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Biomedical subjects

C A Elmets

Publications and source records attributed to C A Elmets.

At least 55 records · Page 3Linked to original sources
PubMed1992

Ultraviolet B-irradiated antigen-presenting cells display altered accessory signaling for T-cell activation: relevance to immune responses initiated in skin.

A principal mechanism by which ultraviolet (UV) B radiation exerts its selective and antigen-specific suppressive influence on immune responses is through its effects on the capacity of antigen-presenting cells (APC) in skin, primarily Langerhans cells (LC), to differentially activate T-cell subsets. Recent evidence has indicated that LC, following UVB radiation, lose the capacity to stimulate proliferation of CD4+ Th1, but not of Th2, clones. Additional work has shown this acquired unresponsiveness of Th1 cells to represent a long-lasting form of clonal anergy that results from a block in their ability to produce IL-2. Although not completely delineated, these defects appear to be the result of preserved delivery of the primary signal transduced by interaction of the MHC/antigen complex on APC with the T-cell receptor complex, in the absence of a viable second signal normally delivered by interaction of a co-stimulatory factor from APC with its appropriate ligand on the T cells. These findings support the notion that the outcome of certain immune responses depends greatly upon conditions that are brought to bear on APC and T cells during the time of antigen presentation.

Animals↗
PubMed1992

Photodynamic therapy of chemically- and ultraviolet B radiation-induced murine skin papillomas by chloroaluminum phthalocyanine tetrasulfonate.

Photodynamic therapy (PDT) of cancer combines irradiation of tumors with visible light following selective uptake of the photosensitizer by the tumor cells. PhotofrinR-II (Pf-II) is the only photosensitizer which is in clinical use in PDT, whereas chloroaluminum phthalocyanine tetrasulfonate (AlPcTS) has also shown promise in preclinical studies. In most such studies, the effectiveness of the photosensitizers has been assessed in implanted tumor model systems rather than in model systems where tumors are allowed to grow in their own connective tissue matrix. In this study the pharmacokinetics, tumor ablation capability and cutaneous photosensitization response of AlPcTS have been assessed in mice bearing chemically- and ultraviolet B radiation (UVB)-induced benign skin papillomas. When tumor-bearing animals were injected intraperitoneally with AlPcTS (5 mg/kg body wt), maximum tumor:normal skin ratio of 2.4 was observed at 48 h, at which time the mice were irradiated within the absorption spectrum of the photosensitizer. In tumor ablation studies with SENCAR mice bearing chemically-induced skin tumors, AlPcTS resulted in greater than 80% ablation in tumor volume at 20 days post-irradiation. In cutaneous photosensitization response, AlPcTS produced only transient effects (no effect after 24 h) in SENCAR mice. Pharmacokinetics data, tumor ablation effects and cutaneous photosensitization response of AlPcTS were comparable in SKH-1 hairless mice bearing UVB-induced skin tumors. Our data indicate that AlPcTS produces significant photodynamic effects towards the ablation of murine skin tumors, and that it does not produce prolonged cutaneous photosensitivity.

Animals↗
PubMed1992

Ultraviolet-irradiated monocytes efficiently inhibit the intracellular replication of Mycobacterium avium intracellulare.

The purpose of this study was to evaluate the effect of ultraviolet (UV) radiation on the antimicrobial activities of monocytes for the intracellular pathogen Mycobacterium avium intracellulare (MAI). UV radiation augmented monocyte antimicrobial activity for MAI in a dose-dependent fashion. UVB doses of greater than or equal to 25 J/m2 resulted in a 50-100-fold reduction in MAI growth 7 d after initiation of culture. The increased monocyte antibacterial effect could be blocked by a plate glass filter, indicating that wavelengths within the UVB were responsible for the effect. UV radiation did not stimulate monocyte phagocytosis, and enhanced inhibition of MAI growth was observed in populations of adherent mononuclear cells that were devoid of T cells. This suggested that UV radiation acted directly to augment intrinsic monocyte antimicrobial activities. The administration of 8-methoxypsoralen plus UVA radiation to monocytes also augmented their antimicrobial activities against MAI. UV radiation thus may serve as a unique agent by which to evaluate the mechanisms by which mononuclear phagocytes control the growth of MAI.

Blood Bactericidal Activity↗
PubMed1992

Photoprotective effects of sunscreens in cosmetics on sunburn and Langerhans cell photodamage.

It has become common practice to add sunscreening agents of variable potency to cosmetics to protect against the adverse effects of ultraviolet (UV) radiation exposure. The purpose of this study was to determine whether cosmetic preparations containing sunscreening agents protected against the adverse effects of acute UV radiation exposure and, if so, to identify the components responsible for the photoprotective effects. Pretreatment of skin with one such cosmetic product provided complete protection against UV-induced erythema, sunburn cell formation and Langerhans cell damage in volunteers, skin types II and III, whose skin was exposed to a 1.5 minimal erythema dose daily for 4 consecutive days. When individual components of the cosmetic preparation were analyzed for their photoprotective activities, it was found that both the cinnamate and benzophenone sunscreen combination and an extract of baker's yeast present in the preparation had photoprotective properties. These studies indicate that incorporation of photoprotective agents into cosmetic preparations provides a beneficial function and should therefore be encouraged.

Adolescent↗
PubMed1991

The accessory function of B lymphocytes is resistant to the adverse effects of UV radiation.

The effect of UV radiation on the accessory activities of B lymphoblastoid cell lines (B-LCL) was investigated in three types of in vitro T lymphocyte proliferation assay, each of which differed in its accessory requirements. In contrast to monocytes whose accessory function was universally sensitive to UV radiation, B-LCL were resistant to UV in oxidative mitogenesis and staphylococcal enterotoxin B assays, in which stimulus processing was not a requirement. Expression of membrane interleukin (IL) 1 and HLA-DR antigens by B-LCL and monocytes was not affected by UV, nor was surface membrane expression of intercellular adhesion molecule-1 (ICAM-1) on B-LCL. These results were in marked contrast to monocytes in which there was a greater than 65% reduction in ICAM-1 expression. When UV-irradiated B-LCL were employed as antigen-presenting cells for tetanus toxoid-dependent T cell stimulation, a reduction in antigen-presenting function was observed. However, pulsing of B-LCL with tetanus toxoid prior to UV irradiation preserved their antigen-presenting capacity in this system also. These findings indicate that there is differential UV sensitivity among accessory cells which may be explained by different effects of UV radiation on antigen processing and adhesion molecule expression.

B-Lymphocytes↗
PubMed1991

Eosinophilic pustular folliculitis.

Eosinophilic pustular folliculitis is characterized by the spontaneous development of recurrent, sterile papules, pustules, and plaques on the face, trunk, arms, and occasionally the palms and soles. Although the large majority of the reported cases have occurred in Eastern Asians, most patients in the United States have been infants or men seropositive for human immunodeficiency virus. We describe a North American woman with eosinophilic pustular folliculitis who was neither seropositive for human immunodeficiency virus nor of Asiatic descent.

Adult↗
PubMed1991

Photodynamic therapy of murine skin tumors using Photofrin-II.

Photodynamic therapy (PDT) is a new experimental cancer therapy in which a photosensitizing chemical that selectively localizes within tumors is given to a tumor-bearing individual and the tumor is then irradiated by wavelengths within the visible spectrum of the photosensitizer. The only photosensitizer currently approved for human clinical trials is Photofrin-II (Pf-II). In most preclinical studies, the effectiveness of Pf-II has been assessed in implanted tumor models rather than in systems in which tumors are grown in their own connective tissue matrix. In this study, the pharmacokinetics, tumor ablation capability and cutaneous photosensitizing capacity of Pf-II were assessed in mice bearing chemically induced or ultraviolet B radiation (UVB)-induced benign skin neoplasms. Intraperitoneal administration of Pf-II (5 mg/kg body weight) to tumor-bearing animals showed maximum tumor: normal skin ratio of the photosensitizer at 72 h. When SENCAR mice bearing chemically induced tumors were irradiated with visible light corresponding to the absorption spectrum of the photosensitizer, up to 89% ablation in tumor volume at 20 d post-irradiation was observed. Animals treated with Pf-II and exposed to visible light showed significant cutaneous photosensitization for at least 6 d after-irradiation. Treatment of SKH-1 hairless mice bearing UVB-induced cutaneous neoplasms with Pf-II exhibited similar pharmacokinetics, skin tumor ablation effects and cutaneous photosensitivity. Our data indicate that Pf-II has significant activity towards the ablation of murine skin benign tumors grown in their own tissue matrix, suggesting that such a murine skin tumor model system could be valuable in evaluating the photodynamic effects of newly developed photosensitizers.

Animals↗
PubMed1990

UVB radiation and human monocyte accessory function: differential effects on pre-mitotic events in T-cell activation.

Purified T lymphocytes fail to proliferate in response to antigenic and mitogenic stimuli when cultured in the presence of accessory cells that have been exposed in vitro to sublethal doses of UVB radiation. Because proliferation represents a final stage in the T-cell activation process, the present study was conducted to determine whether T cells were able to progress through any of the pre-mitotic stages when UVB-irradiated monocytes were used as model accessory cells. In these experiments, monoclonal anti-CD3 antibodies were employed as the mitogenic stimulus. Culture of T cells with UVB-irradiated monocytes did allow the T cells to undergo an increase in intracellular free calcium, which is one of the first steps in the activation sequence. The T cells expressed interleukin-2 receptors, although at a reduced level. However, T cells failed to produce interleukin-2 above background levels when they were placed in culture with monocytes exposed to UVB doses as low as 50 J/m2. Incubation of T cells with UVB-irradiated monocytes did not affect the subsequent capacity of T cells to proliferate, since they developed a normal proliferative response in secondary culture when restimulated with anti-CD3 antibodies and unirradiated monocytes. These studies indicate that T lymphocytes become partially activated when cultured with UVB-irradiated monocytes and mitogenic anti-CD3 monoclonal antibodies. In addition, they suggest that interleukin-2 production is the T-cell activation step most sensitive to inhibition when UVB-irradiated monocytes are employed as accessory cells.

Antigens, CD↗
PubMed1990

Cell membrane is a major locus for ultraviolet B-induced alterations in accessory cells.

In vitro ultraviolet B (UVB) irradiation of human blood monocytes inhibits their accessory cell function for antigen- and mitogen-induced T cell responses. These studies were designed to characterize the nature of the UVB-induced defect in human monocyte accessory cell function. Irradiated monocytes were deficient in their ability to serve as accessory cells for OKT3-induced T cell activation. In vitro exposure of monocytes to 100 J/m2 UVB completely inhibited the T cell proliferative response (51502 cpm, non-UVB-irradiated; 302 cpm, UVB-irradiated). Analysis of the accessory signals altered by UVB indicated that irradiated monocytes were incapable of binding to OKT3 molecules attached to the CD3 antigen on T cells. Provision of an alternative mechanism for binding of OKT3 molecules by attaching anti-mouse IgG to the bottom of microtiter wells completely restored accessory cell function. Further characterization of the defect demonstrated that UVB radiation did not deplete p72 Fc receptors from the surface of irradiated monocytes. However, UVB exposure did produce a dose-dependent decrease in monocyte membrane expression of ICAM-1. It is proposed that UVB radiation leads to changes within the cell membrane that inhibit the ability of monocytes to express selected molecules necessary for binding of T cells.

Antibodies, Monoclonal↗
PubMed1989

Inhibition of the high affinity Fc receptor (Fc gamma RI) on human monocytes by porphyrin photosensitization is highly specific and mediated by the generation of superoxide radicals.

p72 high affinity receptors (Fc gamma RI) for the Fc portion of IgG molecules on human peripheral blood monocytes mediate a variety of beneficial functions, but also have deleterious effects in certain clinical situations. In the present study, the photosensitizing porphyrins hematoporphyrin derivative and dihematoporphyrin ether (DHE), which are known to preferentially affect the cell membrane, were found to significantly inhibit binding of mouse IgG2a antibodies to the ligand binding site of Fc gamma RI on human peripheral blood monocytes and the U937 human monocytic cell line. Fc gamma RI receptors could be identified with a monoclonal antibody which recognizes an epitope distinct from the ligand binding site, indicating that photosensitization induced a structural alteration rather than loss of the receptor molecule from the cell surface. The effect of DHE and light appeared to be highly specific, since binding of monoclonal antibodies to other surface structures was not decreased. DHE plus light-induced modulation of Fc gamma RI was found to be mediated by superoxide anions, since addition of a mimic of superoxide dismutase restored both binding of mouse IgG2a to Fc gamma RI as well as human monocyte accessory cell function. These studies identify porphyrin photosensitization as a unique mechanism by which to selectively down-regulate Fc gamma RI-mediated functions.

Antibodies, Monoclonal↗
PubMed1989

Effects of occlusive and semiocclusive dressings on the return of barrier function to transepidermal water loss in standardized human wounds.

Clinical observation and histologic examination of excised wounds have confirmed that occlusive dressings promote rapid wound reepithelialization. However, normalization of barrier function has not been routinely assessed in studies of occlusive dressing effects on wound healing. We examined the effects of occlusive dressings on the reestablishment of the cutaneous barrier to transepidermal water loss (TEWL) after standardized skin wounds were produced in human subjects. We confirmed previous observations that occlusive dressings augment reepithelialization. No significant improvement in the rate of reestablishment of the barrier to TEWL was measured between the covered test or uncovered control sites in each subject, however. TEWL declined in an exponential fashion after wounding. Measurements of TEWL were over twice that of adjacent normal skin when epithelialization was judged to be overtly complete and did not return to normal until 4 weeks after wounds were produced.

Adult↗
PubMed1989

A novel mechanism for the generation of superoxide anions in hematoporphyrin derivative-mediated cutaneous photosensitization. Activation of the xanthine oxidase pathway.

Prior studies, both in vitro and in vivo, have suggested that cutaneous porphyrin photosensitization requires the generation of superoxide anion (.O2-) and various other reactive oxygen metabolites. No unifying concept has emerged, however, that unequivocally demonstrates the source of generation of these species. Since xanthine oxidase is known to generate .O2- in reperfused ischemic tissue and in certain inflammatory disorders, we attempted to assess its role in porphyrin photosensitization. C3H mice were rendered photosensitive by the intraperitoneal administration of dihematoporphyrin ether (DHE) (5 mg/kg) followed by irradiation with visible light. Murine ear swelling was used as a marker of the acute photosensitization response and involvement of oxygen radicals was evaluated using electron spin resonance (ESR) spectroscopy. The administration of allopurinol, a potent inhibitor of xanthine oxidase, afforded 90% protection against DHE-mediated acute photosensitivity in vivo. Furthermore, xanthine oxidase activity was twofold higher in the skin of photosensitized mice than in unirradiated animals. ESR spectra of 5,5-dimethyl-1-pyrroline N-oxide-trapped radicals from the skin of photosensitized mice verified the presence of .O2- and .OH, while neither of these species was detected in the skin of control mice or mice receiving allopurinol. The administration of a soybean trypsin inhibitor or verapamil before irradiation also partially blocked the photosensitivity response, suggesting that calcium-dependent proteases play a role in the activation of xanthine oxidase in this photodynamic process. These data provide in vivo evidence for the involvement of .O2- in DHE-mediated cutaneous photosensitization and suggest that these radicals are generated through the activation of the xanthine oxidase pathway. The administration of allopurinol and calcium channel blockers may thus offer new approaches for the treatment of cutaneous porphyrin photosensitization.

Allopurinol↗
PubMed1988

In situ evidence for the involvement of superoxide anions in cutaneous porphyrin photosensitization.

Dihematoporphyrin ether, also known as Photofrin-II (Pf-II) is currently used in the diagnosis and management of a variety of epithelial neoplasms, in a modality known as photodynamic therapy (PDT). A major drawback of these porphyrins for PDT is their ability to evoke prolonged cutaneous photosensitization. The mechanism of tumor ablation and cutaneous photosensitization by these photosensitizers is thought to relate to the generation of one or more reactive oxygen species such as superoxide anion, singlet oxygen and hydroxyl radical. However, the role of these oxygen species has not been established unequivocally. In this study, the mechanism of Pf-II-mediated cutaneous photosensitization was examined using murine ear swelling as a marker. The mice treated with Pf-II and light demonstrated two-fold enhancement of ear swelling whereas animals treated with the SOD mimic, beta-carotene and dimethyl sulfoxide (DMSO) had considerably less ear swelling (p less than 0.01). The observed protective effect was dependent on the dose of each quencher and followed the pattern SOD mimic DMSO beta-carotene. The histopathologic alterations caused by Pf-II photosensitization were significantly alleviated by pretreatment with SOD mimic whereas beta-carotene and (DMSO) were less effective. Inhibitors of superoxide dismutase (sodium diethyldithiocarbamate) and catalase (hydroxyl amine and 3, amino 1,2,4-triazole) augmented Pf-II-mediated cutaneous photosensitization. These data provide the first in vivo evidence for the involvement of superoxide anion in cutaneous porphyrin photosensitization.

Animals↗
PubMed1988

Impaired immunological surveillance by 7,12-dimethylbenz(a)anthracene augments its skin tumorigenicity in C3H mice.

7,12-dimethylbenz(a)anthracene (DMBA) is a polyaromatic hydrocarbon with potent mutagenic, carcinogenic and immunomodulatory activities. It has been postulated that the immunosuppressive effects of DMBA may contribute to the carcinogenicity of this agent. We investigated this issue by examining whether the pre-administration of DMBA at one skin site would augment its carcinogenic activity at a distant skin site. In animals placed on a cutaneous chemical carcinogenesis protocol to the skin of the back, pre-sensitization with DMBA to the abdomen augmented skin tumorigenicity whether the tumor data are considered as cumulative number of tumors, percent of mice with tumors, number of tumors per mouse, or numbers of tumors per tumor bearing mouse as a function of weeks on test. These data demonstrate that pre-treatment with DMBA augments its skin tumorigenicity by impairing immunological surveillance.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Induction of contact hypersensitivity to dimethylbenz(a)anthracene and benzo(a)pyrene in C3H/HeN mice.

The potential for allergic contact sensitization to two polyaromatic hydrocarbons, 7,12-dimethylbenz(a)anthracene and benzo(a)pyrene, was investigated in C3H/HeN mice. For each agent, contact hypersensitivity was achieved by applying a 100-micrograms dose to the shaved abdomen. An ear swelling response was observed following application of 20 micrograms of the sensitizing dose to the ear dorsum, whereas unsensitized animals or animals sensitized to the alternate agent did not develop ear swelling. Histological sections of DMBA-challenged ears revealed edema with a marked dermal mononuclear infiltrate. Following adoptive transfer of draining lymph node cells of DMBA-sensitized mice to naive syngeneic mice, ear challenge of recipient mice with the same agent resulted in an ear swelling response. This demonstration of in vivo cell-mediated immunological reactivity to polyaromatic hydrocarbon carcinogens indicates that the immune system can interact with and, potentially, modify the course of chemical carcinogens at a time prior to morphological changes or development of tumor-specific transplantation antigens.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Inhibition of postbinding target cell lysis and of lymphokine-induced enhancement of human natural killer cell activity by in vitro exposure to ultraviolet B radiation.

In vitro exposure of human peripheral blood mononuclear cells (PBMC) to ultraviolet B (uvB) radiation has been shown to inhibit natural killer (NK) cell-mediated cytotoxicity in a dose-dependent fashion. The purpose of this study was to examine the manner by which uvB produced these deleterious effects. Inhibition of NK activity was not due to lethal injury to NK cells since the viability of cell populations enriched for NK activity was greater than 90% with the uvB doses employed. uvB appeared to directly affect NK cells since procedures which removed suppressor mechanisms, such as removal of monocytes and pharmacologic inhibition of the cyclooxygenase pathway, failed to reverse the response. Furthermore, no suppression of activity of unirradiated NK cells could be produced by coincubation of unirradiated NK cells with uv-irradiated NK cells. When the single cell assay for binding and killing was employed to determine at which stage in the lytic sequence inhibition occurred, it was found that binding was normal but lysis of bound targets and the recycling capacity of active NK cells were markedly reduced. At uvB doses above 50 J/m2, both interferon alpha (IFN-alpha) and interleukin 2 (IL-2) were ineffective in augmenting NK cell-mediated cytotoxic reactions after cells had been irradiated with uvB. Furthermore, incubation of NK cells with IFN-alpha prior to irradiation failed to protect against the inhibitory effects. These studies provide evidence that in vitro exposure of NK cells to uvB radiation inhibits their function by a direct nonlethal effect and that this inhibition occurs selectively at the postbinding stage of target cell lysis.

Cytotoxicity, Immunologic↗