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Biomedical subjects

C E Griffiths

Publications and source records attributed to C E Griffiths.

At least 163 records · Page 9Linked to original sources
PubMed1991

Modulation of leucocyte adhesion molecules, a T-cell chemotaxin (IL-8) and a regulatory cytokine (TNF-alpha) in allergic contact dermatitis (rhus dermatitis).

To understand the molecular events which are important in leucocyte trafficking in cutaneous inflammation, poison ivy/oak extract was applied topically to the skin, and the simultaneous assessment of a variety of clinical and immunopathological parameters performed. The clinical response of subjects was divided into three main groups: I, 2-24h after application, before the onset of erythema; II, 48 h-1 week after application during maximal clinical changes; III, 2-3 weeks after application when the inflammation had subsided. Six different biopsies per subject were evaluated over the study period and the density of dermal cellular infiltrate, and the distribution of intercellular adhesion molecule-1, (ICAM-1), endothelial leucocyte adhesion molecule-1, (ELAM-1), vascular cell adhesion molecule-1, (VCAM-1), interleukin 8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha), determined. Eight hours after exposure, before lymphocytes and monocytes had entered the dermal interstitium or epidermis, the keratinocytes expressed TNF-alpha and ICAM-1, whilst the endothelial cells expressed ELAM-1, VCAM-1 and ICAM-1. Group II biopsies revealed increasing keratinocyte expression of TNF-alpha and ICAM-1 with the appearance of IL-8, which correlated with the onset of epidermal T-cell trafficking. The endothelium was strongly positive for ELAM-1 and VCAM-1, but there was no influx of neutrophils. Group III biopsies showed a decrease in the expression of ICAM-1, VCAM-1 and ELAM-1 by both keratinocytes and endothelium with a reduction in epidermal/dermal inflammation, although the endothelial cell staining of VCAM-1 and ELAM-1 did not completely disappear. These results suggest that on exposure to poison ivy/oak, keratinocytes rapidly produce TNF-alpha which leads to an early autoinduction of ICAM-1, and later IL-8. There is also a paracrinemediated induction and augmentation of underlying endothelial cell ELAM-1, VCAM-1 and ICAM-1.

Adult↗
PubMed1991

Human immunodeficiency virus (HIV) transcripts identified in HIV-related psoriasis and Kaposi's sarcoma lesions.

Persons with HIV infection sometimes develop aggressive psoriasis or Kaposi's sarcoma (KS) not usually seen in other immunosuppressed patients. However, a specific and direct pathophysiological role for HIV-1 in these AIDS-associated disorders remains unclear since HIV has not been easily detected in these skin lesions. By combining in situ hybridization with the sensitive detection technique of confocal laser scanning microscopy, we have demonstrated HIV RNA transcripts in 5 of 15 lesional skin biopsies from HIV-infected psoriasis patients, and in 3 of 8 Kaposi's sarcoma biopsies from HIV-infected patients. HIV transcripts were not detected in normal appearing skin from HIV-infected patients or in psoriatic and normal skin biopsies from uninfected individuals (P = 0.006). Although previous attempts to demonstrate viral sequences in psoriasis and KS lesions have been unsuccessful, in situ hybridization with confocal microscopy has shown the presence of HIV RNA transcripts predominantly within CD4+, Factor XIIIa positive dermal dendrocytes. HIV or cytokines produced by infected cells in skin lesions may therefore play a direct role in the pathogenesis of HIV-associated psoriasis and KS.

Adult↗
PubMed1991

Cellular localization of interleukin-8 and its inducer, tumor necrosis factor-alpha in psoriasis.

The importance of immunologic mechanisms in psoriasis has been deduced from the ability of immunosuppressive therapies to ameliorate this common and chronic skin disease. Certainly the histology of psoriatic lesions suggests a dialogue between the hyperplastic keratinocytes and infiltrating T lymphocytes and macrophages. To begin dissecting the cytokine network involved in the pathophysiology of psoriasis, the location, in both epidermal and dermal compartments, of tumor necrosis factor-alpha, interleukin-8, intercellular adhesion molecule-1, and transforming growth factor-alpha at the protein and/or mRNA levels were identified. Tumor necrosis factor-alpha was selected as a potentially key regulatory cytokine, first because it induces cultured keratinocyte interleukin-8, intercellular adhesion molecule-1, and transforming growth factor-alpha production, and second because intercellular adhesion molecule-1 expression by keratinocytes in psoriatic epidermis had been identified previously. Using immunohistochemical localization, tumor necrosis factor-alpha was identified in 12 psoriatic lesions as intense and diffuse expression by dermal dendrocytes (macrophages) in the papillary dermis (without significant staining of endothelial cells, mast cells, or dermal Langerhans cells), and focally by keratinocytes and intraepidermal Langerhans cells. Functional interaction between the dermal dendrocytes and keratinocytes was suggested by the presence of interleukin-8 expression of suprabasal keratinocytes immediately above the tumor necrosis factor-alpha-positive dermal dendrocytes. Interleukin-8 mRNA and transforming growth factor-alpha mRNA were detectable in the epidermal roof of psoriatic lesions, but neither was detectable at the protein or mRNA levels in any normal skin specimens. Treatment of cultured human keratinocytes with phorbol ester (which experimentally produces psoriasiform changes on mouse skin) or tumor necrosis factor-alpha also increased interleukin-8 and transforming growth factor-alpha mRNAs. Further elucidation of the cellular and molecular basis for the genesis and evolution of psoriasis will provide the framework for a better evaluation of the cause and treatment of this skin disease.

Adult↗
PubMed1991

A review and update of the clinical uses of cyclosporine in dermatology.

Cyclosporine is a hitherto unique immunosuppressive agent that has provided a new approach to therapy in autoimmune diseases and has been increasingly used as a molecular tool for the investigation of immune regulation. It has produced excellent therapeutic responses in the treatment of psoriasis, acrodermatitis continua of Hallopeau, pyoderma gangrenosum, lichen planus, pityriasis lichenoides chronica, Behçets disease, and alopecia areata. Cyclosporine's mechanism of action, side effects, pharmacokinetics, and guidelines for patient monitoring, are discussed in this article.

Alopecia↗
PubMed1990

Effect of topical cyclosporine rinse on oral lichen planus. A double-blind analysis.

BACKGROUND: Oral lichen planus is a relatively common disorder of the mouth that can be debilitating. It is frequently palliated with topical or systemic corticosteroids and retinoids. These treatments require prolonged use, however, and are not always effective. METHODS: In a double-blind trial, 16 patients with symptomatic oral lichen planus were randomly assigned to receive either topical cyclosporine or its vehicle. The patients swished and expectorated 5 ml of medication (containing 100 mg of cyclosporine per milliliter) three times daily. RESULTS: After eight weeks, the eight recipients of cyclosporine had marked improvement in erythema (P = 0.003), erosion (P = 0.02), reticulation (presence of white lacelike lesions; P = 0.007), and pain (P = 0.002), whereas the eight recipients of vehicle had no change or minimal improvement. After a switch to cyclosporine for eight weeks, the vehicle-treated patients had improvement similar to that seen in the patients who initially received cyclosporine. There were no systemic side effects. In most cases blood cyclosporine levels were low or undertectable. Cyclosporine levels present in specimens of oral mucosa at the end of therapy four hours after the patients swished were similar to the levels previously reported in psoriatic lesions after treatment with systemic cyclosporine (14 mg per kilogram of body weight per day). CONCLUSIONS: As a topical preparation, cyclosporine may be useful in the treatment of oral lichen planus and possibly other cutaneous disorders.

Aged↗
PubMed1990

Intralesional cyclosporine in the treatment of psoriasis. A clinical, immunologic, and pharmacokinetic study.

In a double-blind, vehicle-controlled study, all of six psoriatic plaques treated with intralesional cyclosporine administered three times weekly for 4 weeks showed complete clearing or incomplete but significant clearing in comparison with vehicle-treated plaques (p less than 0.01). Epidermal thickness decreased from 0.42 +/- 0.07 to 0.27 +/- 0.08 mm at 4 weeks (p less than 0.03). Biopsy specimens obtained on day 5, before any clinical improvement, revealed a significant reduction of epidermal DR+CD1- antigen-presenting cells, epidermal and dermal monocytes, and keratinocyte intercellular adhesion molecule-1 expression. By day 5 the stratum corneum reverted to normal in the plaques receiving cyclosporine. Pain at the injection site was the major side effect. Steady-state blood cyclosporine levels ranged from 20 to 30 ng/ml during the first 12 hours after injection and became undetectable at 48 hours. These data suggest that cyclosporine improves the skin of patients with psoriasis by a local mechanism of action.

Adult↗
PubMed1990

Oral cyclosporine for the treatment of alopecia areata. A clinical and immunohistochemical analysis.

Cyclosporine inhibits the activation of helper T cells that may be pathogenic in alopecia areata. Therefore we treated six patients with alopecia areata (five men, one woman) with oral cyclosporine, 6 mg/kg/day for 12 weeks. Three patients had alopecia universalis, one had alopecia totalis, and two had patchy alopecia areata of the scalp. Hair regrowth in the scalp of all patients occurred within the second and fourth weeks of therapy, followed by hair regrowth of the face and chest (in the male patients), pubic area, extremities, and axillae. Overall, the site of best response was the scalp. Cosmetically acceptable terminal hair regrowth on the scalp occurred in three of six patients. Significant hair loss, however, occurred in all patients within 3 months of discontinuation of cyclosporine treatment. Clinical response correlated with changes in immune cell infiltration of the hair follicles. The number of leukocytes per hair follicle was quantified in transverse scalp biopsy sections stained with a panel of monoclonal antibodies. The degree of terminal hair regrowth correlated significantly with decreases in follicular epithelial human lymphocyte antigen-DR and intercellular adhesion molecule-1 expression, T cells, helper/inducer (CD4) T cells, suppressor/cytotoxic (CD8) T cells and Langerhans cells (CD1+DR+) from the hair follicles during cyclosporine therapy. A significant decrease in the CD4/CD8 ratio occurred early in the course of treatment and was maintained throughout the therapy. This decrease suggests that cyclosporine not only cleared immune cells from the hair follicles but also altered the balance of regulatory lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1990

Constitutive absence and interferon-gamma-induced expression of adhesion molecules in basal cell carcinoma.

Adhesion of lymphocytes to target cells via certain cell surface molecules is important in cytotoxic T lymphocyte-mediated immune reactions. The binding of lymphocyte function-associated (LFA) antigens 1 and 2, with their respective ligands, intercellular adhesion molecule-1 (ICAM-1) and LFA-3, which are expressed on the surface of nonlymphoid cells, has been shown to be critical for lymphocyte adhesion. To determine whether basal cell carcinomas (BCCs) can escape immunodetection as a result of the inability of cytotoxic T lymphocytes to bind tumor cells, the expression of adhesion molecules on numerous BCCs, before and after exposure to interferon-gamma (IFN-gamma), was examined. Ninety-three percent of 30 freshly excised invasive BCCs did not express ICAM-1 and 73% of 11 BCCs did not express LFA-3. However, the normal-appearing basal keratinocytes in epidermis overlying nests of BCC, did express ICAM-1, particularly when a marked LFA-1+ and LFA-2+ dermal lymphocytic infiltrate was present. After BCC tissue was incubated in vitro with IFN-gamma the expression of ICAM-1 was induced on 85% of tumors studied. Thus tumor cells did not possess an absolute inability to express adhesion molecules; rather the constitutive absence of such molecules may be due to insufficient in vivo cytokine levels necessary to induce expression or a barrier preventing cytokines from reaching and interacting with tumor cells. We conclude that the absence of ICAM-1 and LFA-3 adhesion molecules is a mechanism by which BCCs can avoid immunosurveillance.

Aged↗
PubMed1990

Systemic and local administration of cyclosporine in the treatment of psoriasis.

Since 1984, cyclosporine has been used increasingly for indications other than in prophylaxis of transplant rejection. Current awareness that psoriasis is, at least in part, a T cell-mediated condition has led to the initiation of several studies of cyclosporine's role in the treatment of this disease. The remarkable efficacy of systemically administered cyclosporine, even in severely refractory cases of psoriasis, has not only provided us with a new therapeutic option but also has helped further our understanding of the pathophysiology of psoriasis. Although it has been hailed as a breakthrough, systemic cyclosporine usage is associated with undesirable sequelae, principally hypertension and decreased renal function. These effects limit its more widespread use. This review assesses current knowledge of the capabilities and prospects of systemic cyclosporine in the treatment of psoriasis, as well as the status of topical preparations.

Administration, Oral↗
PubMed1990

Lymphocyte trafficking in psoriasis: a new perspective emphasizing the dermal dendrocyte with active dermal recruitment mediated via endothelial cells followed by intra-epidermal T-cell activation.

Prominent within the inflammatory infiltrate of psoriasis are HLA-DR positive T lymphocytes and factor XIIIa positive dermal dendrocytes. Many investigators studying psoriasis have assumed that the HLA-DR positive T cells are activated, and thereby capable of producing lymphokines such as gamma interferon. However, by immunohistochemical analysis, greater than 95% of the dermal T cells in psoriatic lesions are Ki-67 negative, which suggests that they are in a resting or non-cycling (Go) state. In contrast to the dermal T-cell population, the epidermal T-cell population contains a greater population of Ki-67 positive lymphocytes. The entry of the T cells into the epidermis is, therefore, apparently associated with an important activation event, which in all likelihood involves interaction with the keratinocyte. The presence of activated intraepidermal T cells has been substantiated by the ability to detect gamma interferon mRNA by polymerase chain reaction in epidermal sheets of psoriatic lesions. The pathophysiologic implication in psoriasis for these distinctions and compartmentalization involving dermal and epidermal T cells are placed into the context of a cascade of cellular trafficking events, which are further dissected into a specific network of molecular mediators of inflammation. This report suggests that more attention should be placed on the microenvironment of the skin, with specific emphasis on the mechanism by which T cells accumulate in the dermis and epidermis, and elucidation of the selective inductive and recruitment capabilities of endothelial cells, perivascular dermal dendrocytes, and keratinocytes.

Cell Movement↗
PubMed1990

Cyclosporine A in the treatment of psoriasis: a clinical and mechanistic perspective.

Cyclosporine A, a unique immunomodulatory agent, has been used increasingly over the last 5 years in the management of severe psoriasis. The remarkable efficacy of this drug coupled with its known immunosuppressive properties have enabled a further appreciation of the role of the immune system in the induction and maintenance of psoriatic plaques. Although acting primarily on T lymphocytes, there is also evidence for an effect of cyclosporine A on other constitutive cell types within the skin. The future use of systemically administered cyclosporine A in the treatment of psoriasis and other cutaneous diseases is dependent on the successful balance of efficacy and side-effect profile; namely, the dose-related problems of hypertension and nephrotoxicity. As a result of the toxicity encountered with systemically administered cyclosporine A, attempts to formulate a successful topical preparation for use in cutaneous disease are being made. The advent of cyclosporine A provides the dermatologist with a new therapeutic strategem in the management of psoriasis, although the long-term safety of such interventional therapy remains to be discerned.

Cyclosporine↗
PubMed1990

Cyclophilin content of normal and psoriatic epidermis.

The unique, immunosuppressive agent cyclosporine A has been shown to be of important therapeutic value in the treatment of psoriasis and other inflammatory dermatoses. To investigate the basis for its therapeutic efficacy, the tissue and cellular content of cyclophilin, a cytosolic receptor for cyclosporine A, has been determined in keratome biopsies from normal and psoriatic epidermis and in cultured, adult human keratinocytes. The mean cyclophilin content of normal (n = 10), involved (n = 10), and uninvolved (n = 10) psoriatic epidermal samples was not significantly different (0.126 +/- 0.016, 0.106 +/- 0.009, and 0.153 +/- 0.018 microgram cyclosporine A bound/mg cytosolic protein). Similarly, the cyclophilin content of keratinocytes cultured from normal and psoriatic epidermis (0.21 +/- 0.016 and 0.18 +/- 0.024 microgram/mg protein, respectively) did not differ significantly. Western blot analysis of normal and psoriatic epidermal extracts with monospecific rabbit anti-cyclophilin antisera revealed a single band of 17,000 daltons, which co-migrated with highly purified bovine cyclophilin. The intensity of this band was similar in normal and psoriatic samples, indicating that immunoreactive cyclophilin content was similar. Cyclophilin mRNA was readily detected in normal and involved psoriatic epidermis by RNA blot hybridization, and expression was not significantly different in normal and psoriatic epidermis. These findings indicate that cyclophilin is present in human keratinocytes and epidermis, where it may account for the accumulation of cyclosporine during therapy. However, the similar cyclophilin content of normal and diseased tissue suggests that differences in cyclosporine uptake probably do not account for its therapeutic efficacy in psoriasis.

Blotting, Northern↗
PubMed1990

The role of adhesion molecules, chemotactic factors, and cytokines in inflammatory and neoplastic skin disease--1990 update.

In 1986 it was discovered that cultured human keratinocytes, when treated with gamma interferon, attract and bind T lymphocytes and monocytes. More is now known about trafficking of inflammatory cells in the skin, with specific molecular details involving various cytokines, chemotactic factors, and adhesion molecules. One key element is the in vivo movement of T cells that express LFA-1 into the epidermis, and their subsequent binding to keratinocytes via the surface expression of intercellular adhesion molecule-1 (ICAM-1). This interaction represents a common immunologic pathway, which has been identified in a wide variety of different skin diseases. This review provides a synopsis of advances in this field, which have grown rapidly during the past few years, and adds recent results dealing with coordinate regulation at the gene-transcriptional level of keratinocyte chemotactic factor production and adhesion molecule expression. Moreover, epidermal keratinocytes appear to play a pre-eminent role in the skin, serving as transducing elements converting exogenously applied low-molecular-weight chemical stimuli such as phorbol ester and urushiol (the active ingredient in poison ivy extracts) into the production of endogenously derived immunoregulatory proteins. These keratinocyte-derived molecules may then influence immunocytes and endothelial cells to further amplify the inflammatory response. The identification of keratinocyte-derived molecules such as IL-8 and ICAM-1, which influence the chemotaxis and adherence of T cells, adds substantial evidence supporting an active participatory role for keratinocytes in cutaneous immunohomeostasis. Finally, we highlight the importance of these immunoregulatory molecules in two malignant cutaneous disorders (cutaneous T-cell lymphoma and basal-cell carcinoma) and attempt to integrate these new findings into novel pathophysiologic models for two inflammatory dermatoses (rhus dermatitis and psoriasis).

Biological Factors↗
PubMed1990

Differential modulation of keratinocyte intercellular adhesion molecule-I expression by gamma interferon and phorbol ester: evidence for involvement of protein kinase C signal transduction.

There is growing evidence that keratinocyte (KC) intercellular adhesion molecule-I (ICAM-I) expression is involved in the epidermal trafficking of T lymphocytes. To further characterize the molecular basis of KC ICAM-I expression, the detailed kinetics of induction by gamma interferon (IFN-gamma), as well as the phorbol ester, 12-O tetradecanoylphorbol-13-acetate (TPA), were studied. This study reports that KCs express both the class II major histocompatibility antigen (HLA-DR) and ICAM-I in response to IFN-gamma, although the response is distinctive for each molecule. Also, TPA induces ICAM-I, but not HLA-DR expression, whilst the protein kinase inhibitor, H7, blocks the TPA, but not the IFN-gamma-mediated response. The results provide a molecular basis whereby non-cytokine-mediated stimuli (e.g. TPA) alter KC signal transduction events involving protein kinase-C (PK-C) and thereby generate such immunologically relevant events as ICAM-I expression. Thus, KCs may be targets for both T-cell derived cytokines (e.g. IFN-gamma), and non-cytokine TPA-like molecules which stimulate PK-C. Induction of ICAM-I by either mechanism would be capable of instigating intraepidermal T-cell trafficking.

Cell Adhesion↗