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S Grabbe

Publications and source records attributed to S Grabbe.

At least 73 records · Page 4Linked to original sources
PubMed1998

Ultraviolet light-induced immune tolerance is mediated via the Fas/Fas-ligand system.

Hapten sensitization through UV-exposed skin induces tolerance that is mediated via the induction of hapten-specific T suppressor cells. However, the detailed mechanisms underlying tolerance induction remain unclear to date. We show here that the apoptosis-related surface Ag Fas (APO-1, CD95) and its ligand, Fas ligand (FasL) are critically involved, since Fas-deficient lpr mice and FasL-deficient gld mice do not develop UV-induced tolerance. Adoptive transfer experiments revealed that the mediation of tolerance does not require the expression of Fas or FasL by the T suppressor cells but does require the expression of both molecules by the cells of mice receiving the T suppressor cells. To identify the mechanisms involved, the effect of suppressor cells on Ag-presenting dendritic cells (DC) was studied. Coincubation of hapten-pulsed DC with T cells that were obtained from UV-tolerized mice resulted in an enhanced death rate of DC, and this cell death was dependent upon Fas expression. The addition of IL-12, which recently was found to break established tolerance in vivo, prevented DC death. Moreover, IL-12 did not only rescue DC from T suppressor cell-induced death but also from apoptosis induced by rFasL, suggesting that IL-12 may interfere with the Fas/FasL system. Together, these data indicate a crucial role for the Fas/FasL system in UV-induced tolerance, and suggest that UV-induced T suppressor cells may act by inducing the cell death of APCs via the Fas pathway. The ability of IL-12 to break established tolerance may be due to the prevention of DC death induced by T suppressor cells.

Animals↗
PubMed1998

High-dose UVA1 therapy for atopic dermatitis: results of a multicenter trial.

BACKGROUND: The results of an open, single-center study suggested that phototherapy with high doses of UVA1 radiation (UVA1R; 340-400 nm) is effective for acute, severe exacerbations of atopic dermatitis (AD). OBJECTIVE: The purpose of this study was to assess the effectiveness of high-dose UVA1 phototherapy for acute, severe AD in a randomized multicenter trial in direct comparison with topical glucocorticoid therapy. METHODS: Patients were treated with high-dose UVA1R (10 days, 130 J/cm2/day; n = 20), topically with fluocortolone (10 days, 1 x daily; n = 17), or with UVA-UVB therapy (10 days, 1 x daily, minimal erythema dose-dependent; n = 16). RESULTS: With a clinical scoring system, significant differences in favor of high-dose UVA1R and fluocortolone therapy were observed (p < 0.0001), as compared with UVA-UVB therapy. At day 10, high-dose UVA1R was superior to fluocortolone (p < 0.002) therapy. Serum levels of eosinophil cationic protein and the blood eosinophil count were significantly reduced after high-dose UVA1 or fluocortolone, but not UVA-UVB therapy. CONCLUSION: This study confirms the therapeutic effectiveness of high-dose UVA1 monotherapy for treatment of severe exacerbations of AD.

Administration, Topical↗
PubMed1998

Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells.

Melanoma is the main cause of death in patients with skin cancer. Cytotoxic T lymphocytes (CTLs) attack melanoma cells in an HLA-restricted and tumor antigen-specific manner. Several melanoma-associated tumor antigens have been identified. These antigens are suitable candidates for a vaccination therapy of melanoma. Dendritic cells (DCs) are antigen-presenting cells (APCs) specialized for the induction of a primary T-cell response. Mouse studies have demonstrated the potent capacity of DCs to induce antitumor immunity. In the present clinical pilot study, DCs were generated in the presence of granulocyte/macrophage-colony stimulating factor (GM-CSF) and interleukin 4 (IL-4) and were pulsed with tumor lysate or a cocktail of peptides known to be recognized by CTLs, depending on the patient's HLA haplotype. Keyhole limpet hemocyanin (KLH) was added as a CD4 helper antigen and immunological tracer molecule. Sixteen patients with advanced melanoma were immunized on an outpatient basis. Vaccination was well tolerated. No physical sign of autoimmunity was detected in any of the patients. DC vaccination induced delayed-type hypersensitivity (DTH) reactivity toward KLH in all patients, as well as a positive DTH reaction to peptide-pulsed DCs in 11 patients. Recruitment of peptide-specific CTLs to the DTH challenge site was also demonstrated. Therefore, antigen-specific immunity was induced during DC vaccination. Objective responses were evident in 5 out of 16 evaluated patients (two complete responses, three partial responses) with regression of metastases in various organs (skin, soft tissue, lung, pancreas) and one additional minor response. These data indicate that vaccination with autologous DCs generated from peripheral blood is a safe and promising approach in the treatment of metastatic melanoma. Further studies are necessary to demonstrate clinical effectiveness and impact on the survival of melanoma patients.

Adult↗
PubMed1998

Psoriasis vulgaris treated successfully with mycophenolate mofetil.

Mycophenolate mofetil (MMF) is a new immunosuppressive drug which non-competitively and reversibly blocks the de novo synthesis of guanine nucleotides required for DNA and RNA synthesis during T- and B-cell proliferation. This induces a selective inhibition of lymphocyte proliferation. Thus MMF is currently used to prolong graft survival in renal transplant patients. In this communication we describe the first case of a man with severe psoriasis treated successfully with oral MMF without short-term side-effects. The psoriasis area and severity index score decreased during therapy (5 weeks) from 22.0 to 11.4. Thus MMF appears to be an effective therapeutic alternative in the treatment of severe psoriasis.

Aged↗
PubMed1998

Interleukin 12 breaks ultraviolet light induced immunosuppression by affecting CD8+ rather than CD4+ T cells.

Recent studies showed that injection of interleukin (IL)-12 prevents ultraviolet (UV) light mediated suppression of contact hypersensitivity and breaks UV-induced hapten specific tolerance. UV-mediated suppression can be adoptively transferred by injecting splenocytes from UV-irradiated mice; however, suppression is not transferable when donor mice are treated with IL-12 after UV-irradiation. This study was performed to elucidate the mechanisms by which IL-12 counteracts this immunosuppression. To characterize the cells transferring suppression, depletion studies were performed revealing that UV-induced suppression is transferred via CD8+ T cells. To investigate whether IL-12 counteracts UV-induced suppression by either inhibiting the development of CD8+ suppressor T cells or inducing CD4+ effector T cells, splenocytes from mice, which were IL-12 treated and sensitized through UV-exposed skin, were depleted from CD4+ T cells and transferred into naive mice that were subsequently sensitized. Whereas transfer of splenocytes from UV-irradiated mice inhibited sensitization of recipients, no inhibition was observed after transfer of splenocytes from UV-exposed and IL-12 treated mice. Recipients that received CD4 depleted spleen cells from UV-exposed and IL-12 treated donors, were still fully sensitizable. IL-12 also blocked transfer of UV-induced suppression when it was injected into UV-exposed donor animals at a time point when suppressor cells had already developed. CD4 depletion of such splenocytes did not result in a loss of the reconstitutive effect of IL-12. This suggests that IL-12 may break UV-induced tolerance not by inducing CD4+ effector T cells, but rather by inhibiting or inactivating suppressor T cells belonging to the CD8 subtype.

Adoptive Transfer↗
PubMed1998

Differential regulation of epidermal cell tumor-antigen presentation by IL-1alpha and IL-1beta.

IL-1 exists in two forms, termed IL-1alpha and IL-1beta, which exert similar effects in a number of biologic models. Recently, there have been reports of some differences in the activities of these two species in some systems. To address this issue with regard to Langerhans cells, Langerhans cell-enriched preparations of epidermal cells were treated with either IL-1alpha or IL-1beta before pulsing with S1509a tumor-associated antigens and subsequent use for immunization of naive mice to S1509a. While epidermal cells treated with 100 U IL-1beta per ml were able to induce protective tumor immunity (as indicated by the rejection of a subsequent tumor challenge with viable S1509a tumor cells), epidermal cells treated with 100 U IL-1alpha per ml failed to confer protective immunity. At 1000 U per ml, IL-1beta also inhibited the ability of epidermal cells to induce tumor immunity. To investigate the effects of the two IL-1 forms on elicitation of tumor immunity, naive mice were immunized against the S1509a tumor by s.c. injection of dead S1509a cells. Epidermal cells enriched for Langerhans cells were treated with either 100 U IL-1alpha or IL-1beta per ml before tumor-associated antigens-pulsing. Epidermal cells were then washed and injected into a hind footpad of tumor immune mice and 24 h footpad swelling was assessed as a measure of delayed-type hypersensitivity. Exposure to IL-1alpha led to suppressed elicitation of delayed-type hypersensitivity, whereas IL-1beta treated epidermal cells elicited a normal (100 U per ml) or enhanced (1000 U per ml) level of delayed-type hypersensitivity. Previous experiments indicated that the suppressive effects of IL-1alpha on induction of immunity may be mediated by TNF alpha. Therefore, the ability of IL-1alpha or IL-1beta to induce epidermal cell production of TNF alpha was assessed. IL-1alpha induced epidermal cells to secrete significantly higher amounts of TNF alpha protein compared with stimulation with IL-1beta. IL-1alpha and IL-1beta appear to differentially regulate epidermal cell antigen presenting capability.

Animals↗
PubMed1997

Frog PNKT-4B cells express specific extracellular matrix-degrading enzymes and cytokines correlated with an invasive phenotype.

A temperature-dependent metastatic phenotype reported for a frog cell line, PNKT-4B, provided a means for studying potential mediators of cell-matrix interaction involved in metastatic invasion. Zymography revealed that these cells secreted enzyme species with properties and characteristics of mammalian metalloproteinases: collagenase, stromelysin, gelatinase A, and gelatinase B. These enzymes were produced by PNKT-4B cultures maintained at both invasive-permissive (28 degrees C), and invasion-restrictive (20 degrees C) temperatures. However, under the invasive-permissive culture condition cells produced more of the putative gelatinase B and A enzymes. In addition, an activated form of gelatinase A was produced only in invasion-permissive cultures. DNA synthesis bioassays (Mv1Lu cell line and mouse thymocytes) to detect growth promoting and/or inhibitory cytokines, revealed that PNKT-4B cultures kept at 28 degrees C released significantly higher levels of stimulatory (interleukin-1-like) and latent inhibitory (transforming growth factor-beta-like) substances into the medium compared to 20 degrees C cultures. Pre-absorption of media samples with heparin-sepharose indicated a second stimulatory cytokine as well. A corneal fibroblast bioassay that tests for mediators of collagenase synthesis, detected a stimulatory substance whose activity was greatly reduced in the presence of interleukin-1 receptor antagonist protein. Collagenase stimulatory activity present in 28 degrees C culture medium was significantly higher than equal samples from 20 degrees C cultures. These studies provide a molecular correlation between release of cytokines with properties of the metastatic phenotype seen in vivo. They further provide some of the first characterizations of frog MMPs and cytokines, which are likely to be involved in other tissue remodeling events.

Animals↗
PubMed1997

CD14 is expressed by subsets of murine dendritic cells and upregulated by lipopolysaccharide.

The CD14 surface molecule is predominantly expressed by cells of myeloid origin and regarded as a specific marker for macrophages (M phi). Thus, in human mononuclear cell preparations, CD14 expression is a widely used parameter to distinguish M phi from dendritic cells (DC). Since a murine homologue of CD14 was recently identified, this study investigated expression of CD14 by murine M phi and DC. Flow cytometry with a monoclonal antibody directed against murine CD14 revealed that bone marrow-derived DC express CD14 to various extents during differentiation. Functionally, CD14high and CD14low DC did not differ significantly in their capacity to present alloantigen, protein antigen or immunogenic peptide. Furthermore, surface expression of CD14 could be modulated by interleukin (IL)-4 and LPS. Incubation of bone marrow-derived DC with IL-4 (100 U/ml) resulted in downregulation of CD14 surface expression, whereas exposure of BmDC to LPS (1 microgram/ml) led to upregulation of CD14. After blockage of CD14 molecules by incubation of DC with anti-CD14 antibodies, downregulation of LPS triggered IL-1 release could be detected. In addition, other M phi markers such as CD11b, F4/80, BM8, and ER-TR9, are also expressed on DC. Therefore, we conclude that CD14, like other M phi markers, is expressed on murine DC during maturation. Thus, M phi and DC cannot be distinguished by flow cytometry using these markers. Moreover, CD14 may be involved in mediating LPS-induced activation of murine DC.

Animals↗
PubMed1997

The role of alpha-melanocyte-stimulating hormone in cutaneous biology.

alpha-Melanocyte stimulating hormone is a neuroimmunomodulating peptide that was recently detected in many non-pituitary tissues including the skin. Accordingly, epidermal cells such as keratinocytes and melanocytes (as well as dermal cells such as fibroblasts and endothelial cells), after stimulation with pro-inflammatory cytokines or UV light, synthesize, and release alpha MSH. The effects of these peptides are mediated through specific melanocortin (MC) receptors that can be detected on immunocompetent and inflammatory cells as well as on keratinocytes, melanocytes, fibroblasts, and endothelial cells. In addition to its well known pigment-inducing capacity, alpha MSH is able to modulate keratinocyte proliferation and differentiation. Endothelial cell and fibroblast cytokine production and fibroblast collagenase production are also regulated by alpha MSH. The immunosuppressive capacity of alpha MSH is mediated mainly through its effects on monocyte and macrophage functions. Accordingly, alpha MSH downregulates the production of pro-inflammatory cytokines and accessory molecules on antigen-presenting cells. The production of suppressor factors such as IL-10, however, is upregulated by alpha MSH. The in vivo relevance of these data is documented by the finding that systemic application of alpha MSH inhibits the induction and the elicitation of murine contact hyper-sensitivity and induces hapten-specific tolerance. These findings indicate that alpha MSH is part of the mediator network that regulates cutaneous inflammation and hyper-proliferative skin diseases.

Adjuvants, Immunologic↗
PubMed1996

Dissection of antigenic and irritative effects of epicutaneously applied haptens in mice. Evidence that not the antigenic component but nonspecific proinflammatory effects of haptens determine the concentration-dependent elicitation of allergic contact dermatitis.

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.

Administration, Cutaneous↗
PubMed1996

Neutralization of IL-12 in vivo prevents induction of contact hypersensitivity and induces hapten-specific tolerance.

IL-12 is a heterodimeric cytokine with a powerful positive regulatory influence on the development of Th1 cell-mediated immune responses. Th1 cells are critically involved in contact hypersensitivity (CHS), so we were interested in studying whether IL-12 is of relevance in the induction phase of CHS. BALB/c mice were sensitized by epicutaneous application of 0.5% 2,4-dinitrofluorobenzene (DNFB) on the abdomen, draining lymph nodes obtained at various time points thereafter. RNA was extracted, and PCR analysis was performed using primers specific for the IL-12 subunits p35 and p40. Although p35 was constitutively expressed and not affected by hapten application, p40 transcripts were found to be enhanced in lymph nodes obtained between 12 and 24 h after sensitization. To study whether IL-12 is functionally relevant for the induction of CHS, an mAb directed against recombinant murine IL-12 was injected i.p. 3 and 24 h before sensitization. Challenge was performed 5 days later by painting the left ear with 0.3% DNFB. Whereas mice injected with sodium chloride or an isotype control Ab responded with a normal ear swelling after challenge with DNFB, mice treated with anti-IL-12 Ab showed a significantly reduced ear swelling response. To study whether injection of the IL-12 Ab causes transient nonresponsiveness or tolerance, resensitization was performed after a resting period of 14 days. Groups of mice initially treated with the anti-IL-12 Ab plus DNFB showed only a minimal response to DNFB after resensitization, suggesting that these mice became tolerant. Tolerance appeared to be hapten-specific because these mice could be successfully sensitized with the nonrelated hapten 2,4,6-trinitrochlorobenzene. Furthermore, when the anti-IL-12 Ab was injected into already sensitized mice before challenge, ear swelling response was significantly suppressed, suggesting that IL-12 also is involved in the effector phase of CHS. To exclude the possibility that the inhibitory effect of the anti-IL-12 Ab is simply due to an anti-inflammatory activity of the Ab, the anti-IL-12 Ab was injected i.p. 3 and 24 h before epicutaneous application of the toxic compound croton oil. However, irritant dermatitis elicited by croton oil was not affected by the Ab. Thus, the present study demonstrates that in vivo application of an anti-IL-12 Ab inhibits sensitization and induces hapten-specific tolerance and thus suggests that IL-12 may play a dominant in vivo role in the induction of CHS.

Animals↗
PubMed1996

alpha-Melanocyte-stimulating hormone induces hapten-specific tolerance in mice.

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a proopiomelanocortin-derived peptide with known immunoregulatory effects, acting mainly via modulation of cytokine secretion by lymphocytes and monocytes. When applied epicutaneously, alpha-MSH inhibits both induction as well as elicitation of contact hypersensitivity (CHS) responses in mice. We questioned whether systemically administered alpha-MSH leads to the induction of hapten-specific tolerance. For this purpose, mice were injected i.v. with 75 microgram/kg synthetic bioactive alpha-MSH 2 h before sensitization (day 0) or challenge (day 6) with the hapten, trinitrochlorobenzene (TNCB). Intravenous administration of alpha-MSH 2 h before sensitization or 2 h before challenge resulted in a markedly reduced CHS response. To distinguish between unresponsiveness and tolerance, these mice were sensitized and challenged a second time, but in the absence of alpha-MSH. Mice that had been injected with alpha-MSH before the first sensitization (day 0), but not before challenge (day 6), were also unable to develop a significant CHS response after an additional sensitization and challenge with the same Ag 10 to 14 days later. In contrast, sensitization to the unrelated hapten, dinitrofluorobenzene, was unaffected in these mice, indicating the induction of hapten-specific tolerance by alpha-MSH. Moreover, regional lymph node cells obtained from alpha-MSH-treated mice 5 days after resensitization failed to produce IL-2 in response to trinitrobenzosulfonic acid, the water-soluble analogue of TNCB, whereas lymph node cells from TNCB-sensitized, not alpha-MSH-treated, mice as well as from mice treated with alpha-MSH before challenge readily exhibited trinitrobenzosulfonic acid-specific IL-2 production in this assay. Finally, in vivo tolerance induction by alpha-MSH could be abrogated by the administration of anti-IL-10 Ab at the site of sensitization. These data indicate that alpha-MSH, in addition to its suppressive effect on induction and elicitation of CHS, is able to induce hapten-specific tolerance in mice. Thus, alpha-MSH may be a significant regulatory mediator of cutaneous immune responses in vivo.

Animals↗
PubMed1996

Interaction of murine dendritic cells with collagen up-regulates allostimulatory capacity, surface expression of heat stable antigen, and release of cytokines.

In vivo, dendritic cells (DC) reside in direct proximity to extracellular matrix (ECM) proteins. Because ECM proteins affect morphology and function of a number of cell types, this study investigated potential effects of ECM proteins on functional properties of DC. DC were generated from murine bone marrow cultures, supplemented with granulocyte-macrophage colony-stimulating factor, and subsequently cultured on tissue culture plates coated with various ECM proteins. Among the ECM proteins tested, collagen (COL) up-regulated the T cell stimulatory capacity of DC. This effect was accompanied by sustained surface expression of the co-stimulatory molecule heat stable antigen on DC and by enhanced release of interleukin-1 and interleukin-6, respectively. Because fibronectin or solubilized COL were unable to cause similar changes in DC phenotype or function, we conclude that adherence to COL interferes specifically with DC function. These data suggest that ECM proteins may be involved in regulation of DC phenotype as well as in their functional activation.

Animals↗
PubMed1996

[PUVA-induced acro-bullous dermatosis].

PUVA-induced acrobullous dermatosis is characterized by the occurrence of blisters on the acral extremities during PUVA therapy. The tense blisters apparently arise as a result of PUVA damage to the epidermodermal cohesion coupled with friction or trauma. They must be distinguished from phototoxic reactions induced either by UVA over-dosage or excessive psoralen uptake. We report on, two cases of acrobullous PUVA-induced dermatosis, discussing clinical features, pathophysiological aspects and differential diagnosis.

Adult↗
PubMed1996

Regulation of the immune response by epidermal cytokines and neurohormones.

The ability of the cellular components of the skin immune system to mount various types of immune responses is largely dependent upon their ability to release and to respond to different signals provided by immunoregulatory mediators such as cytokines and neuropeptides. In principle, almost every cytokine known so far, including interleukins (IL), interferons (IFN), tumor necrosis factors (TNF), colony stimulating factors (CSF) and several growth factors can be detected in the skin under certain physiological or pathological conditions. There is recent evidence that neuropeptides such as substance P, calcitonin-related gene product (CGRP) a.o. as well as neurohormones such as proopiomelanocortin (POMC), which is the precursor of several peptidehormones including melanocyte stimulating hormones (MSH), are present in epidermal cells, cutaneous tumors and inflammatory cells infiltrating the skin. In addition to their well known functions as neurotransmitters or hormones, these peptides have recently been recognized as potent immunomodulating agents which inhibit the production and activity of immunoregulatory and proinflammatory cytokines (IL-1, IL-2, IFN gamma) but induce the release of factors, e.g., IL-10, which downregulate immune responses. Accordingly, in animals, alpha MSH and CGRP have been shown to inhibit the induction of contact hypersensitivity reactions. Therefore, a complex network of interacting mediators including cytokines and neuropeptides within the cutaneous microenvironment are crucial elements of the induction, elicitation and regulation of cutaneous immune responses.

Animals↗