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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...

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SUMMARYNaive T cells mount a vigorous proliferative response to superantigen (SAg) stimulation in vivo. The proliferative response is followed by a partial deletion of responder T cells. Part of the deletion process has recently been attributed to the action of regulatory cytotoxic T cells that recognize major histocompatibility complex (MHC ) class I-associated antigen receptor determinants on the target cell surface. Responder T cells that survived the SAg response were found to be incapable of generating a secondary proliferative response to a SAg challenge. We show here that this 'anergy' is enforced by CD8-positive regulatory suppressive T cells. These regulatory cells inhibit cell division of preactivated T cells but not the SAg response of naive T cells. Regulatory T cells are not generated in the presence of cyclosporin A and, once activated, become inactivated or deleted when restimulated in the presence of this immunosuppressive drug.

Monocyte-derived macrophage (M⌽) subsets are generated by antagonistic induction pathways. A helper M⌽-type (Mh-M⌽) is induced by interferon gamma (IFN-␥), whereas a cytotoxic M⌽-type (Mc-M⌽), induced by interleukin-10 (IL-10), is a potent mediator of antibody-dependent cellular cytotoxicity (ADCC). Compared with M⌽ from healthy adults [peripheral blood monocyte-derived macrophages (PBM⌽)], cord blood M⌽ (CBM⌽) were found less capable of generating Mh-M⌽. Here we tested the hypothesis that their generation of Mc-M⌽ via IL-10 is also impaired. M⌽ surface markers were phenotyped. IL-10 protein and mRNA production were detected after stimulation [␣CD3 monoclonal antibody (mAb)]. CBM⌽ or PBM⌽ were co-cultured with M⌽-depleted mononuclear cells of adults and CD4-targeting antibodies as models for ADCC were added. In cord blood, we found diminished ␣CD3-induced IL-10 protein and mRNA production (p Ͻ 0.05 versus adults). Basal CD16 and HLA-DR expressions on CBM⌽ of preterm and full-term neonates were lower (p Ͻ 0.05 versus PBM⌽). IL-10 had reduced effects on CD16 up-and HLA-DR down-modulation on CBM⌽ (p Ͻ 0.05 versus PBM⌽). CD4-directed receptor modulation and deletion were reduced in the presence of CBM⌽ (p Ͻ 0.05 versus PBM⌽). IL-10 failed to enhance their ADCC capacity, which was in contrast to PBM⌽ (p Ͻ 0.05). These data suggest that CBM⌽ have an impaired cytotoxic capacity via lower sensitivity toward IL-10. (Pediatr Res 60: 152-157, 2006)