Oropharyngeal lichen planus associated with interferon-alpha treatment for mycosis fungoides: a rare side-effect in the therapy of cutaneous lymphomas.
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Aged↗
Biomedical subjects
T A Luger
Publications and source records attributed to T A Luger.
Pentoxifylline reduces the formation of sunburn cells.
Irradiation with ultraviolet (UV) B light results in the formation of apoptotic keratinocytes called sunburn cells (SC). Although generation of SC appears to be one of the most characteristic features of UV-induced skin damage and has been a well-known phenomenon for a long time, the mechanisms involved are not quite clear. Recently, it was demonstrated that tumor necrosis factor alpha (TNF alpha) appears to be involved in the formation of SC since neutralization of TNF alpha both in vitro and in vivo reduced UVB-induced apoptosis of keratinocytes. Pentoxifylline is a methylxanthine derivative suppressing the release of TNF alpha. Therefore, we studied whether PTX is able to prevent the formation of SC. Addition of PTX to UVB-exposed HaCaT cells reduced DNA-fragmentation as examined by nick translation evaluated by flowcytometry. To prove whether PTX also reduces UVB-induced apoptosis in vivo, BALB/c mice were exposed to UVB on their abdomens, skin biopsies performed 24 h later and SC counted. A single dose of 2000 J/m2 caused a significant induction of SC which were remarkably reduced when PTX was injected intraperitoneally 3 h before and 12 h after UVB exposure. In summary, the data demonstrate that PTX can reduce the formation of SC both in vitro and in vivo and thus further support that TNF alpha is involved in UVB-induced apoptosis of keratinocytes.
Animals↗
Endothelial cells and angiogenesis.
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Angiogenesis Inducing Agents↗
Persistent pruritus after hydroxyethyl starch infusion therapy: a result of long-term storage in cutaneous nerves.
A high incidence of severe pruritus has been observed after the administration of hydroxyethyl starch (HES) on account of plasma volume substitution and improvement of the microcirculation. The aim of this study was to elucidate the possible pathomechanisms of HES-induced itching. Skin biopsies were taken from 93 patients, half of them presenting with pruritus, who received HES of various preparations and cumulative dosages. The samples were subjected to immunoelectron microscopical investigation using an antibody highly specific for HES. After infusion therapy with HES, formation of intracytoplasmic storage vacuoles in the skin could be demonstrated in all patients. A dose-dependent uptake of HES was first detectable in macrophages and, thereafter, in endothelial and epithelial cells. Consecutive control biopsies taken from single patients revealed a subsequent reduction of the vacuoles, in size and number, within 3 years, thus indicating a regular cutaneous metabolism of HES. Patients suffering from pruritus consistently showed additional deposition of HES in small peripheral nerves. HES-reactive vacuoles could be demonstrated in the Schwann cells of unmyelinated, as well as small myelinated, nerve fibres, and in endoneural and perineural cells. Neural devacuolization paralleled the clinical improvement in the symptoms. In conclusion, HES deposits in cutaneous nerves, as a consequence of a higher cumulative dosage, may account for the itching seen after HES infusion.
Adolescent↗
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↗
Pro-opiomelanocortin-derived peptides induce IL-10 production in human monocytes.
There is strong evidence for the existence of a neuroimmune axis which is regulated by a network of interacting cytokines and neuropeptides. Accordingly, pro-opiomelanocortin-derived peptide hormones such as melanocyte-stimulating hormones (MSH), adrenocorticotropin, and beta-endorphin not only could be detected in many immunocompetent cells but also turned out to be potent immunomodulating and anti-inflammatory mediators, mainly through regulating cytokine production. Thus, it was investigated whether alpha-MSH, which is known to inhibit immune and inflammatory responses, would influence the production of the cytokine synthesis inhibitor IL-10 by human PBMC. Stimulation of PBMC with alpha-MSH resulted in a significantly enhanced release of, IL-10 protein. These data were confirmed by Northern blot analysis, which demonstrated increased IL-10 mRNA expression induced by alpha-MSH. This effect of alpha-MSH was dose-dependent; maximum IL-10 release and mRNA expression were obtained at a concentration of 10(-13) M. There is also clear evidence that only the C-terminal tripeptide of alpha-MSH was required to enhance IL-10 production. In addition, alpha-MSH and its tripeptide strongly induced IL-10 in purified monocytes. In contrast, neither unstimulated nor activated T lymphocytes produced increased amounts of IL-10 in response to alpha-MSH. These findings indicate that pro-opiomelanocortin peptides such as alpha-MSH are able to up-regulate the production of suppressor factors such as IL-10 in monocytes and thereby may contribute to immunosuppression.
Amino Acid Sequence↗
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↗
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↗
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↗
[Successful topical administration of cyclosporin A in pyoderma gangraenosum].
Therapy of pyoderma gangrenosum can be complicated by side effects of the various systemic therapies, including corticosteroids, azathioprin and cyclosporin A. In this paper we report on a 49-year-old patient presenting with recalcitrant pyoderma gangrenosum who was treated successfully by topical application of cyclosporin A. Cyclosporin A serum levels were always in the subtherapeutic range, and no side effects were observed.
Administration, Topical↗
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↗
Mycosis fungoides presenting as an acquired ichthyosis.
A 25-year-old patient with an acquired ichthyosis-like condition is described. Histologic and molecular biologic examination of the fine, whitish, scaling skin lesions suggested the diagnosis of mycosis fungoides. Typical lesions of mycosis fungoides, such as patches, plaques, or tumors, were not present. To the best of our knowledge, this is the first case of mycosis fungoides presenting solely with the clinical features of acquired ichthyosis. The sudden appearance of ichthyosiform skin changes in adults must be taken seriously and the underlying cause must be evaluated. A skin biopsy should be performed in all cases of acquired ichthyosis to rule out mycosis fungoides.
Adult↗
Progressive growth of human papillomavirus type 16-transformed keratinocytes is associated with an increased release of soluble tumour necrosis factor (TNF) receptor.
Analysis of conditioned media generated by weakly and highly tumorigenic SKv-1 keratinocyte lines harbouring integrated human papillomavirus type 16 (HPV16) DNA sequences revealed a factor inhibiting TNF-alpha and TNF-beta cytotoxic activity. This inhibitory activity was specifically blocked by htr-9 monoclonal antibody (MAb) recognising 55/60 kDa type I TNF receptor suggesting that it is related to a soluble form of this particular receptor (sTNF-RI). The presence of sTNF-RI was confirmed by Western blot analysis of SKv-1 cell-conditioned medium showing a band of 31.5 kDa as well as by the specific enzyme-linked immunobiological assay (ELIBA). Release of sTNF-RI was a result of shedding because Northern blot analysis showed that SKv-1 cells expressed a full-length TNF-RI mRNA, and radioimmunoprecipitation of TNF-RI from [32S]cysteine-labelled cell extracts demonstrated the presence of normal 55 kDa molecule. Evaluation by ELIBA showed that highly tumorigenic SKv-12 cells released significantly more sTNF-RI than their weakly tumorigenic SKv-11 parental cells. Furthermore, human recombinant as well as SKv cell-derived sTNF-RI stimulated proliferation of weakly tumorigenic SKv-11 cells. This suggests that a progressive growth of some neoplastic cells may be, at least partially, a result of an increased spontaneous release of sTNF-RI that enables the cells to escape from local TNF-alpha-mediated growth inhibition.
Carcinoma in Situ↗
Glycoproteins of the carcinoembryonic antigen (CEA) family are expressed in sweat and sebaceous glands of human fetal and adult skin.
The carcinoembryonic antigen (CEA) family comprises a group of glycoproteins including the classical CEA, nonspecific cross-reacting antigens (NCA), and biliary glycoprotein (BGP). CEA glycoproteins have been identified in many glandular and mucosal tissues. In view of their putative role in cell adhesion, protein sorting, and signal transduction, CEA glycoproteins are thought to be involved in embryogenesis, architectual integrity, and secretory mechanisms of glandular epithelia. Since there are few data available on the expression of CEA-like proteins in human skin, the aim of this study was to immunohistochemically specify and localize the CEA glycoproteins in cutaneous adult and fetal glands using a panel of well-characterized antibodies. The secretory parts of eccrine sweat glands expressed CEA, NCA-90, and BGP, whereas apocrine glands remained unreactive for CEA glycoproteins. The ductal epithelia of both eccrine and apocrine glands contained CEA and NCA-90. Sebaceous glands were stained for BGP only. Electron microscopy of sweat glands showed CEA glycoprotein expression in cytoplasmic organelles and on microvilli lining the ductal surface. In sebaceous glands, BGP were demonstrated in small vesicles and along the cell membranes of differentiating sebocytes. Fetal development of cutaneous glands was associated with early expression of CEA glycoproteins. Additionally, mice transgenic for human CEA were shown to express CEA in sweat glands. The overall distribution of CEA glycoproteins in cutaneous glands was consistent with that in epithelia of other glandular tissues.
Adult↗
Interleukin-12 prevents ultraviolet B-induced local immunosuppression and overcomes UVB-induced tolerance.
Ultraviolet (UV) light abrogates contact hypersensitivity (CHS) responses and induces hapten-specific tolerance. Because Th-1 cells are critically involved in CHS and are induced to develop by the cytokine interleukin (IL)-12, we asked whether IL-12 might overcome UV-induced local immunosuppression. C3H/HeN mice exposed to low doses of UV light over 4 d and hapten sensitized through the irradiated skin area with dinitrofluorobenzene showed profound inhibition of the CHS response, which was completely prevented upon intraperitoneal injection of murine recombinant IL-12 (rIL-12) after the last UV exposure. UV-treated mice resensitized 14 d after the first challenge displayed hapten-specific tolerance, whereas UV-exposed mice injected with rIL-12 before the first sensitization exhibited a vigorous CHS response. Furthermore, mice that were initially sensitized through UV-exposed skin also produced a significant CHS reaction when they received rIL-12 before resensitization. Adoptive transfer of spleen and lymph node cells from UV-irradiated mice treated with rIL-12 had no effect on the CHS response in recipient mice, whereas transfer of cells from UV-treated mice inhibited the immune response. These findings demonstrate that rIL-12 can prevent UV-induced local immunosuppression and overcome UV-induced hapten-specific tolerance.
Animals↗
Transforming growth factor-alpha induces interleukin-6 in the human keratinocyte cell line HaCaT mainly by transcriptional activation.
There is ample evidence that several cytokines, including transforming growth factor-alpha (TGF-alpha), interleukin (IL)-6, and IL-8 are upregulated in psoriasis, suggesting a pathogenic role for these cytokines. The sequence of these events, however, has not been elucidated. Recently it has been reported that TGF-alpha induces IL-6 in thymocytes through posttranscriptional regulation; therefore, we were interested in whether TGF-alpha can also induce IL-6 in human keratinocytes. Thus, we stimulated the human keratinocyte cell line HaCaT with TGF-alpha and tested supernatants for IL-6 activity. TGF-alpha resulted in a significant induction of the release of IL-6. This was also confirmed by northern blot analysis, which revealed a transient increase in IL-6 mRNA. This increase was unlikely due to enhanced mRNA stability, because we could not observe induction of IL-6 -specific transcripts by TGF-alpha in the presence of actinomycin D. To determine whether IL-6 induction by TGF-alpha is transcriptionally regulated, we transfected fragments of the IL-6 upstream region, subcloned into a plasmid just upstream of the chloramphenicol acetyl transferase coding region, into HaCaT cells. A 238-bp fragment and a 123-bp fragment, both containing nuclear factor (NF)-IL-6 and NFkappaB sites, exhibited significant induction of chloramphenicol acetyl transferase activity upon treatment with TGF-alpha. Because IL-6 transcription is known to be regulated by activation of NFkappaB and NF-IL-6, we analyzed the activation of these DNA-binding proteins by electrophoretic mobility shift assays. NF-IL-6 binding to a 32P-labeled NF-IL-6 binding sequence was enhanced 20 min after TGF-alpha stimulation and returned to basal levels within 90 min, whereas NFkappaB binding activity was enhanced after 20 min and returned to normal 60 min after stimulation. We conclude that TGF-alpha induces IL-6 in HaCaT cells and, in contrast to thymocytes, may do so by transcriptional activation, possibly through activation of NFkappaB and NF-IL-6.
Base Sequence↗
Neoplasms with sweat gland differentiation express various glycoproteins of the carcinoembryonic antigen (CEA) family.
Carcinoembryonic antigen (CEA) is a well-established marker for sweat gland differentiation in adnexal neoplasms. In contrast to previous assumptions, CEA does not represent a single oncofetal antigen but comprises a family of homologous glycoproteins, i.e. the classical CEA-180, biliary glycoprotein (BGP), and non-specific crossreacting antigens (NCA). The aim of the study was to evaluate the distribution of the respective glycoproteins of the CEA family in sweat gland neoplasms, as compared to normal sweat glands. A panel of mono-specific antibodies was applied to a total of 83 samples of hyperplastic and cystic alterations of sweat glands, sweat gland neoplasms, and cutaneous metastases of different origin. Within a single group of neoplasms the immunohistochemical profile was rather consistent. Staining for both CEA-180 and NCA-90 indicated ductal differentiation of both eccrine and apocrine glands. Co-expression of CEA-180, NCA-90, and BGP was consistent with differentiation towards the secretory part of eccrine glands or the transitional portion of proximal ducts. Neoplasms with signs of apocrine secretion showed a preferential immunoreactivity for NCA-90 and BGP. In conclusion, a specification of the members of the CEA family may be of some value in the differential diagnosis of adnexal neoplasms, but not in the discrimination of sweat gland carcinoma from metastatic carcinoma.
Adnexal Diseases↗
Ultrastructural localization of carcinoembryonic antigen (CEA) glycoproteins and epithelial membrane antigen (EMA) in normal and neoplastic sweat glands.
Glycoproteins of the carcinoembryonic antigen family (CEA) and epithelial membrane antigen (EMA) are established markers for glandular and mucosal tissues. However, their precise ultrastructural distribution in sweat glands has not been determined as yet. Therefore, normal human skin, 19 cases of various sweat gland neoplasms, Paget's disease, and cutaneous metastases of visceral carcinomas were stained with well-defined antibodies using a postembedding immunogold technique. In some cases, a new method of re-embedding paraffin material for immunoelectron microscopy was applied. In normal sweat glands, immunoreactivity of the endoplasmic reticulum and vesicles indicated biosynthesis and processing of CEA and EMA. Along the luminal surfaces both CEA and EMA represented an integral part of microvilli. However, a differential expression of CEA and EMA was demonstrated in apocrine epithelia, mucous cells of eccrine glands, and sweat ducts. In fetal glands, CEA was associated with formation of secretory and ductal lumina. The overall cellular distribution of CEA and EMA was highly preserved in benign sweat gland neoplasms whereas malignant neoplasms were characterized by loss of protein targeting and cellular polarity. In conclusion, these immunoelectron microscopical findings suggest a role of CEA and EMA for cell differentiation and secretory mechanisms of sweat gland epithelia.
Adult↗