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Biomedical subjects

T A Luger

Publications and source records attributed to T A Luger.

At least 109 records · Page 6Linked to original sources
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

Ultraviolet light and interleukin-10 modulate expression of cytokines by transformed human dermal microvascular endothelial cells (HMEC-1).

Exposure of the skin to ultraviolet (UV) light causes DNA damage, inflammation, and impairment of local as well as systemic immune responses. Dermal microvascular endothelial cells are key elements for the recruitment of inflammatory cells during the pathogenesis of inflammatory skin diseases via the expression of adhesion molecules and the release of cytokines. Because UVB may directly affect the function of dermal cells it was investigated whether UVB irradiation alters the production of proinflammatory and chemotactic cytokines by endothelial cells. UVB exposure of transformed human microvascular endothelial cells (HMEC-1) resulted in a dose dependently increased mRNA expression as well as release of interleukin (IL)-1beta, IL-6, IL-8, and growth-regulated oncogene alpha (GROalpha). Maximum cytokine production was observed 16-24 h after irradiation when 7.5-12.5 mJ UVB per cm2 were used. In addition, it was examined whether IL-10, which is upregulated in keratinocytes following UVB irradiation and accounts for UV mediated immunosuppression such as inhibition of contact hypersensitivity, also affects endothelial cell cytokine production. Treatment of HMEC-1 with IL-10 significantly enhanced IL-6 and IL-8 release and further upregulated UVB-induced IL-6 and IL-8 mRNA expression. These findings demonstrate that UVB both directly and indirectly via the release of IL-10 stimulates microvascular endothelial cells to produce proinflammatory cytokines and chemokines that are required for the migration and activation of inflammatory cells in UV-mediated inflammatory skin reactions.

Cells, Cultured↗
PubMed1998

The pilosebaceous unit is part of the skin immune system.

It is well established that the functional state of sebaceous glands in vivo is a tightly regulated process orchestrated through the interaction of male sex hormones and functional androgen receptors expressed on sebocytes. In the last few years, however, it has become increasingly apparent that sebocytes like epidermal keratinocytes express a variety of cytokines which are implicated in inflammatory and immune responses. For example, sebocytes in vivo have been found to highly express tumor necrosis factor alpha (TNF-alpha) as determined by immunohistochemical and electron-microscopic methods. Moreover, certain neuropeptides including vascular intestinal peptide and proopiomelanocortin (POMC) peptides as well as their receptors have been localized within the pilosebaceous unit of murine and human skin. Since POMC peptides such as alpha-melanocyte-stimulating hormone have recently been shown to exert important immunoregulatory effects by antagonizing the function of proinflammatory cytokines (e.g interleukin 1, interleukin 6 and TNF-alpha), induction of immunosuppressive cytokines (like interleukin 10), modulation of costimulatory molecule expression (e.g. B7-2) or suppression of macrophage-derived nitric oxide, complex interactions between these mediators and their target cells within the pilosebaceous gland seem to exist. The successful cultivation of sebocytes will provide a model by which the effect of these mediators can be studied in detail in order to shed light onto the various pathophysiological conditions of sebaceous glands.

Animals↗
PubMed1998

Neuropeptides: role in inflammatory skin diseases.

The cutaneous nervous system recently has been demonstrated to interact with multiple target cells in the skin and to mediate actions important in inflammatory conditions. Neuropeptides released by cutaneous neurons such as substance P (SP), vasointenstinal peptide (VIP), calcitonine gene regulated peptide (CGRP), proopiomelancortin (POMC) peptides and others modulate the function of immunocompetent and inflammatory cells as well as epithelial and endothelial cells. They have been found to function as mediators of cell proliferation, cytokine and growth factor production as well as adhesion molecule and cell surface receptor expression. In addition many cells including keratinocytes, fibroblasts, endothelial cells and inflammatory cells have been shown to release several neuropeptides and they express their corresponding receptors. These findings indicate that neuropeptides participate in the complex network of mediators that regulate cutaneous inflammation, hyperproliferation and wound healing.

Humans↗
PubMed1997

Down-regulation of interferon gamma-activated STAT1 by UV light.

STAT1 is a cytoplasmic transcription factor that is phosphorylated by Janus kinases (Jak) in response to interferon-gamma (IFNgamma). Phosphorylated STAT1 translocates to the nucleus, where it turns on specific sets of IFNgamma-inducible genes. Here, we show that UV light interferes with tyrosine phosphorylation of STAT1, thereby hindering IFNgamma from exerting its biological effects. This effect is not due to a down-regulation of the IFNgamma receptor because phosphorylation of upstream-located Jak1 and Jak2 was not suppressed by UV light. In contrast, UV light had no effect on the phosphorylation of STAT3, which is activated by the proinflammatory cytokine interleukin 6. The UV light effect on STAT1 phosphorylation could be antagonized by vanadate, indicating at least partial involvement of a protein tyrosine phosphatase. Therefore, this study indicates a mechanism by which UV light can inhibit gene activation and suggests STAT1 as a new extranuclear UV target closely located to the membrane.

Animals↗
PubMed1997

Human dermal microvascular endothelial cells express the melanocortin receptor type 1 and produce increased levels of IL-8 upon stimulation with alpha-melanocyte-stimulating hormone.

Pro-opiomelanocortin (POMC)-derived peptides such as alpha-melanocyte-stimulating hormone (alpha-MSH) recently have been recognized as mediators with potent immunomodulating and anti-inflammatory properties. Their effects are mediated via different protein G-coupled melanocortin (MC) receptors that are capable to bind one or more POMC-derived peptides. Among these receptors, MC-1 is specific for alpha-MSH and adrenocorticotropin. The purpose of the present study was to investigate whether MC receptors are expressed on normal human dermal microvascular endothelial cells (HDMEC) as well as transformed human dermal microvascular endothelial cells (HMEC-1). Using semiquantitative reverse transcriptase-PCR and MC receptor-specific primers, both HDMEC and HMEC-1 were found to express MC-1 constitutively. In addition, MC-1 expression was increased upon stimulation with IL-1beta or alpha-MSH itself. Other known MC receptors were neither detectable in unstimulated nor in IL-1beta- or alpha-MSH-stimulated cells. The binding of alpha-MSH by HMEC-1 was specific and saturable as demonstrated by competitive and saturation-binding studies with 125I-labeled alpha-MSH (Kd: 1.1 nM). To evaluate the physiologic relevance of MC-1 expression, HMEC-1 were treated with various concentrations of alpha-MSH (10(-15)-10(-6) M) and were investigated for their cytokine-producing capacity. Alpha-MSH (10(-10)-10(-8) M) significantly up-regulated IL-8 release and mRNA expression by HMEC-1. In contrast, the production of IL-1 or IL-6 by HMEC-1 was not affected upon treatment with alpha-MSH. These data provide first evidence that HDMEC express functional MC receptors. Therefore, alpha-MSH, which is released in the skin during cutaneous inflammation via inducing chemokines may represent an important signal required for leukocyte-endothelial cell interaction.

Binding Sites↗
PubMed1997

Ultraviolet light suppresses IFN-gamma-induced IL-7 gene expression in murine keratinocytes by interfering with IFN regulatory factors.

UV light is a potent stimulus for keratinocytes to release several cytokines. Recently, UV light was shown to inhibit keratinocyte release of IL-7, a growth factor for dendritic epidermal T cells. Since to date IL-7 is the only keratinocyte-derived cytokine down-regulated by UV light, we addressed the molecular mechanisms involved. IFN-gamma treatment of the murine keratinocyte cell line Pam 212 resulted in an up-regulation of IL-7 mRNA, while IL-7 transcripts were suppressed in cells exposed to UV before IFN-gamma. Because IFN-gamma induces IL-7 via activation of an IFN-stimulated response element (ISRE) located in the 5' upstream region of the IL-7 gene, bandshift assays were performed using the ISRE sequence from the IL-7 gene. Nuclear extracts from untreated cells revealed two bands, a slower migrating band identified by supershift analysis as IFN regulatory factor-2 (IRF-2), a transcriptional repressor, and a more rapidly migrating band identified as IRF-1, a transcriptional activator. IFN-gamma significantly induced IRF-1 binding, whereas UV treatment plus IFN-gamma decreased IRF-1 binding, suggesting that UV light suppresses IFN-gamma-induced expression of IL-7 by interfering with IRF-1. Chloramphenicol transferase assay confirmed functional relevance, showing that the minimal promoter sequence for the ISRE explicitly responded to IFN-gamma, which was suppressed by UV irradiation. Northern blot analysis using an IRF-1 cDNA probe revealed that UV light reduced IFN-gamma-induced IRF-1 mRNA. This study demonstrates that UV light can inhibit cytokine activities by interference with transcriptional activators. This newly described ability of UV light may contribute to its immunosuppressive properties.

Animals↗
PubMed1997

Evidence for the differential expression of the functional alpha-melanocyte-stimulating hormone receptor MC-1 on human monocytes.

alpha-Melanocyte-stimulating hormone (alpha-MSH) is released by immunocompetent cells as well as the pituitary gland and functions as a potent inhibitor of immune and inflammatory reactions. Therefore, it was investigated whether normal human monocytes express melanocortin (MC) receptors specific for alpha-MSH. Upon FACS analysis using biotin-labeled alpha-MSH, a low number of alpha-MSH binding sites was detectable on unstimulated monocytes. alpha-MSH receptor expression was up-regulated when monocytes were treated with endotoxin (LPS) or mitogen (PHA) for 3 to 5 days and was further augmented by the addition of cytokines such as IL-2, IFN-gamma, IL-4, and IL-10. Adrenocorticotropin, a precursor of alpha-MSH, but not the structurally unrelated beta-MSH, competitively inhibited alpha-MSH binding, suggesting that the receptor expressed on monocytes is specific for alpha-MSH. This was further confirmed by reverse transcription-PCR, which demonstrated that monocytes express mRNA specific for the MC receptor MC-1, which binds alpha-MSH and adrenocorticotropin, whereas mRNA specific for other known melanocortin receptors was not detectable. To investigate whether the immunosuppressing capacity of alpha-MSH is associated with the up-regulation of MC-1, its effect on the expression of costimulatory molecules (CD86 and CD80) on human monocytes was investigated. alpha-MSH significantly inhibited the expression of CD86 on LPS-treated monocytes, which exhibited a high density of MC-1, whereas CD80 expression was not altered. These findings indicate that human monocytes, depending on their activation and maturation state, are able to express MC-1, and up-regulation of MC-1 seems to be required to enable alpha-MSH to modulate immune responses in which costimulatory molecules play a decisive role.

Binding Sites↗
PubMed1997

Aging and the skin immune system.

OBJECTIVE: To give a brief summary of age-related alterations that occur in the immune system (immunosenescence), with special regard to the skin immune system. DATA SOURCES: MEDLINE and institutional libraries were searched for relevant articles on immunosenescence and corresponding key words. DATA SYNTHESIS: The immune system of aged animals and humans undergoes alterations that may account for an increased susceptibility to certain infections, autoimmune diseases, or malignancies. However, some data on the parameters of immunosenescence are controversial. This appears to be caused by variations in study designs or by the many external influences that superimpose on intrinsic alterations of the immune system. Well characterized are age-related changes of T cells and cell-mediated immunity. With advancing age, human and murine T cells undergo a shift from the naive to the memory phenotype, associated with a change in cytokine profile. The cells also reveal reductions in the proliferative response to activation, in diversity of the T-cell receptor antigen repertoire, and in cytolytic activity. B cells of aging individuals show a restricted diversity of their antibody repertoire due to a decline in somatic mutations, resulting in a reduced response to certain viral infections or vaccinations. The number of Langerhans cells appears to decline with age, contributing to a reduced rate of sensitizations. Macrophages and keratinocytes also undergo age-related changes, although these are less well characterized. They entail alterations in cytokine production, which could play a role in increased susceptibility to endotoxins in elderly individuals. CONCLUSIONS: With aging, the skin immune system shows a decline in its adaptive capability, one of its outstanding qualities. Manipulations to revert age-related dysfunctions are being tested and may help to extend a healthy life.

Adaptation, Physiological↗
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

p53 abnormalities are rare events in neuroendocrine (Merkel cell) carcinoma of the skin. An immunohistochemical and SSCP analysis.

The aim of the present study was to assess a possible role of the tumour suppressor gene p53 in neuroendocrine (Merkel cell) carcinoma of the skin with regard to tumour development and tumour progression. p53 was investigated in a series of routinely processed Merkel cell carcinomas, with application of four different p53 antibodies (CM-1, PAb1801, DO7, and PAb240) to 25 carcinomas and screening for p53 mutations of exons 4-8 by single-strand conformation polymorphism (SSCP) analysis in 9 cases. All 25 tumours in the present series showed the characteristic microscopic and immunohistochemical features of Merkel cell carcinoma of the skin. In 5 of the 25 Merkel cell carcinomas investigated 5-10% of tumour cell nuclei showed a positive p53 reaction with at least one anti-p53 antibody. A few scattered p53 positive nuclei were found in an additional 9 cases. The remaining 11 cases completely lacked p53 immunostaining. SSCP analysis of exons 4-8 revealed no significant alterations in the mobility shift of the single strand DNAs in the five cases with 5-10% p53-immunoreactive tumour nuclei or in five cases lacking p53 accumulation significant. Our results suggest that alterations of the p53 gene play only a minor part in the development or progression of Merkel cell carcinoma of the skin.

Aged↗
PubMed1997

[Lichenoid pseudolymphomatous tattooing reaction].

A 35 year old patient developed swellings in the red colored areas of his tattoo. Histological examination revealed a lichenoid, pseudolymphomatous infiltrative pattern, that could be distinguished from frank lymphoma by means of electron microscopy, immunohistochemistry and molecular biology. The presence of dermal dendritic cells suggests a dermal-allergic pathogenesis of non-granulomatous tattoo reactions. Therapy of choice is an excision of the inflamed areas.

Adult↗
PubMed1997

Recent developments in the treatment of atopic eczema.

Atopic eczema remains a therapeutic challenge. However, new developments in the understanding of the pathogenesis of this complex disease have prompted new therapeutic strategies. This review focuses on recently described treatment modalities for atopic eczema that are currently available or under investigation. The effectiveness of phototherapy, cytokines, and immunosuppressive drugs is evaluated. In addition, some new and promising but still experimental approaches are discussed.

Cytokines↗
PubMed1997

Borrelia burgdorferi-associated primary cutaneous B cell lymphoma: complete clearing of skin lesions after antibiotic pulse therapy or intralesional injection of interferon alfa-2a.

We report two patients with low-grade malignant primary cutaneous B cell lymphoma in association with Borrelia burgdorferi infection. Extracutaneous manifestations were ruled out by standard staging procedures. Infection with Borrelia burgdorferi was confirmed by cultivation from lesional skin in both patients. In the first patient skin lesions cleared completely after pulse therapy with cefotaxime, whereas in the second patient antibiotic treatment failed. In this patient, however, skin lesions completely cleared after intralesional injection of interferon alfa-2a. Antibiotic treatment or intralesional injection of interferon alfa-2a should be considered as a first-line treatment of Borrelia burgdorferi-associated primary cutaneous B cell lymphoma before more aggressive conventional therapeutic modalities (e.g., radiation therapy) are applied.

Adult↗
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↗
PubMed1997

alpha-Melanocyte stimulating hormone downregulates differentiation-driven heat shock protein 70 expression in keratinocytes.

Heat shock proteins are versatile tools engaged in several cellular functions. In particular, the stress-inducible 70-kDa heat shock protein (hsp70) not only confers protection on cells but also is involved in the regulation of the production of cellular stress response mediators including cytokines. In addition to cytokines, neurohormones such as alpha-melanocyte stimulating hormone (alphaMSH) were recently found to be potent mediators of inflammatory and immune responses. Thus, the current study was performed to investigate the role of alphaMSH in the expression of hsp70 in a human keratinocyte cell line (HaCaT). Proliferation and differentiation of HaCaT cells are known to be regulated by changing extracellular Ca2+ concentrations. HaCaT cells induced to differentiate in high Ca2+ medium (1.5 mM) were found to express higher levels of hsp70 protein than cells grown under low Ca2+ conditions. Moreover, differentiated HaCaT cells were markedly more resistant to oxidative stress than undifferentiated control cells. alphaMSH significantly suppressed hsp70 expression in a concentration-dependent manner in differentiated HaCaT cells but had only a minor effect on undifferentiated cells. Upon treatment with alphaMSH, HaCaT cells grown in high Ca2+ medium were rendered more sensitive to oxidative stress, which significantly decreased their survival rate. These findings indicate that alphaMSH, which is released by keratinocytes in an autocrine fashion following injurious stimuli such as tumor promoters or ultraviolet light, is able to regulate the cells' cytoprotective protein equipment.

Calcium↗