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)

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

Haematopoiesis and immune functions in cord blood (CB) are developmentally immature when compared with adult peripheral blood (APB). The defects in CB immune function and cytokine production may both contribute to the immaturity of CB immunity. We have studied the mechanisms associated with the dysregulation of myeloid lineage cytokines, GM-CSF and M-CSF, and lymphokines, IL-12, and IL-15 in activated CB when compared with APB MNC. Furthermore, we have studied the effects of IL-12 and IL-15 on induction of IFN-gamma and TNF-alpha production, NK, and LAK activities in CB and APB. GM-CSF, M-CSF, IL-12 and IL-15 protein and mRNA are decreased in activated CB MNC. These discrepancies are secondary, at least in part, to the altered post-transcriptional regulation. The impaired ability of CB to produce IL-12 and IL-15 in response to stimulation may contribute to the decrease in IFN-gamma, TNF-alpha production, NK and LAK activities. Furthermore, combination of low dose IL-12 and IL-15 may augment cytotoxic activities and minimize toxicity. These findings suggest that reduced cytokine expression from activated CB may contribute to the impaired CB cellular immunity and exogenous lymphokines may compensate for the immaturity in CB.
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PMID:Dysregulation of lymphokine production in the neonate and its impact on neonatal cell mediated immunity. 971 74

The decreased incidence of graft-vs.-host disease found following umbilical cord blood (CB) transplantation, and the increased susceptibility of newborns to infections, have been attributed, in part, to functional and phenotypic immaturity of neonatal T cells. We investigated the phenotypic changes of CB T cells induced by two immunoregulary cytokines, interleukin (IL)-12 and IL-15, alone or in combination. Adult peripheral blood (APB) mononuclear cells (MNCs) were also tested for comparison. Prior to culture, the percentages of CD3+ CD8+, CD3+ CD25+, and CD3+ CD56+ cells were significantly lower in CB MNCs than in APB MNCs. IL-15, but not IL-12, significantly increased CD3+ CD8+ expression among the CB MNCs after 1 week of culture. Combining IL-12 and IL-15, however, resulted in decreased CB CD3+ CD8+ expression compared with IL-15 alone. The percentage of CD3+ CD25+ cells in CB MNCs spontaneously increased in the absence of cytokines, while that of CD3+ CD56+ cells in CB MNCs could not be enhanced with cytokines. In contrast, the percentages of CD3+ CD25+ and CD3+ CD56+ cells among the APB MNCs could be increased with IL-12, IL-15, and further with IL-12 and IL-15 combined. Thus, different patterns of T-cell subset changes were demonstrated between CB MNCs and APB MNCs in response to IL-12 and/or IL-15. These data may serve as a foundation for using cytokine therapy in newborns and children receiving CB transplants.
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PMID:Phenotypic changes of T-lymphocyte subsets induced by interleukin-12 and interleukin-15 in umbilical cord vs. adult peripheral blood mononuclear cells. 1125 61

The reduced incidence of graft-vs.-host disease following umbilical cord blood (CB) transplantation may be related to the functional immaturity of newborn T cells expressing mainly the naive CD45RA phenotype. Expansion of CD4(+) CD45RA(+) T cells using cytokines may benefit neonates and infants with human immunodeficiency virus (HIV) infection, as a preferential decline in CD4(+) CD45RA(+) cells has been noted as HIV disease progresses. The aim of the study was to investigate the effect of interleukin (IL)-15, a novel cytokine similar to IL-2 in biological activities, on CD45RA/RO expression and apoptosis in umbilical cord blood (CB) and adult peripheral blood (APB) mononuclear cells (MNCs). Prior to culture, CB MNCs contained a greater number of CD4(+) CD45RA(+) cells and fewer CD4(+) CD45RO(+) cells than did APB MNCs. When incubated with RPMI-1640 containing 10% fetal calf serum for 7 days, the percentage of CD45RA(+) cells within CD4(+) T cells (%CD45RA(+)/CD4(+)) significantly decreased compared to that of fresh CB MNCs. IL-15 exerted a dose-dependent increase of %CD45RA(+)/CD4(+) and a corresponding decrease of %CD45RO(+)/CD4(+) in CB MNCs, an effect not observed with APB MNCs treated with IL-15. The percentages of CD45RA(+) and CD45RO(+) expression within CD8(+) cells, however, were not influenced by IL-15, in either CB or APB MNCs. A greater number of CB MNCs underwent apoptosis than did APB MNCs after 7 days of culture in RPMI-1640 containing 10% fetal calf serum. IL-15 did not inhibit apoptosis but induced proliferation comparable to that achieved in APB MNCs. The ability of IL-15 to preferentially enhance the proliferation of CD4(+) CD45RA(+) cells in CB MNCs suggests a role for immunomodulative therapy in HIV-infected newborns and infants.
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PMID:Interleukin-15 enhances CD4(+) CD45RA(+) expression on umbilical cord blood mononuclear cells. 1155 15

Decreased graft-versus-host disease (GVHD) in cord blood (CB) transplantation may be attributed to the immunological immaturity and susceptibility to apoptosis of CB mononuclear cells (MNCs). Cytokines like interleukin (IL)-12 and IL-15 may be used for in vivoadministration or ex vivo expansion of lymphoid cells for more rapid recovery following stem cell transplant, and for providing a graft-versus-leukemia (GVL) effect. We investigated the effects of IL-12 and IL-15, alone or in combination on apoptosis and proliferation of both CB and adult peripheral blood (APB) MNCs, with particular emphasis on CB CD4+, CD8+ and CD56+ lymphocyte subpopulations. The results of our study indicated that: (1) the combination of IL-12+IL-15 resulted in a greater degree of CB and APB apoptosis than either cytokine alone; (2) the level of both spontaneous and cytokine-induced apoptosis by IL-12 and/or IL-15 are greater in CB MNCs than in APB MNCs using TUNEL assays; (3) IL-15 is superior to IL-12 in enhancing the proliferative response in CB and APB MNCs; (4) the combination of IL-12+IL-15, but not either cytokine alone, significantly enhanced apoptosis in CD8+ and CD56+ CB subsets, but not in CD4+ CB subsets; (5) IL-12 or IL-15 alone resulted in increased proliferation in CD4+, CD8+ and CD56+ CB subsets, with IL-12+IL-15 producing the greatest increase of proliferation in all three CB subsets; and (6) IL-15 and/or IL-12 significantly upregulate Fas (CD95) expression on CB T and NK cells. These findings may have therapeutic implications when designing cytokine therapy in patients receiving CB transplant.
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PMID:Effect of interleukin (IL)-12 and IL-15 on apoptosis and proliferation of umbilical cord blood mononuclear cells. 1159 16

Endoglin (CD105) is a component of the transforming growth factor-beta (TGF-beta) receptor (TGF-betaR) complex. Together with betaglycan, CD105 is considered as a TGF-betaR accessory molecule (also called TGF-betaRIII), but its functions in the receptor-ligand interactions are still poorly understood. A small subset of human CD34+ hematopoietic stem/progenitor cells that has phenotypic and functional features suggestive of very primitive hematopoietic cells expresses the CD105 antigen. CD34+/CD105+ cells recirculate in the peripheral blood of mobilized subjects and can be purified by immunomagnetic isolation strategies. The hematopoietic potential of these CD34+/CD105+ cells appears to be sustained by a combination of hematopoietic and non-hematopoietic cytokines, which comprises Flt3 ligand, erythropoietin, interleukin-15 and vascular endothelial growth factor. Endogenous TGF-beta1 is a crucial factor for the maintenance of CD34+/CD105+ immaturity acting through positive modulation of both CD105 and CD34 molecules in the absence of relevant effects on the cell cycle profile. CD105 is absent on very primitive CD34-/lineage-/CD45+ (CD34-Lin-) human hematopoietic cells isolated from cord blood. However, in vitro exposure of CD34-Lin- cells to exogenous TGF-beta1 causes the appearance of a discrete population of CD34+/CD105+ cells. Collectively, available data on CD105 expression and function in primitive hematopoiesis indicate that this molecule could cooperate with the dissociation of TGF-beta1 cell cycle effects from its other effects on cell survival and differentiation.
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PMID:CD105 (endoglin) expression on hematopoietic stem/progenitor cells. 1191

In contrast to astrogliosis, which is common to injuries of the adult CNS, in the developing brain this process is minimal. Reasons postulated for this include the relative immaturity of the immune system and the consequent insufficient production of cytokines to evoke astrogliosis. To explore this hypothesis, the study was undertaken to detect the presence of some proinflammatory cytokines in the injured rat brain following perinatal asphyxia (ischaemia/hypoxia). The localisation of TNF-alpha, IL-15, IL-17 and IL-17 receptors was visualised by means of immunohistochemistry. In numerous neurones of the rat brain, the IL-17 appeared to be constitutively expressed. In the early period of inflammation the IL-15 was produced mainly by the blood cells penetrating the injured brain but later it was synthesised also by reactive astrocytes surrounding brain cysts and forming dense astrogliosis around necrotic brain regions. The direct effect on astrogliosis of other estimated cytokines seems to be negligible. All the results lead to the conclusion that from all cytokines identified in the injured immature rat brain the IL-15 plays the most important role during inflammatory response and participates in the gliosis of reactive astrocytes.
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PMID:Proinflammatory cytokines in injured rat brain following perinatal asphyxia. 1257 74

We have previously demonstrated dysregulation of IL-12 and IL-15 gene and protein expression between activated cord blood (CB) versus peripheral blood (PB) mononuclear cells (MNCs). In the present study, we compared IL-18 gene expression and protein production and IL-18 mRNA half-life in basal versus activated CB versus PB MNCs, the effects of IL-18 +/- IL-12 on MNCs IFN-gamma protein production and ex vivo expansion and activation of CB with IL-12 + IL-2 + anti-CD3 +/- IL-18. Basal and activated levels of IL-18 were significantly higher in PB versus CB MNCs (P < 0.05). IL-18 mRNA was coincidental with protein levels and significantly lower in CB (P < 0.05) and its half-life significantly shorter in CB versus PB MNCs (P < 0.05). IL-18 synergistically with IL-12 induced IFN-gamma production from PB greater than CB MNCs (P < 0.05). NK cells expansion (P < 0.001) and cytotoxicity (P < 0.01) was significantly increased with IL-12 + IL-2 + anti-CD3 and IL-18. In summary IL-18 gene expression and protein production are significantly decreased in activated CB versus PB MNCs, in part secondary to increased degradation of CB IL-18 mRNA. These results may have implications for the mechanism(s) in part responsible for the immaturity of CB T-cell immunity.
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PMID:Immaturity of IL-18 gene expression and protein production in cord blood (CB) versus peripheral blood (PB) mononuclear cells and differential effects in natural killer (NK) cell development and function. 1602 58

Exposure of human skin to solar ultraviolet (UV) light induces local and systemic immune suppression. It is known that alterations of immune functions of Langerhans cells (LCs) and dermal dendritic cells (DDCs) mediate this phenomenon. The purpose of this study was to mimic in vitro the early UV-induced skin disruption to better understand the involvement of the skin micro-environment in triggering this immunosuppressive state. We therefore developed skin equivalents (SEs) integrating LCs and DDCs derived from monocytes (mo-LCs and mo-DDCs, respectively). First, we showed that Langerin(+) mo-LC and dendritic cell (DC)-specific ICAM-3 grabbing nonintegrin (SIGN)(+) mo-DDCs were immunolocalized in situ in epidermal and dermal compartments of SEs, respectively. The SE micro-environment without immune cells displayed full cytokine profile that may ensure and maintain differentiation, localization, and immaturity of LCs and DDCs in situ, as shown by secretion of granulocyte-macrophage colony-stimulating factor, transforming growth factor beta (beta)-1, interleukin (IL)-4, IL-13, and IL-15 involved in cell differentiation; presence of complete chemokine network as macrophage inflammatory protein 3 alpha (alpha); low secretion of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha), IL-1 beta, IL-6, and IL-8; and surprising secretion of immunosuppresive cytokine IL-10. Second, we demonstrated that skin micro-environment homeostasis was greatly disrupted under solar UV irradiation of SEs. In fact, we showed a pro-inflammatory state characterized by high secretion of TNF-alpha, IL-1 beta, IL-6, and IL-8 and low secretion of IL-10. This breakdown of immune homeostasis was visualized at the same time as in situ migration of mo-LCs and mo-DDCs into the dermal equivalent of SEs. Moreover, this tissue migration of mo-LCs and mo-DDCs into SEs was in accordance with the chemokine (C-C motif) receptor 7 expression and the DC-lysosome-associated membrane glycoprotein acquisition only on mo-LCs. Our results highlighted major participation of the skin micro-environment in the triggering and modulating of UV-induced skin immune responses. In addition, it could be concluded that these SEs are reliable tools for modeling biological events inaccessible in humans.
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PMID:Effects of solar ultraviolet radiation on engineered human skin equivalent containing both Langerhans cells and dermal dendritic cells. 1788 23

Newborn foals are very susceptible to infections by opportunistic pathogens such as Rhodococcus equi. This susceptibility is thought to be due to the immaturity of their immune system, in particular their inability to produce interferon-gamma. This deficiency may result from an insufficiency in accessory signals. We therefore compared monocyte-derived dendritic cells (MoDC) from foals and from adult horses. CD172, MHC-I and MHC-II were generally expressed on more than 90% MoDC from foals and adults. CD1w2(+)CD86(+) cells tended to be less represented in 2-3-week-old foals than in adults. This difference was significant among CD14(-) cells. The percentage of CD14(-)CD1w2(+)CD86(+) cells tended to be increased at 3 months. This suggests that very young foal dendritic cells are quantitatively less mature than their adult counterparts. The expression of IL-1, IL-12, IL-15 and IL-18 mRNA was not different in foal and adult MoDC, but the levels of TNF-alpha, IL-10, MCP-1 and TGF-beta were lower in foal cells. TNF-alpha and IL-10 expression was increased by LPS; TNF-alpha even reached the level of adult MoDC. This may mean that the lack of IFN-gamma in foals is not due to decreased levels of IL-12, IL-15 or IL-18, but rather to lower constitutive levels of TNF-alpha.
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PMID:Young foal and adult horse monocyte-derived dendritic cells differ by their degree of phenotypic maturity. 1934 79


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