a dose of 0.1 microg/kg, showed minimal systemic effects. In conclusion, when IL-12 is used as an adjuvant, doses should not exceed 0.1 microg/kg, in order to avoid severe systemic inflammatory responses.
authors.affiliation: Department of Medical Oncology, Erasmus Medical Center, Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands.
authors.forename: Johanna E A
authors.initials: JE
authors.lastname: Portielje
authors.forename: Wim H J
authors.initials: WH
authors.lastname: Kruit
authors.forename: Anke J M
authors.initials: AJ
authors.lastname: Eerenberg
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: Cor H J
authors.initials: CH
authors.lastname: Lamers
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Gratama
authors.forename: Gerrit
authors.initials: G
authors.lastname: Stoter
authors.forename: Christoph
authors.initials: C
authors.lastname: Huber
authors.forename: C Erik
authors.initials: CE
authors.lastname: Hack
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007279:Injections, Subcutaneous; D018664:Interleukin-12 / Q000008:administration & dosage / Q000009:adverse effects*; D007958:Leukocyte Count; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010741:Phospholipases A / Q000097:blood; D054467:Phospholipases A2; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced* / Q000188:drug therapy; D013997:Time Factors
chemical_list: D000276:Adjuvants, Immunologic; D018664:Interleukin-12; D010741:Phospholipases A; D054467:Phospholipases A2