Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0029713 (immaturity)
 4,335 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon-gamma (IFN-gamma), a lymphokine produced by lymphocytes with the help of monocytes, is essential for host resistance to intracellular pathogens. Leukocytes from normal term newborn infants cannot produce IFN-gamma in vitro in response to stimulation by antigen or mitogens in vitro or in vivo. We investigated the production of IFN-gamma in vitro using endotoxin from Salmonella typhimurium as a stimulus. In contrast to those from adults, mononuclear cells derived from the cord blood of newborn infants did not produce IFN-gamma in response to this endotoxin. We investigated the contribution of the functional immaturity of cord blood monocytes to this relative inability to produce IFN-gamma. Aging of the monocytes for 2 weeks in vitro or treatment of freshly isolated cord blood monocytes with conditioned medium (from cultures of mononuclear cells from healthy adults) greatly enhanced IFN-gamma production stimulated by endotoxin. Furthermore, recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), or IFN-gamma was able to substitute in part for the conditioned medium from adult cells. Thus correction of the functional immaturity of monocytes derived from newborn infants can result in enhanced production of IFN-gamma in vitro.
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PMID:Enhancement in vitro of the low interferon-gamma production of leukocytes from human newborn infants. 831 52

Interleukin-12 (IL-12) is a critical cytokine regulating natural killer (NK) and T-cell function. We hypothesized that the impaired ability of cord blood (CB) to produce normal adult levels of IL-12 in response to stimulation may contribute to the immaturity of CB immunity. Furthermore, exogenous IL-12 may compensate for the immaturity in CB cellular immunity and have the potential for immunotherapy post cord blood transplantation. We compared the expression and production of IL-12 from activated cord versus adult mononuclear cells (MNC), regulatory mechanisms associated with IL-12 expression in CB MNC, and the effects of IL-12 on induction of CB interferon (IFN)-gamma production, NK, and lymphokine-activated killer (LAK) cytotoxicity. Northern analysis and enzyme-linked immunosorbent assay were performed in lipopolysaccharide (LPS)-stimulated CB and adult peripheral blood (APB) MNC. IL-12 mRNA expression was induced within 6 hours with LPS (10 micrograms/ml) and reached peak levels at 12 hours in both CB and APB MNC. However, IL-12 mRNA expression and protein accumulation in CB MNC were 35.8% +/- 4.84% (12 hours, n = 11, P < .05), and 17.6% +/- 1.7% (24, 72, 96 hours, n = 9, P < .05) respectively, when compared with APB MNC. Nuclear run-on assays showed no differences between CB and APB MNC in both the basal levels of transcription and the degree of transcriptional activation. However, the half-life of IL-12 p40 mRNA was approximately threefold lower in activated CB MNC than in activated APB MNC (CB: 114 +/- 3.0 minutes v APB: 353 +/- 7.8 minutes, n = 3, P < .05). Exogenous IL-12 (10 U/mL) induced a significant increase of IFN-gamma from both CB and APB MNC (24 hours, 72 hours, P < .05, n = 3). The stimulated CB IFN-gamma level reached comparable levels produced by unstimulated APB. IL-12 treatment also significantly enhanced CB NK cytotoxicity against K562 and NB-100 cell lines to the comparable levels of APB (P < .05, n = 4). CB MNC was more responsive to IL-12 stimulation with respect to IFN-gamma production, NK, and LAK cytotoxicity when compared with APB. The present study suggests that IL-12 mRNA and protein expression is decreased in activated CB. This discrepancy in IL-12 production is secondary, at least in part, to the altered posttranscriptional regulation. The impaired, ability of CB MNC to produce IL-12 in response to stimulation may contribute to the decrease in IFN-gamma production and NK cytotoxicity. However, IL-12 enhanced IFN-gamma and NK activity in CB MNC up to the comparable levels of APB MNC. These findings suggest that reduced expression and production of IL-12 from activated CB may contribute to the immaturity in CB cellular immunity and contribute, in part, to decreased graft-versus-host disease following CB stem cell transplantation.
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PMID:Decreased interleukin-12 (IL-12) from activated cord versus adult peripheral blood mononuclear cells and upregulation of interferon-gamma, natural killer, and lymphokine-activated killer activity by IL-12 in cord blood mononuclear cells. 870 53

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.
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PMID: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. 937 92

Interleukin 12 (IL-12) is a pleiotropic cytokine and mediates several biological activities on human T and natural killer (NK) cells, including induction of IFN-gamma production, enhancement of cell-mediated cytotoxicity and comitogenic effects on resting T-cells. The major cellular sources producing IL-12 are antigen-stimulated monocytes, macrophages, and B-cells isolated from peripheral blood mononuclear cells (PBMC). Our laboratory has investigated the regulation of IL-12 gene expression in both cord blood and adult PBMC, and the effects of IL-12 on induction of IFN-gamma production, NK, and lymphokine-activated killer (LAK) cytotoxicity. IL-12 mRNA expression and protein production in LPS-stimulated cord blood MNC were 3-4 fold decreased when compared with adult PBMC. There were no differences between cord blood and adult PBMC in both basal levels of transcription or the degree of transcriptional activation of the IL-12 gene. Additionally, the half-life of IL-12 p40 mRNA was 3-fold lower in activated cord blood compared to adult PBMC. Exogenous IL-12 induced a significant increase of IFN-gamma from both cord and adult PBMC. Cord MNC has significantly reduced levels of NK activity, and IL-12 significantly enhanced cord blood NK cytotoxicity up to similar levels in adult PBMC. IL-12 also significantly enhanced cord blood NK and LAK activities against a broad range of neuroblastoma, leukemia, and lymphoma cell lines. Lower doses of IL-12 and IL-15 concomitantly generated either synergistic or additive effects on cord blood NK and LAK cytotoxicities. In light of the important biological functions of IL-12, reduced expression and production of IL-12 from activated cord blood may contribute to the immaturity of cord blood cellular immunity and contribute, in part, to decreased severe graft vs. host disease following unrelated cord blood stem cell transplantation. IL-12 enhancement of IFN-gamma, NK, and LAK activity in activated cord blood MNC up to comparable levels in adult PBMC suggests that exogenous IL-12 stimulation can compensate for the immaturity in cord blood cellular immunity. These characteristics of IL-12 biological activity strongly suggest its potential usefulness in future cancer immunotherapy.
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PMID:The regulation and biological activity of interleukin 12. 964 57