title: Decreased interleukin-15 from activated cord versus adult peripheral blood mononuclear cells and the effect of interleukin-15 in upregulating antitumor immune activity and cytokine production in cord blood.
abstract: Interleukin-15 (IL-15) is an important lymphokine regulating natural killer (NK) activity, T-cell proliferation, and T-cell cytotoxic activities. We hypothesized that the reduced expression and production of IL-15 from cord blood (CB) may contribute to the immaturity of CB immunity and potentially delay immune reconstitution after CB transplantation. We compared the expression and production of IL-15 from activated cord versus adult mononuclear cells (MNCs) and the regulatory mechanisms associated with IL-15 expression in CB MNCs. We have also studied the effect of exogenous IL-15 stimulation on CB and adult peripheral blood (APB) MNCs in terms of NK and lymphokine-activated killer (LAK) activities and cytokine induction. Lipopolysaccharide (LPS)-stimulated CB and APB MNCs were used to determine IL-15 expression and protein production by Northern analysis and Western immunoblot analysis. IL-15 mRNA expression and protein accumulation in CB MNC were 25% +/- 2.0% (12 hours, n = 4, P < .05) and 30% +/- 2.5% (12 hours, n = 3, P < .05), respectively, when compared with APB MNCs. Nuclear run-on assays showed no differences between CB and APB MNCs during basal levels of transcription and after transcriptional activation. However, the half-life of IL-15 mRNA was approximately twofold lower in activated CB MNCs than in activated APB MNCs (CB: 101 +/- 5.8 minutes v APB: 210 +/- 8.2 minutes, n = 3, P < .05). Exogenous IL-15 significantly enhanced CB NK and LAK activities up to comparable levels of APB (P < .05). IL-15 also significantly induced interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) protein production (days 1, 3, and 6, P < .05, n = 3) in CB MNCs. IL-15-stimulated LAK cells induced a significant lytic response against two acute lymphoblastic cell lines and two pediatric neuroblastoma cell lines. Both NK and LAK activities were augmented by the combination of IL-12 and IL-15, and the low-dose combination of IL-12 and IL-15 achieved similar levels of in vitro NK and LAK cytotoxicity compared with higher doses of either lymphokine. The present study suggests that IL-15 mRNA and protein expression is decreased in activated CB, secondary, in part, to altered posttranscriptional regulation. The reduced production of IL-15 from CB MNCs in response to stimulation may contribute to the decrease in IFN-gamma and TNF-alpha production and CB cellular immunity. However, exogenous IL-15 enhanced IFN-gamma and TNF-alpha production and NK and LAK cytotoxicities in CB MNCs. The reduced production of IL-15 from activated CB may contribute to the immaturity of CB cellular immunity and delayed immune reconstitution after unrelated CB transplantation. Exogenous IL-15 administration may compensate for the immaturity of CB immunity. The synergistic in vitro effects of low-dose IL-12 and IL-15 also implies the possible use of low doses each of IL-12 and IL-15 for enhancing immune reconstitution and/or possibly as a form of antitumor immunotherapy after CB transplantation.
authors.affiliation: Division of Hematology/Oncology and Blood and Marrow Transplantation, Children's Hospital of Orange County, CA 92868, USA.
authors.forename: J X
authors.initials: JX
authors.lastname: Qian
authors.forename: S M
authors.initials: SM
authors.lastname: Lee
authors.forename: Y
authors.initials: Y
authors.lastname: Suen
authors.forename: E
authors.initials: E
authors.lastname: Knoppel
authors.forename: C
authors.initials: C
authors.lastname: van de Ven
authors.forename: M S
authors.initials: MS
authors.lastname: Cairo
mesh_terms: D000328:Adult; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004357:Drug Synergism; D005312:Fetal Blood / Q000737:chemistry*; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000494:pharmacology; D019409:Interleukin-15 / Q000097:blood* / Q000235:genetics / Q000494:pharmacology; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000737:chemistry*; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D019409:Interleukin-15; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma