Effect of Dexamethasone on B7 Regulation and T Cell Activation in Neonates and Adults

Abstract

The safety of dexamethasone for neonates has been questioned, partly because of its multiple unspecific effects on the immune system. Specific effects of dexamethasone on costimulatory and immune suppressive functions of neonatal compared with adult macrophages (M⌽) are not known. We evaluated the effect of dexamethasone on the expression and regulation of M⌽ B7 family receptors (B7-1, CD80; B7-2, CD86) and on their ability to co-stimulate T cells. Cord blood macrophages (CBM⌽) and M⌽ from healthy adults (PBM⌽) were isolated, and cell surface markers were phenotyped by flow cytometry. In tissue culture, cells were exposed to dexamethasone, interferon-␥ (IFN-␥), cAMP, or a T cell mitogen (␣CD3) and examined for their capacity to activate or destroy T cells. CBM⌽ were less able to up-regulate CD80 and CD86 than PBM⌽ (p Ͻ 0.05). Dexamethasone inhibited the up-regulation of CD80, CD86, and HLA-DR on PBM⌽ and even more so on CBM⌽ (p Ͻ 0.05 versus PBM⌽ for CD80 and CD86). In the presence of dexamethasone, stimulation with ␣CD3 MAb enhanced cytotoxic functions of PMBM⌽ and CB⌴⌽ with an increase in deleted T cells, a reduced fraction of enlarged T cells, and an inhibition of T cell CD28 up-regulation, which again were more pronounced with CBM⌽ (p Ͻ 0.05 versus PBM⌽). In conclusion, neonatal M⌽ are exquisitely sensitive to the inhibitory effects of dexamethasone on B7 expression. Although perhaps producing the desired therapeutic effect, dexamethasone may do so in newborns at the expense of a near complete paralysis of M⌽-dependent T cell function. Preterm newborns have been exposed to dexamethasone for the prevention or treatment of bronchopulmonary dysplasia (BPD) for many years (1,2). Dexamethasone is a synthetic glucocorticoid that reduces the recruitment of inflammatory cells (3,4) and thereby is thought to inhibit the development of BPD. Its effects on other developing organs such as the CNS were only recognized much later. Because follow up-studies provided evidence of abnormal neurodevelopment, early postnatal use of dexamethasone is not recommended any more (2). Nevertheless, glucocorticoids continue to be given to pregnant women to accelerate fetal lung development.Besides the endocrinium, the primary target of dexamethasone is the immune system, which is incompletely developed in neonates. Evidence that the immunosuppressive effects of dexamethasone are primarily mediated via an inhibition of cytokine production has been produced. Mononuclear cells from adults and neonates respond differently to treatment with dexamethasone. With respect to proinflammatory cytokines, cord blood cells show an increased sensitivity toward the inhibitory action of dexamethasone compared with cells from adult donors, resulting in a more pronounced inhibition of IL-1␤, IL-6, tumor necrosis factor-␣, 6).Dexamethasone may directly inhibit T cell proliferation (7), induce apoptosis (8), promote long-lasting changes in the T cell receptor v␤ repertoire (9), or decrease the CD4/CD8 ratio in infants with BPD (10). Dexamethasone also infl...

Diminished Response to Interleukin-10 and Reduced Antibody-Dependent Cellular Cytotoxicity of Cord Blood Monocyte-Derived Macrophages

“…2), confirming earlier reports (12,20,21). Conflicting phenotypic results showing equivalent or even increased CD16 expression on M⌽ from preterm neonates (22) may be related to maternal steroids or other medication.…”

“…We found CBM⌽ less capable of generating Mh-M⌽ due to diminished IFN-␥ effects on B7 molecules, thereby inhibiting M⌽-dependent T cell activation (11,12). Here, we tested the hypothesis that their generation of Mc-M⌽ via IL-10 in cord blood is also impaired.…”

Diminished Phagocytosis-Induced Cell Death (PICD) in Neonatal Monocytes upon Infection with Escherichia coli

“…Neonatal monocytes express human leukocyte antigen-DR, toll-like receptor-2 (TLR2), and TLR4 in lower densities (31)(32)(33)(34)(35) and produce less interferon-gamma (IFNgamma) and interleukin-12 (IL-12) (36). Moreover, they are less sensitive to IFN-gamma induced phenotypic and functional changes with respect to costimulatory signals by way of B7-1 (CD86) and B7-2 (CD80), resulting in diminished neonatal T-cell activation compared with adults (31,32). With regard to monocytes and monocyte-derived macrophages, a septic scenario in neonates versus adults would include diminished cell numbers with comparable phagocytic and ROSproducing activities (Tables 1 and 2) (15,22) but with deficiencies in costimulation, activation, and IFN-gamma production.…”

Differential effect of surfactant and its saturated phosphatidylcholines on human blood macrophages

“…Peripheral blood mononuclear cells (PBMNCs) were isolated using Ficoll-Hypaque (Biochrom AG; Berlin, Germany) density gradient sedimentation as previously described (13). Cells were placed at 2 3 10 6 cells/ml in flat-bottom 24-well cell culture plates (Costar; Bodenheim, Germany) in VLE-RPMI 1640 medium (Biochrom), containing 10% heat-inactivated fetal calf serum (Sigma).…”