Meike Steinert

University of Münster, Muenster, North Rhine-Westphalia, Germany

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Publications (7)52.84 Total impact

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    ABSTRACT: Pimecrolimus (SDZ ASM981) is a non-steroid member of calcineurin inhibitors recently developed for the treatment of inflammatory skin diseases. In this study, we compared the effect of pimecrolimus and corticosteroids on the differentiation, maturation and function of murine bone marrow-derived dendritic cells (BM-DC). We added pimecrolimus at concentrations of 5-500 ng/ml or 0.5 ng/ml mometasone furoate at different timepoints to the BM-DC culture and checked (i) the number of matured cells, (ii) the expression of activation markers, (iii) the release of cytokines and (iv) the stimulatory capacity of the resulting BM-DC in vivo. Even at the highest concentration, pimecrolimus treatment resulted in only modest effects. In the pimecrolimus-treated culture, we observed a decrease in the numbers of matured cells but no significant effects on the expression of activation markers. The release of some inflammatory cytokines was reduced, but the stimulatory capacity in vivo was not affected. In contrast, mometasone furoate has pronounced effects on BM-DC at a concentration ten to 1000 times lower than those used with pimecrolimus. Furthermore, topical treatment of mice with clobetasole cream 0.05% resulted in almost complete depletion of splenic DC and a severe hyposplenia, while high-dose oral pimecrolimus treatment did not show any effects on the spleen or on splenic DC. These results support that pimecrolimus, unlike corticosteroids, has little effects on dendritic cells. To the best of our knowledge, this is the first study of this type with use of BM-DC.
    Experimental Dermatology 02/2006; 15(1):43-50. · 3.58 Impact Factor
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    ABSTRACT: Toll-like receptor (TLR) ligands lead to the induction of proinflammatory cytokines and are potent enhancers of specific immune responses. We show here that a single systemic dose of R-848, a ligand for TLR7, potently enhanced hapten sensitization during the induction of contact hypersensitivity (CHS). However, R-848 administration also resulted in a rapid and almost complete depletion of leukocytes from the blood. This effect was transient and was associated with general induction of endothelial adhesiveness. In response to R-848, endothelial cells up-regulated adhesion molecules in vitro and in vivo and leukocytes exhibited increased rolling on endothelia in R-848-treated animals. Adhesion molecule induction appeared to be a direct effect, because endothelial cells expressed TLR7 in vitro and in vivo. After R-848 treatment, the tissue residence time of leukocytes was markedly prolonged in all major peripheral organs. The resulting transiently reduced availability of peripheral-blood leukocytes (PBLs) (TRAP) significantly inhibited otherwise potent CHS responses until the effector cells returned. Thus, although TLR7 ligands are effective adjuvants for the induction of cell-mediated immunity, they can transiently inhibit the elicitation of localized immune responses, possibly due to a systemic endothelial activation throughout the vasculature.
    Blood 11/2005; 106(7):2424-32. · 9.06 Impact Factor
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    ABSTRACT: Inflammatory processes are associated with the rapid migration of dendritic cells (DCs) to regional lymph nodes and depletion of these potent antigen-presenting cells (APCs) from the inflamed tissue. This study examined whether sites of cutaneous inflammation can be repopulated with DCs from a pool of immature DCs circulating in the blood. In adoptive transfer experiments with ex vivo-generated radioactively labeled primary bone marrow-derived DCs injected into mice challenged by an allergic contact dermatitis reaction, immature DCs were actively recruited from the blood to sites of cutaneous inflammation, whereas mature DCs were not. Immature, but not mature, DCs were able to adhere specifically to immobilized recombinant E- and P-selectin under static as well as under flow conditions. P-selectin-dependent adhesion of immature DCs correlates with their higher level of expression of the carbohydrate epitope cutaneous lymphocyte-associated antigen (CLA) and is blocked by a novel inhibitory antibody against mouse P-selectin glycoprotein ligand 1 (PSGL-1). Surprisingly, however, emigration of immature DCs into inflamed skin is retained in the presence of this anti-PSGL-1 antibody and is also normal when immature DCs are generated from fucosyltransferase (Fuc-T) Fuc-TVII-deficient mice. By contrast, emigration of wild-type immature DCs is reduced by adhesion-blocking anti-E- and P-selectin antibodies, and immature DCs generated ex vivo from Fuc-TVII/Fuc-TIV double-deficient mice emigrate poorly. Thus, fucosylated ligands of the endothelial selectins, determined in part by Fuc-TIV, and independent of PSGL-1, are required for extravasation of DCs into sites of cutaneous inflammation.
    Blood 03/2002; 99(3):946-56. · 9.06 Impact Factor
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    ABSTRACT: Beta2 integrins are of critical importance for leukocyte extravasation through vascular endothelia and for T cell activation. To elucidate the role of beta2 integrins in T cell-mediated immune responses, allergic contact dermatitis (ACD), irritant dermatitis, and delayed-type hypersensitivity (DTH) were assessed in mice lacking the beta2 integrin subunit, CD18. ACD and DTH responses, but not edema formation, were severely suppressed in CD18(-/-) mice. Extravasation of CD18(-/-) T cells into eczematous skin lesions was greatly impaired, whereas migration of Langerhans cell precursors and dendritic cells was normal in CD18(-/-) mice. CD18(-/-)lymph nodes (LNs) contained an abnormal population of CD3(-)CD44(high) lymphocytes and showed evidence of widespread T cell activation. T cells from regional LNs of sensitized CD18(-/-) mice proliferated in response to hapten challenge, and subcutaneous injection of sensitized syngeneic LN cells directly into ears of hapten-challenged naive recipients restored the defective ACD in CD18(-/-) mice, suggesting that CD18 is not required for priming of naive T cells but is indispensable for T cell extravasation. Thus, a dysfunction of T cells, in addition to granulocytes, may contribute to the pathophysiology of leukocyte adhesion deficiency type I, which arises from mutations in the human CD18 gene.
    Journal of Clinical Investigation 02/2002; 109(2):183-92. · 12.81 Impact Factor
  • Journal of Dermatological Science - J DERMATOLOGICAL SCI. 01/1998; 16.
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    ABSTRACT: Allergic contact dermatitis differs from most other immune reactions by its strict dose dependence during the elicitation phase. Moreover, almost all known contact allergens can also induce dose-dependent irritative dermatitis and in general only elicit allergic contact dermatitis in sensitized individuals when applied within a narrow dose range. Therefore, we hypothesized that elicitation of contact hypersensitivity (CHS) may require two signals, antigen-specific effector cell activation and a non-antigen-specific proinflammatory signal, both of which are provided by application of a sufficient dose of hapten. To dissociate these putative two signals, oxazolone-sensitized mice were ear challenged with a dose of the specific hapten which was too low to elicit CHS. At the same time, an unrelated hapten was applied in a conventional concentration to the same skin site. Whereas neither treatment alone elicited a significant CHS response, application of both compounds together resulted in a strong CHS response that was indistinguishable from that elicited by the full dose of the specific hapten. Upon coadministration of the irrelevant hapten, allergic contact dermatitis could be elicited even when the dose of the specific hapten was further reduced by a factor of 10(3). In contrast, a dose reduction of the irrelevant hapten by a factor of two resulted in the loss of the CRS response. These data indicate that non-antigen-specific effects of epicutaneously applied haptens significantly contribute to the elicitation of CHS responses and that the capacity of the hapten to evoke this proinflammatory stimulus rather than its antigenicity is responsible for the strict concentration dependence.
    Journal of Clinical Investigation 10/1996; 98(5):1158-64. · 12.81 Impact Factor
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    ABSTRACT: Whereas epidermal Langerhans cells (LC) are thought to be the principal APCs for initiation of contact hypersensitivity (CHS) responses, their role as APC in the effector phase of CHS is still unclear. It is currently thought that LC elicit the CHS response by presenting Ag to trafficking Ag-specific T cells within the skin. To test this hypothesis, we removed the majority of resident LC at the site of CHS challenge by topical application of various steroid creams to one ear in BALB/c mice (> 85% LC depletion). Either 2 days before or 4 days after steroid treatment of the ear, mice were sensitized on the abdomen with the hapten trinitrophenyl and challenged 10 days later at the steroid-pretreated ear. At that time point, direct anti-inflammatory effects of the steroid were no longer present. Surprisingly, CHS responses were markedly stronger at the sites of prior steroid application when compared with vehicle-treated controls, indicating that depletion of most of the resident LC not only fails to impair, but enhances, the expression of CHS significantly. UV irradiation or application of croton oil at the challenge site, as well as systemic steroid application, all of which are alternative methods of diminishing the number of epidermal LC, also significantly up-regulated CHS. In contrast, irritant dermatitis and sensitization or elicitation of CHS in steroid-treated mice at distant sites, as well as delayed-type hypersensitivity responses against the same hapten, were unaffected by topical steroid pretreatment. In conclusion, our data suggest that resident LC are not the relevant APC in the effector phase of CHS and that they may even provide down-regulatory, rather than stimulatory, signals during elicitation of CHS.
    The Journal of Immunology 12/1995; 155(9):4207-17. · 5.52 Impact Factor

Publication Stats

333 Citations
52.84 Total Impact Points

Institutions

  • 2002–2006
    • University of Münster
      • Institute of Cell Biology
      Muenster, North Rhine-Westphalia, Germany