Pediatric rheumatology: autoimmune mechanisms and therapeutic strategies

Kümmerle-Deschner, Jasmin; Hoffmann, Michael K.; Niethammer, D.; Dannecker, Günther

doi:10.1016/s0167-5699(98)01263-8

Cited by 20 publications

(25 citation statements)

References 8 publications

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“…CD3 and CD28 (8). These phenomena were found on the remaining CD4 T cells with both M⌽ subsets (Fig.…”

Section: Il-10 Production After Stimulation With a T Cell Mitogenmentioning

confidence: 59%

“…blood monocytes or M⌽. Via antagonistic cytokine induction pathways, at least two M⌽ subsets, displaying distinct phenotypes and functions, have been distinguished (7): IFN-␥ generates a costimulatory helper M⌽-type (Mh) which expresses and up-regulates B7 family receptors (CD80, B7-1 and CD86, B7-2) (8). Its engagement of T cell CD28 family molecules influences T cell survival, activation, and TH1/TH2 cytokine production [for review, see Salomon and Bluestone (9)].…”

mentioning

confidence: 99%

“…Its engagement of T cell CD28 family molecules influences T cell survival, activation, and TH1/TH2 cytokine production [for review, see Salomon and Bluestone (9)]. In contrast, IL-10 not only mediates inhibitory and immunoregulatory signals, but induces a cytotoxic M⌽-type (Mc) (8), which fails to up-regulate HLA-DR and B7 molecules. Mc-M⌽ instead express Fc-gamma III receptors (CD16) in high density (7).…”

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confidence: 99%

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

et al. 2006

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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)

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“…CD3 and CD28 (8). These phenomena were found on the remaining CD4 T cells with both M⌽ subsets (Fig.…”

Section: Il-10 Production After Stimulation With a T Cell Mitogenmentioning

confidence: 59%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2006

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“…One, referred to as helper macrophages (38), is characterized by high expression of HLA-DR and costimulatory molecules CD80 and CD86, which facilitate T cell stimulation (39,40). The other, referred to as cytotoxic macrophages (38), lacks expression of CD80 and CD86 but expresses the Fc-g III receptor (CD16) in high density and acts as a negative immune regulator (41). In light of this, our results suggest that lipid extract surfactants, and in particular their component PC16:0/14:0, influence costimulatory receptors on macrophages.…”

Section: Discussionmentioning

confidence: 99%

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

Gille

Spring

Bernhard

et al. 2007

Journal of Lipid Research

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Blood monocyte-derived macrophages invading the alveolus encounter pulmonary surfactant, a phospholipoprotein complex that changes composition during lung development. We tested the hypothesis that characteristic phosphatidylcholine (PC) components differentially influence macrophage phenotype and function, as determined by phagocytosis of green fluorescent protein-labeled Escherichia coli and aCD3-induced T cell proliferation. Human macrophages were exposed to surfactant (Curosurf:), to two of its characteristic phosphadidylcholine (PC) components (dipalmitoyl-PC and palmitoylmyristoyl-PC), and to a ubiquituous PC (palmitoyloleoyl-PC) as control. Interaction of Curosurf and PC species with macrophages was assessed using Lissaminei-dihexadecanoyl-phosphoethanolaminelabeled liposomes. Curosurf and both saturated surfactant PC species downregulated CD14 expression and upregulated CD206. HLA-DR and CD80 were upregulated by Curosurf and palmitoylmyristoyl-PC, whereas dipalmitoyl-PC showed no effect. The latter upregulated TLR2 and TLR4 expression, whereas Curosurf and palmitoylmyristoyl-PC had no effect. PC species tested were incorporated in comparable amounts by macrophages. Curosurf and PC species inhibited phagocytosis of E. coli. Scavenger receptor CD36, CD68, SR-A, and LOX-1 mRNA expression was upregulated by Curosurf, whereas PC species only upregulated SR-A. Curosurf and palmitoylmyristoyl-PC inhibited aCD3-induced T cell proliferation by 50%, whereas dipalmitoyl-PC and palmitoyloleoyl-PC showed no effect. These data identify individual surfactant PC species as modifiers of macrophage differentiation and suggest differential effects on innate and adaptive immune

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“…One, referred to as cytotoxic M⌽ (Mc) (31), lacks B7 expression (32) and is induced by IL-10 (33). The second subset, referred to as helper M⌽ (Mh) (31), is induced by IFN-␥ and expresses CD80, CD86, or both. Disturbances in the Mh/Mc balance have been reported in various diseases (34 -38).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2005

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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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Pediatric rheumatology: autoimmune mechanisms and therapeutic strategies

Cited by 20 publications

References 8 publications

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

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

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

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

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