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Biomedical subjects

C A Elmets

Publications and source records attributed to C A Elmets.

At least 37 records · Page 2Linked to original sources
PubMed1997

Phthalocyanine photodynamic therapy: disparate effects of pharmacologic inhibitors on cutaneous photosensitivity and on tumor regression.

The phthalocyanines are promising second-generation photosensitizers that are being evaluated for the photodynamic therapy (PDT) of malignant tumors. In vivo studies with the silicon phthalocyanine Pc 4 have shown that it is highly effective at causing regression of RIF-1 tumors in C3H/HeN mice in PDT protocols. Because cutaneous photosensitivity is the major complication of photosensitizers used for PDT, experiments were performed to evaluate the effect of inhibitors of the inflammatory response (cyproheptadine, dexamethasone, pentoxifylline, and tumor necrosis factor alpha [TNF-alpha] antibodies) on Pc 4-induced cutaneous photosensitivity and tumor regression. The C3H/HeN mice were injected with either Pc 4 or Photofrin and were exposed to 86 J/cm2 of filtered radiation emitted from a solar simulator. Animals were irradiated at 1, 3, 7, 10, 14 and 28 days postinjection. Cutaneous photosensitivity was assessed using the murine ear-swelling response. Cyproheptadine, dexamethasone, pentoxifylline and TNF-alpha antibodies were administered prior to illumination to assess their ability to block Pc 4-induced cutaneous photosensitivity and to evaluate whether such treatment adversely influenced Pc 4 PDT-induced tumor regression. Compared to Photofrin, Pc 4 produced cutaneous photosensitivity that was transient, resolving within 24 h, and that could be elicited for only 10 days after administration. In contrast, Photofrin caused photosensitivity that required 4 days to resolve and could be elicited for at least 1 month after it was administered. The Pc 4-induced cutaneous photosensitivity could be blocked by corticosteroids and an inhibitor of vasoactive amines (cyproheptadine). The TNF-alpha gene transcription was found to increase in keratinocytes following treatment with Pc 4 and light. The anti-TNF-alpha antibodies and pentoxifylline, an inhibitor of cytokine transcription, also prevented cutaneous photosensitivity, implicating TNF-alpha in the pathogenesis of Pc 4-induced cutaneous photosensitivity. None of these agents had any effect on Pc 4 PDT-induced tumor regression. Cyproheptadine, dexamethasone, pentoxifylline and TNF-alpha antibodies may be valuable pharmacologic agents in the management of cutaneous photosensitivity associated with PDT without altering the efficacy of this new therapeutic modality. The findings suggest that it should be possible to devise PDT protocols that block cutaneous photosensitivity without impairing the anti-tumor response to the agents.

Animals↗
PubMed1997

Analysis of tumor-infiltrating lymphocytes in cutaneous squamous cell carcinoma.

OBJECTIVE: To characterize tumor-infiltrating lymphocytes (TILs) within lesions of cutaneous squamous cell carcinoma (SCC) and related disorders. DESIGN: Case series with 1- and 2-color immunohistologic, molecular biological analysis of T-cell clonality and in vitro cytotoxicity assays. SETTING: Academic medical center. PATIENTS: Twenty-one patients, including 6 with actinic keratoses, 4 with SCC in situ, and 11 with invasive SCC. RESULTS: CD8+ TILs were present within lesions of cutaneous SCC and AK. These cells constituted a variable minority of the total T-cell infiltrate, and many expressed a phenotype consistent with major histocompatibility complex-restricted cytotoxic T lymphocytes: CD3+, TIA1+, CD16-, CD56-, CD57-. They also expressed HLA-DR, suggesting their activation in vivo. Virtually all T cells were T-cell receptor (TCR)-beta + delta, indicating that they expressed the TCR-alpha beta protein heterodimer. Molecular biological analysis of TCR-gamma gene rearrangements by the polymerase chain reaction and denaturing gradient gel electrophoresis technique indicated that the TILs were polyclonal. Functional studies suggested that TILs derived from SCC lesions were cytotoxic for autologous tumor cell targets. CONCLUSION: Tumor-infiltrating lymphocytes within cutaneous SCC lesions contain a subpopulation of polyclonal, major histocompatibility complex-restricted cytotoxic T lymphocytes expressing the TCR-alpha beta heterodimer.

Carcinoma, Squamous Cell↗
PubMed1996

Major histocompatibility complex class I molecule serves as a ligand for presentation of the superantigen staphylococcal enterotoxin B to T cells.

Superantigens, such as staphylococcal enterotoxin B (SEB), elicit a strong proliferative response in T cells when presented in the context of major histocompatibility complex (MHC) class II molecules. We observed a similar T-cell response, when MHC class II-negative epidermal cell lines were employed as antigen-presenting cells. Immunoprecipitation studies indicated that the ligand to which SEB bound had a molecular mass of 46 kDa. Radiolabeled SEB could be immunoprecipitated from isolated membrane proteins on the SCC13 epidermal cell line with a monoclonal antibody directed against the MHC class I molecule, and transfection of the K-562 cell line with MHC class I molecules showed a 75% increased SEB-binding capacity compared with the nontransfected MHC class I- and class II-negative counterpart. In functional studies, antibodies to the MHC class I molecule inhibited T-cell proliferation by at least 50%. From these studies, we conclude that MHC class I molecules on malignant squamous cell carcinomas serve as ligands for SEB, which, given the appropriate costimulatory signals, is sufficient to allow for superantigen-induced T-cell proliferation.

Antibodies, Monoclonal↗
PubMed1996

In situ changes in the relative abundance of human epidermal cytokine messenger RNA levels following exposure to the poison ivy/oak contact allergen urushiol.

Abstract: Epidermal keratinocytes in culture have been shown to produce many cytokines, and their proteins have been identified in skin tissue samples. It has therefore been assumed that these cytokines are transcribed in vivo by the epidermis in response to contact allergens. In this report, in situ hybridization was used to detect the messenger RNAs for interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) in samples of human skin prior to and at various times after application of urushiol, the immunogenic component of poison ivy/oak. In sensitive subjects, IL-1 alpha and TNF-alpha mRNAs showed a progressive increase in transcript levels that paralleled the clinical and histological features of the inflammatory process. The time-course of the IL-1 beta response differed from that of IL-1 alpha and TNF-alpha, in that there was an early (by 6 h after urushiol administration) elevation in IL-1 beta mRNA that occurred before there was evidence of inflammation and had returned to background levels by 72 h when the reaction had reached its peak. In contrast to urushiol-sensitive subjects, urushiol-anergic individuals did not exhibit an increase in IL-1 alpha, IL-1 beta or TNF-alpha mRNA levels. The data provide evidence for an in vivo role for epidermal IL-1 alpha, IL-1 beta and TNF-alpha transcription in the regulation of IL-1 beta and TNF-alpha polypeptide levels in the epidermis in response to this common contact allergen.

Adult↗
PubMed1995

Metabolic requirements for induction of contact hypersensitivity to immunotoxic polyaromatic hydrocarbons.

Experiments were performed to define the metabolic requirements for induction of contact hypersensitivity to polyaromatic hydrocarbons (PAHs), environmental xenobiotics that are both immunotoxic and carcinogenic. Evidence that conversion of the parent compound to a reactive metabolite was necessary for the development of contact hypersensitivity included the fact 1) that contact hypersensitivity to the polyaromatic hydrocarbon dimethylbenz(a)anthracene (DMBA) only occurred in strains of mice that could metabolize the compound, 2) that among the PAHs, only those that could induce aryl hydrocarbon hydroxylase, the rate-limiting enzyme in the PAH metabolic pathway, were immunogenic, and 3) that inhibitors of PAH metabolism reduced DMBA contact hypersensitivity. Cells from the XS52 Langerhans cell-like dendritic cell line were able to metabolize the PAH benzo(a)pyrene to its diol, quinone, and phenol metabolites. GM-CSF augmented benzo(a)pyrene metabolism in XS52 cells. Finally, in vivo depletion of CD8+, but not CD4+, T cell populations inhibited contact hypersensitivity to DMBA. The implications of these experiments are that at least for some contact allergens, the metabolic status of the host is a key determinant of individual susceptibility to the development of allergic contact dermatitis, and the metabolic pathway of an individual hapten may have ramifications for the T cell subpopulation-CD4 or CD8-that is activated.

Animals↗
PubMed1995

Photoexacerbation of cutaneous lupus erythematosus due to ultraviolet A emissions from a photocopier.

This report describes a woman with systemic lupus erythematosus (LE) who worked as a photocopy technician and developed cutaneous LE of the hands, neck, face, and chest. Her skin lesions improved when she discontinued her employment. Testing of several photocopy devices showed emission of small quantities of ultraviolet A (UVA), but no UVB. Phototesting of the patient with UVA and UVB induced skin lesions that were clinically and histopathologically consistent with LE. Thus, the action spectrum of cutaneous LE may be within the UVB range, the UVA range, or both ranges of the solar spectrum, and repeated exposure to short bursts of light may induce clinical disease. This case suggests that occupational sources of UV light should be considered as possible exacerbating factors in LE.

Biopsy↗
PubMed1995

Cutaneous photosensitivity diseases induced by exogenous agents.

Cutaneous photosensitivity diseases may be idiopathic, produced by endogenous photosensitizers, or associated with exogenous photosensitizers. Those caused by exogenous agents include phototoxicity, photoallergy, and the exacerbation or induction of systemic disorders in which photosensitivity is a prominent clinical manifestation. Phototoxic disorders have a high incidence, whereas photoallergic reactions are much less frequent. The action spectra for most phototoxins and photoallergens lie in the UVA range. Phototoxic and photoallergic reactions can be distinguished on the basis of pathogenesis, clinical characteristics, diagnosis, and management. Drugs capable of causing phototoxic reactions include psoralens, porphyrins, coal tar, antibiotics, and nonsteroidal antiinflammatory agents. Drugs capable of causing photoallergic reactions include topical antimicrobial agents, fragrances, sunscreens, nonsteroidal antiinflammatory agents, plants, and psychiatric medications. Drug-induced systemic diseases in which photosensitivity is a prominent component include drug-induced lupus erythematosus, porphyria, and pellagra.

Allergens↗
PubMed1995

Reduced growth factor requirements and accelerated cell-cycle kinetics in adult human melanocytes transformed with SV40 large T antigen.

Melanomas develop with high frequency in transgenic mice in which oncogenic sequences of the SV40 DNA tumor virus have been specifically targeted to melanocytes. To investigate the role of SV40 in melanomagenesis, cultured human melanocytes were transformed with a retroviral shuttle vector encoding the SV40 large T antigen and examined for changes in cell-cycle kinetics and growth-factor dependence. Colonies expressing the viral oncogene were morphologically indistinguishable from their non-T-antigen-transformed counterparts. Also like normal melanocytes, the infected cells remained anchorage dependent and non-tumorigenic in nude mice. However, T-antigen-positive cultures exhibited significantly accelerated population doubling times, increased saturation densities with highly confluent monolayers and a three- to fourfold extended life span. Most interestingly, cell-cycle analysis revealed a measurable shift from quiescent to cycling cells in T-antigen-expressing cultures and an acquired ability to progress more rapidly through G1. Moreover, T-antigen-positive melanocytes proliferated in the absence of PMA and required markedly reduced levels of exogenous bFGF. These studies indicate that the viral oncogen of simian virus 40 provides melanocytes with distinct growth advantages that may render these cells unusually susceptible to additional environmental challenges necessary for full expression of the malignant phenotype.

Adult↗
PubMed1995

Messenger RNAs for the multifunctional cytokines interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor-alpha are present in adnexal tissues and in dermis of normal human skin.

Interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) are 3 cytokines that play a key rôle in cutaneous homeostasis and in the immunopathogenesis of a number of dermatologic diseases. Most studies have focused on their production by keratinocytes and Langerhans cells. To determine whether there are non-epidermal sites of cytokine transcription, biopsy specimens of normal human skin were probed for IL-1 alpha, IL-1 beta and TNF-alpha messenger RNAs using the method of in situ hybridization. The results demonstrate that each cytokine mRNA is present at multiple sites within the skin, including epidermal appendages and adnexal structures (hair follicles, sebaceous glands), the dermal microvasculature, arrectores pilorum smooth muscle, and the dermal connective tissue. These data provide evidence that in vivo there are multiple sites other than the epidermis of constitutive IL-1 alpha, IL-1 beta, and TNF-alpha gene transcription in normal human skin.

Hair Follicle↗
PubMed1995

Protection against ultraviolet-B radiation-induced local and systemic suppression of contact hypersensitivity and edema responses in C3H/HeN mice by green tea polyphenols.

Exposure of skin to UV radiation can cause diverse biological effects, including induction of inflammation, alteration in cutaneous immune cells and impairment of contact hypersensitivity (CHS) responses. Our laboratory has demonstrated that oral feeding as well as topical application of a polyphenolic fraction isolated from green tea (GTP) affords protection against the carcinogenic effects of UVB (280-320 nm) radiation. In this study, we investigated whether GTP could protect against UVB-induced immunosuppression and cutaneous inflammatory responses in C3H mice. Immunosuppression was assessed by contact sensitization with 2,4-dinitrofluorobenzene applied to UVB-irradiated skin (local suppression) or to a distant site (systemic suppression), while double skin-fold swelling was used as the measure of UVB-induced inflammation. Topical application of GTP (1-6 mg/animal), 30 min prior to or 30 min after exposure to a single dose of UVB (2 kJ/m2) resulted in significant protection against local (25-90%) and systemic suppression (23-95%) of CHS and inflammation in mouse dorsal skin (70-80%). These protective effects were dependent on the dose of GTP employed; increasing the dose (1-6 mg/animal) resulted in an increased protective effect (25-93%). The protective effects were also dependent on the dose of UVB (2-32 kJ/m2). Among the four major epicatechin derivatives present in GTP, (-)-epigallocatechin-3-gallate, the major constituent in GTP, was found to be the most effective in affording protection against UVB-caused CHS and inflammatory responses. Our study suggests that green tea, specifically polyphenols present therein, may be useful against inflammatory dermatoses and immunosuppression caused by solar radiation.

Animals↗
PubMed1994

Management of common superficial fungal infections in patients with AIDS.

Cutaneous fungal infections are a major source of morbidity in HIV-infected patients, and their management poses special challenges. Superficial mycoses, such as tinea pedis, tinea cruris, tinea corporis, and onychomycosis, are no more common in HIV-infected patients than in the HIV-negative population but are of greater severity. Although they respond to topical and systemic antifungal agents, HIV-positive patients are predisposed to frequent recurrences. Unusual types of fungal infections such as Majocchi's granuloma are more likely to develop in HIV-infected patients and respond best to systemic antifungal therapy with imidazoles or triazoles. Infections with Candida albicans develop in virtually all HIV-positive patients. Although mucosal involvement is the most common, patients may also develop superficial cutaneous infections. Topical agents are frequently all that is necessary, but in some, oral medications are required. Although fluconazole is effective, an appreciable number of isolates are resistant. Patients with pityriasis versicolor and seborrheic dermatitis, in which Pityrosporum species are thought to be involved, respond well to short courses of oral ketoconazole. Milder forms of seborrheic dermatitis can also be treated with low-potency topical steroids or topical ketoconazole. The oral triazole fluconazole is not particularly effective in the management of seborrheic dermatitis. Although the cause of eosinophilic pustular folliculitis, a common disorder in immunosuppressed HIV-positive patients, is unknown, some can be cured with high doses of itraconazole, suggesting that fungi are important in the pathogenesis of the disease in some patients.

Acquired Immunodeficiency Syndrome↗
PubMed1994

An inflammatory eruption associated with recombinant human IL-6.

Interleukin 6 (IL-6) is an endogenous cytokine with multiple biological functions, including amplification of the inflammatory response. Recombinant human IL-6, administered as part of a chemotherapeutic regimen, has recently been shown to cause regression of certain types of malignant tumours. We report a patient who developed a cutaneous eruption consisting of coalescent, erythematous, scaling macules and papules after administration of recombinant human IL-6, given as part of her chemotherapy for ductal carcinoma of the breast.

Adult↗
PubMed1994

In situ detection of cytokine messenger RNAs in the eccrine sweat gland of normal human skin.

Human sweat and eccrine sweat glands contained the multifunctional polypeptide cytokines, interleukin-1 alpha and beta (IL-1 alpha and beta). To determine whether the sweat gland itself is an actual site of transcription for cytokines we performed in situ hybridization on histologic sections of normal human skin. In this report we show that the mRNAs encoding the cytokines IL-1 alpha, IL-1 beta, and tumor necrosis factor-alpha (TNF-alpha) are present in normal human skin eccrine sweat gland duct and secretory coil epithelium. These results suggest that in vivo the sweat gland is a production site for cytokine polypeptides and may contribute to the exceedingly large quantities of these cytokine proteins found in the epidermis.

Cytokines↗
PubMed1993

In situ expression of a B7-like adhesion molecule on keratinocytes from human epidermis.

The B7 adhesion molecule, a member of the immunoglobulin superfamily, has previously been identified primarily on cells of hematopoietic origin. Because B7 has been shown to facilitate interactions with T cells and because cells of the epidermis are proficient at binding and activating T lymphocytes, studies were performed to determine whether B7 was expressed in human epidermis. A subpopulation of brightly staining B7-positive cells was observed in situ in normal human epidermis. Flow-cytometric examination of epidermal cell suspensions that had been cultured for 24 h or longer demonstrated that between 10 and 40% of cells expressed B7 or a closely related antigen. Immunoelectron microscopy, double-staining procedures, and examination of epidermal suspensions depleted of Langerhans cells all confirmed that the B7-positive cells were keratinocytes. These studies identify human epidermal keratinocytes, a non-hematopoietic cell population, as a cell type capable of expressing a B7-like adhesion molecule.

Animals↗
PubMed1993

Modulation of interferon-gamma-induced HLA-DR expression on the human keratinocyte cell line SCC-13 by ultraviolet radiation.

Cell surface expression of major histocompatibility determinants on epidermal keratinocytes is a characteristic feature of a number of inflammatory dermatoses and in all likelihood is caused by diffusion of human leukocyte antigen (HLA)-DR-inducing cytokines from cells present in the dermal mononuclear cell infiltrate. Many of these same disorders respond to ultraviolet (UV) radiation phototherapy. Using the human SCC-13 keratinocyte cell line as a model, UV radiation was found to inhibit interferon-gamma-induced HLA-DR expression. Inhibition correlated closely with decreased steady-state levels of HLA-DR mRNA. These findings provide evidence that the therapeutic effect of UV radiation phototherapy may be mediated by its capacity to down-regulate cytokine-induced keratinocyte HLA-DR expression.

Cell Line↗
PubMed1992

Immunogenetic influences on the initiation stage of the cutaneous chemical carcinogenesis pathway.

While it is generally agreed that environmental exposure to solar radiation and to certain classes of chemicals are the major causes of nonmelanoma skin cancer, it is also believed that genetic polymorphisms regulating immunological responses are important determinants of individual susceptibility to skin cancer. However, little is known about their interactions with the chemical carcinogenesis pathway prior to the actual development of tumors. This issue was examined by comparing susceptibility to skin cancer in C3H/HeN and C3H/HeJ mice, two strains that differ only at the lipopolysaccharide genetic locus, which serves as a regulator of a number of immunological activities. When subjected to a two-stage cutaneous tumorigenesis protocol, C3H/HeJ mice, which have a mutation at the lipopolysaccharide genetic locus that renders them deficient in their capacity to produce cytokines and to activate macrophages, developed nearly three times as many tumors as did C3H/HeN mice, which do not have this mutation. Epidermal DNA binding of 7,12-[3H]dimethylbenz(alpha)anthracene, an index of tumor initiation, was also significantly greater in C3H/HeJ than in C3H/HeN mice. Immunological activities regulated by the lipopolysaccharide genetic locus thus confer resistance to DMBA-induced cutaneous tumorigenesis in mice and are associated with changes that occur early in the tumorigenesis pathway, prior to the development of tumors.

9,10-Dimethyl-1,2-benzanthracene↗