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Biomedical subjects

J C Simon

Publications and source records attributed to J C Simon.

At least 55 records · Page 3Linked to original sources
PubMed1999

Stimulation of CD40 on immunogenic human malignant melanomas augments their cytotoxic T lymphocyte-mediated lysis and induces apoptosis.

Here, we report the functional expression of CD40 on human malignant melanomas (MMs). Comparison of tumor specimen from MM precursor lesions, primary tumors, and metastases revealed that CD40 surface expression is down-regulated during tumor progression. CD40 expression was confirmed in 7 human MM cell lines established from immunogenic primary tumors or metastases, whereas 11 cell lines established from advanced stages were CD40 negative. CD40 expression could be enhanced in CD40-positive MM by stimulation with IFN-gamma and tumor necrosis factor-alpha but not by interleukin (IL)-1beta or CD40 triggering. CD40 ligation on MM by CD40L-transfected murine L-cells or by a soluble CD40L fusion protein up-regulated their expression of intercellular adhesion molecule-1 and MHC class I and class II molecules and their secretion of IL-6, IL-8, tumor necrosis factor-a, and granulocyte macrophage colony-stimulating factor and also induced a rapid activation of the transcription factor nuclear factor kappaB. Furthermore, CD40 ligation of a HLA-A2+, MelanA/MART1+ MM cell line enhanced its susceptibility to specific lysis by a HLA-A2-restricted, MelanA/MART-1-specific CTL clone. Finally, CD40 ligation induced growth inhibition and apoptosis in MM. These results indicate that CD40-CD40L interactions may play an important role in augmenting antitumor immunity and inducing apoptosis in some CD40-positive immunogenic human MMs.

Adjuvants, Immunologic↗
PubMed1999

[Bullous phototoxic contact dermatitis caused by Ruta graveolens L. (garden rue), Rutaceae. Case report and review of literature].

A patient developed severe bullous phototoxic contact dermatitis caused by Ruta graveolens L. (garden rue) which belongs to the Rutaceae family. To date only a few cases of phototoxic reactions to the garden rue have been reported. The phototoxic components of Ruta graveolens L. are the fouranocoumarins 5-methoxypsoralen (bergapten) and 8-methoxypsoralen (xanthotoxine), and the furanoquinoline dictamnine whose phototoxic properties were recently discovered. Since the garden rue is frequently cultivated, it should be considered in the differential diagnosis of phototoxic phytodermatitis.

5-Methoxypsoralen↗
PubMed1999

[Comparison of balneophototherapy and UVA/B mono-phototherapy in patients with subacute atopic dermatitis].

In a controlled prospective study we compared the efficacy of combined salt water bath and UVA/B phototherapy to a UVA/B mono-phototherapy in patients with subacute atopic dermatitis (AD). The patients in the balneophototherapy group (n=16) were treated with baths containing 3-5% of the synthetic salt Psori-sal(trade mark), followed immediately by UVA/B irradiation, while the other treatment arm (n=12) received UVA/B phototherapy alone. After 20 treatments the balneophototherapy group showed a statistically significant (p</=0.0015) reduction of the SCORAD score from 69.5 before to 36.8 after therapy. No statistically significant reduction in the SCORAD score could be observed in the UVA/B phototherapy group (50.6 before to 44.3 after therapy). The cumulative UVB dose was significantly lower in the balneophototherapy group (0.9 J/cm2) as compared to the UVA/B monotherapy group (2.0 J/cm2). Balneophototherapy was well tolerated by patients with atopic dermatitis and no side effects were observed. We conclude that balneophototherapy expands the therapeutic options for patients with subacute atopic dermatitis.

Adult↗
PubMed1999

Colocalization of basic fibroblast growth factor and CD44 isoforms containing the variably spliced exon v3 (CD44v3) in normal skin and in epidermal skin cancers.

Previous in vitro studies have shown CD44 isoforms containing the alternatively spliced exon v3 (CD44v3) to be modified with heparan sulphate (HS) and to bind HS-binding basic fibroblast growth factor (bFGF). Here, we demonstrate that exogenously added bFGF is also bound in vivo by CD44v3-positive keratinocytes in normal skin and by tumour cells in basal cell carcinoma and squamous cell carcinoma (SCC), two skin cancers of keratinocyte origin. bFGF binding and CD44v3 expression were colocalized in cultured human normal keratinocytes (HNK) and on the SCC cell line A431. By contrast, benign or malignant tumours of melanocyte origin failed to express CD44v3 and bound no bFGF. The bFGF binding to normal or transformed keratinocytes in vivo and in vitro was dependent on HS modification, as it was completely eliminated by pretreatment with heparitinase or by blocking with free heparin, whereas chondroitinase had no effect. In addition, specific removal of CD44v3 by antibody-induced shedding also diminished bFGF binding to keratinocytes. Furthermore, bFGF stimulated the proliferation of CD44v3-positive HNK and A431 in a dose-dependent fashion. This bFGF effect was again completely abolished by heparitinase or free heparin, but not by chondroitinase. In aggregate, our results suggest that a function of HS-modified CD44 isoforms such as CD44v3 in skin is to present the HS-binding growth factor bFGF, thereby stimulating the proliferation of normal or transformed keratinocytes.

Antigens, Neoplasm↗
PubMed1999

Analysis of mouse dendritic cell migration in vivo upon subcutaneous and intravenous injection.

Dendritic cells (DC) have an increasingly important role in vaccination therapy; therefore, this study sought to determine the migratory capacity and immunogenic function of murine bone-marrow (BM)-derived DC following subcutaneous (s.c.) and intravenous (i.v.) injection in vivo. DC were enriched from BM cultures using metrizamide. Following centrifugation, the low-buoyant density cells, referred to throughout as DC, were CD11c(high), Iab(high), B7-1(high) and B7-2(high) and potently activated alloreactive T cells in mixed lymphocyte reactions (MLR). In contrast, the high-density cells expressed low levels of the above markers, comprised mostly of granulocytes based on GR1 expression, and were poor stimulators in MLR. Following s.c. injection of fluorescently labelled cells into syngeneic recipient mice, DC but not granulocytes migrated to the T-dependent areas of draining lymph nodes (LN). DC numbers in LN were quantified by flow-cytometric analysis, on 1, 2, 3, 5 and 7 days following DC transfer. Peak numbers of around 90 DC per draining LN were found at 2 days. There was very little migration of DC to non-draining LN, thymus or spleen at any of the time-points studied. In contrast, following i.v. injection, DC accumulated mainly in the spleen, liver and lungs of recipient mice but were largely absent from peripheral LN and thymus. The ability of DC to induce T-cell-mediated immune responses was examined using trinitrobenzenesulphate (TNBS)-derivatized DC (TNBS-DC) to sensitize for contact hypersensitivity responses (CHS) in naive syngeneic recipients. Following s.c. injection, as few as 105 TNBS-DC, but not TNBS-granulocytes, sensitized for CHS responses. However, the same number of TNBS-DC failed to induce CHS following i.v. injection. In summary, this study provides new and quantitative data on the organ specific migration of murine BM-derived DC following s.c. and i.v. injection. The demonstration that the route of DC administration determines the potency of CHS induction, strongly suggests that the route of immunization should be considered in the design of vaccine protocols using DC.

Adoptive Transfer↗
PubMed1999

Reproductive mode and population genetic structure of the cereal aphid Sitobion avenae studied using phenotypic and microsatellite markers.

As French populations of the aphid Sitobion avenae exhibit a range of reproductive modes, this species provides a good opportunity for studying the evolution of breeding system variation. The present analysis combined ecological and genetic investigations into the spatial distribution of variation in reproductive mode. Reproductive mode was characterized in 277 lineages of S. avenae from France, and these aphids were scored for five microsatellite loci. The analyses revealed strong geographical partitioning of breeding systems, with obligate asexuals mostly restricted to the south of France, while lineages producing sexual forms were more common in the north. Contrary to what might be anticipated for organisms with frequent parthenogenesis, there was substantial genic and genotypic diversity, even in the obligately asexual lineages. More than 120 different genotypes were detected among the 277 aphid lineages, with an average of 5.9 alleles per locus (range four to 16) and heterozygosity of 56.7%. As with previous studies of allozyme variation in aphids, most loci showed heterozygote deficits, and disequilibrium was common among allelic variants at different loci, even after removal of replicate copies of genotypes that might have been derived through clonal reproduction. Our results suggest that selection is important in structuring reproductive systems and genetic variation in French S. avenae. Canonical correspondence analysis was employed to examine the associations between genotypic and phenotypic variables, enabling the identification of alleles correlated with life-history traits.

Animals↗
PubMed1999

Molecular markers linked to breeding system differences in segregating and natural populations of the cereal aphid Rhopalosiphum padi L.

The aphid Rhopalosiphum padi shows coexistence of sexual and asexual populations, providing an opportunity to study the evolution of breeding system variation in the context of theories on the origin and maintenance of sex. However, assessments of the distribution of sexual and asexual lineages of this aphid are complicated by the difficulties in rapidly characterizing their breeding system. To facilitate this task and to gain insight into the genetic relatedness between sexual and asexual genotypes, molecular markers linked to breeding system differences were recently developed. In this study, we have successfully converted a random amplified polymorphic DNA (RAPD) marker associated with life-cycle variation in R. padi into a codominant sequences-characterized amplified region (SCAR). Segregating and natural populations of known breeding systems were examined to evaluate the life cycle-SCAR marker association. Complete linkage was found in segregating populations while the association averaged 94% in field populations. Detailed analysis of allelic distribution and sequence divergence of the SCAR locus among sexual and asexual populations provides further evidence for a unique and apparently ancient loss of sexuality in this aphid. It also suggests that occasional gene flow occurs between populations differing in their breeding system, mediated by males produced by 'asexual' lineages. This system provides the possibility for the recurrent emergence of new asexual lineages, ensuring the longer persistence of asexuality, and would have important implications for the assessment of costs and benefits of sex in aphids.

Animals↗
PubMed1999

In vivo UVA-1 and UVB irradiation differentially perturbs the antigen-presenting function of human epidermal Langerhans cells.

Ultraviolet B (UVB, 290-320 nm) radiation is known to suppress the immune function of epidermal Langerhans cells. We have recently described that in vitro UVB irradiation perturbs the antigen-presenting cell function of Langerhans cells by inhibiting their expression of functional B7 costimulatory molecules (B7-1, B7-2). The aim of this study was to determine wavelength-specific UV effects on Langerhans cells function in vivo, specifically UVB and UVA-1. To address this issue, volunteers were irradiated on the sun protected volar aspects of their forearms with 3 x minimal erythema dose of UVB (Philips TL-12) and UVA-1 (UVASUN 5000 Mutzhaas). Langerhans cells were isolated from suction blister roofs immediately following irradiation. Langerhans cells isolated from UVB- but not from UVA-1-irradiated skin failed to activate naïve resting allogeneic T cells (mixed epidermal cell leukocyte reaction) or primed tetanus toxoid reactive autologous T cells. Langerhans cells isolated from sham-irradiated or UVA-1-irradiated skin strongly upregulated B7-2 molecules during short-term tissue culture. By contrast, Langerhans cells from UVB-irradiated skin did not upregulate B7-2 molecules. Furthermore, exogenous stimulation of the B7 pathway by anti-CD28 stimulatory monoclonal antibodies restored the capacity of UVB-irradiated Langerhans cells to activate both alloreactive and tetanus toxoid-reactive T cells, implying suppressed antigen-presenting cell activities and perturbed B7 expression of Langerhans cells isolated from UVB-irradiated skin are related. Those studies demonstrate that in vivo UVB, but not UVA-1, interferes with the activation-dependent upregulation of B7 molecules on Langerhans cells, which in turn is of functional relevance for the perturbed antigen-presenting cell function of Langerhans cells within UVB- but not UVA-1-irradiated skin.

Antigen Presentation↗
PubMed1999

Expression of the adhesion molecules ICAM-1, VCAM-1, LFA-1 and VLA-4 in the skin is modulated in progressing stages of chronic venous insufficiency.

In inflammation and wound healing, dynamic changes in cell adhesion and migration are fundamental properties of the cells involved. Disturbed interaction of leukocytes with microvascular endothelial cells has been proposed to be a central pathogenic factor in chronic venous insufficiency. This disease may therefore serve to elucidate dysregulated modulation of adhesion molecule expression in conditions of chronic inflammation and impaired wound healing. In this study, we determined how the expression of ICAM-1/VCAM-1 on endothelial cells and their ligands LFA-1/VLA-4 on leukocytes is modulated in skin of progressing stages of chronic venous insufficiency. Immunohistochemical staining of skin biopsies revealed an increase in the expression of ICAM-1 and VCAM-1 on endothelial cells in an early stage of venous disease such as stasis dermatitis. Such protein expression correlated with an increase of corresponding mRNA in skin biopsies. Expression of these CAMs on endothelial cells was accompanied by the occurrence of a marked perivascular infiltration of leukocytes, which expressed increased levels of LFA-1 and VLA-4. In progressing stages of chronic venous insufficiency, characterized by hyperpigmentation and lipodermatosclerosis, which precede skin ulceration, all these CAMs remained upregulated on endothelial cells and infiltrating leukocytes. Our findings indicate that following an initial peak expression during stasis dermatitis, vascular ICAM-1 and VCAM-1 expression is not downmodulated to baseline levels, but remains upregulated. This possibly promotes tissue damage by a perpetuated, upregulated influx of activated leukocytes, finally leading to skin ulceration.

Adult↗
PubMed1999

In vitro and in vivo activation of hypericin with the incoherent light source PDT 1200 SOA (520-750 nm) and with solar simulated radiation (290-2500 nm).

The photodynamic active plant pigment hypericin is a possible new photosensitizer for photodynamic therapy. Hypericin shows absorption maxima in the ultraviolet (330 nm) and visible light range (550 and 588 nm). The present study compared the photoactivation of hypericin with the incoherent light source PDT 1200 SOA (520-750 nm) to that with a 1000 watt solar simulator (290-2500 nm). Hypericin displayed dose and time dependent phototoxic effects in the keratinocyte cell line HaCaT in vitro and after intracutaneous in vivo application with both light sources. In vivo, delayed (48 h) photosensitivity in hypericin-sensitized skin was observed. With intracutaneous application of 100 ng/ml hypericin, no phototoxic reaction could be produced. The PDT 1200 SOA was about four times more effective in vitro and about ten times more effective in vivo when compared to the solar simulator. Since the PDT 1200 SOA allows homogenous irradiation of large areas, we conclude that the PDT 1200 SOA is an effective and convenient light source for in vitro and in vivo studies using hypericin.

Anthracenes↗
PubMed1999

Salt water bathing prior to UVB irradiation leads to a decrease of the minimal erythema dose and an increased erythema index without affecting skin pigmentation.

The combination of salt water baths and solar radiation is known as an effective treatment for patients with psoriasis and atopic dermatitis. To determine whether increased susceptibility to UVB radiation may contribute to this therapeutic effect we have studied the effect of bathing the skin in salt water prior to UVB irradiation. Twelve subjects were phototested on the volar aspects of their forearms with increasing doses of UVB radiation. One forearm was exposed to 5% salt water prior to irradiation. The minimal erythema dose (MED) was determined and the erythema index and skin pigmentation were assessed by photometric measurement. The combination of salt water bath and irradiation yielded a significant decrease of the MED when compared to UVB alone (median 90 mJ/cm2 vs 130 mJ/cm2, P < 0.01). Analysis of variance showed a significant influence of salt water bath on erythema (P < 0.05) but not on skin pigmentation. Within the MED test area the erythema index of the salt water exposed forearms was elevated significantly (P < 0.05) while skin pigmentation was not affected. Thus, bathing the skin in salt water leads to a decreased threshold level for the elicitation of UVB-induced erythema and a selective increase of the erythemal response. This sensitization to the effects of shortwave UVB radiation may increase immunosuppressive effects of UVB radiation and may lead to an increased efficacy of UVB phototherapy. However, there is also an increased sunburn risk when salt water baths are followed by exposure to UV radiation.

Adolescent↗
PubMed1998

Urocanic acid and cutaneous antigen presentation.

Exposure to UVB results in the isomerization of trans-urocanic acid (UCA), localized in the stratum corneum, to cis-UCA. Cis-UCA can mediate at least some of the immunosuppressive effects of UVB, though the mechanism of cis-UCA action remains incompletely defined. Here, we review the evidence that cis-UCA acts through alterations in cutaneous antigen presentation.

Animals↗
PubMed1998

[Effect of various salt solutions on ultraviolet B-induced erythema and pigmentation].

The combination of saltwater baths and subsequent ultraviolet irradiation is an effective treatment for psoriasis and atopic dermatitis. The aim of the present study was to determine the photosensitizing properties of two commercially available bath salts, original salt from the Dead Sea and sodium chloride. To address this issue, test areas on the volar aspects of the forearms were soaked with salt solutions for 15 minutes prior to ultraviolet-B (UVB) irradiation. The salt concentrations tested were 1%, 3% 5% and 15%. Tap water followed by UVB and UVB alone served as controls. Erythema was determined by visual and photometric measurement, and delayed tanning was assessed by colorimetry. Erythema obtained by wetting the skin prior to UVB irradiation was more pronounced than erythema induced by UVB alone. The most prominent erythema was yielded by tap water + UVB. The salts had a differing photosensitizing capacity and the strongest erythema was produced by the 5% solutions. There was only a moderate influence on delayed tanning by bathing the skin prior to irradiation. The results from the present study indicate that soaking the skin with salt solutions or tap water increases skin sensitivity to subsequent UVB irradiation. This may contribute to the effectiveness of salt water baths followed by UV irradiation and may account for an increased sunburn risk after bathing.

Adult↗
PubMed1998

Increased expression of platelet-derived growth factor receptor alpha and beta and vascular endothelial growth factor in the skin of patients with chronic venous insufficiency.

Growth factors produced by a variety of cells act as signalling peptides through specific cell surface receptor pathways. Functions such as cell proliferation, migration and differentiation have been assigned to each of them. Here, we report alterations of platelet-derived growth factor receptor alpha (PDGFR-alpha) and beta (PDGFR-beta) and vascular endothelial growth factor (VEGF) expression patterns in the progressive clinical stages of chronic venous insufficiency (CVI). A total of 30 punch biopsies were taken from patients with CVI, and VEGF and PDGFR were detected by indirect immunofluorescence and immunoperoxidase techniques. PDGFR-alpha and PDGFR-beta expression was strongly increased in endothelial cells of capillaries, pericapillary cells and connective tissue cells in the stroma of the skin of venous eczema and venous leg ulcer patients, and to a smaller extend in the dermis of those with lipodermatosclerosis. VEGF staining showed a similar expression pattern in the progressive CVI stages. However, staining of vessels in particular might simply reflect binding of VEGF, secreted by keratinocytes or fibroblasts, to its receptors. Growth factor and receptor expression in specimens from telangiectases and reticular veins, and from pigmented areas, resembled that of normal skin. We conclude that PDGFR-alpha, PDGFR-beta and VEGF play an important role in mediating inflammation and epithelial hyperproliferation in venous eczema, inducing connective tissue sclerosis in lipodermatosclerosis, and causing the reduced reepithelialization tendency in venous ulcers. We speculate that endothelial proliferation with chronic venous hypertension might be mediated by these growth factors.

Adult↗
PubMed1998

Determination of T-lymphocyte adhesion to endothelial cells using a novel luminescence marker.

Here we report the quantification of T cell adhesion to endothelial cells using the luminescence marker BioLite. A new application for this substance was established using a microassay for the detection of TK-1 mouse T-lymphoma cell adhesion to unstimulated or TNF alpha-stimulated eEnd.2 mouse vascular endothelioma cells. Prelabelling of TK-1 with the marker resulted in luminescence values linearly related to the number of adherent T cells. The marker was not toxic for T cells or endothelial cells nor did it interfere with the expression or function of adhesion molecules on T cells (LFA-1, VLA-4) or endothelial cells (ICAM-1, VCAM-1). When compared with established techniques to quantify T cell/endothelial cell adhesion, i.e. microscopical evaluation or isotope prelabelling of T cells, this method was found to be just as reliable and sensitive.

Animals↗
PubMed1998

The low molecular weight Dextran 40 inhibits the adhesion of T lymphocytes to endothelial cells.

Dextrans are complex colloidal macromolecules widely used as haemorrheologic substances and anti-thrombotic agents. Here we describe a novel function of Dextran 40 by demonstrating an inhibition of T lymphocyte adhesion to endothelial cells (EC). We applied an established microassay in which constitutive and tumour necrosis factor-alpha (TNF-alpha)-induced binding of mouse T lymphoma cells (TK-1) to mouse endothelioma (eEND.2) cells is mediated by the interaction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on EC with their counter-receptors the LFA-1 heterodimer (CD11a/CD18) and VLA-4 on T cells. Dextran 40 in therapeutically achievable levels (2-32 mg/ml) reduced both constitutive and TNF-alpha-stimulated TK-1 adhesion to eEND.2. Selective preincubation of eEND.2 or TK-1 revealed that Dextran 40 acted exclusively on the T cells. To explore further the mechanisms by which Dextran 40 interfered with TK-1 adhesion, their LFA-1 and VLA-4 expression was analysed by FACS. The surface expression levels of neither receptor were affected by Dextran 40. However, confocal microscopy revealed that Dextran 40 interfered with the activation-dependent capping and clustering of LFA-1 and VLA-4 on the surface of TK-1. We conclude that Dextran 40 inhibits the capacity of TK-1 T cells to adhere to eEND.2 endothelial cells and thus may be useful for therapeutic intervention in diseases associated with enhanced T lymphocyte binding to microvascular endothelium.

Animals↗
PubMed1998

Activation-dependent modulation of hyaluronate-receptor expression and of hyaluronate-avidity by human monocytes.

During inflammation, activated monocytes (Mo) migrate into tissues where they interact with extracellular matrix components such as hyaluronate (HA), produced in high amounts at inflammatory sites. We determined whether Mo that had invaded sites of cutaneous inflammation bind HA and express the putative HA receptors CD44 isoforms, ICAM-1, or receptor for hyaluronate-mediated motility (RHAMM). In cutaneous inflammation, activated infiltrating Mo displayed high HA avidity and expressed epitopes encoded by CD44s, CD44 variant exons v3, v4, v5, v6, v7, and v9, and ICAM-1, but not RHAMM. We further investigated how activation affects the avidity of Mo for HA and which receptors were responsible for such binding. Mo freshly purified from human peripheral blood bound little HA and expressed CD44s but no epitopes encoded by CD44v exons, ICAM-1, or RHAMM. During short-term tissue culture, Mo upregulated their HA avidity and expression of ICAM-1, CD44s, and epitopes encoded by CD44v, all of which were further augmented by IFN-gamma or lipopolysaccharide, whereas RHAMM was not detectable. Thus in vitro activated Mo resembled Mo that had migrated to inflammatory sites in vivo. Lipolysaccharide or IFN-gamma-induced HA binding was inhibited by more than 90% with monoclonal antibodies directed against N-terminal HA binding domains of CD44s, but not by monoclonal antibodies against CD44v epitopes or ICAM-1. In conclusion, we show that upon in vitro or in vivo activation, Mo enhance their capacity to bind HA. This is critically dependent upon the expression ofCD44s epitopes. Regulated CD44-HA interactions may be important for the ability of Mo to migrate into and within sites of inflammation and for Mo effector functions.

Humans↗