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Biomedical subjects

Mary Norval

Publications and source records attributed to Mary Norval.

At least 19 recordsLinked to original sources
PubMed2006

The mechanisms and consequences of ultraviolet-induced immunosuppression.

Exposure to ultraviolet radiation (UVR) can result in immune suppression to antigens encountered within a few days of the irradiation. The process leading to the down-regulation in immune responses is complex. It is initiated by several photoreceptors located in the skin surface, namely DNA, trans-urocanic acid and membrane components. The absorption of UVR by these chromophores then leads to the release of a wide range of mediators that can affect antigen presenting cells locally or systemically. The final steps include the generation of antigen-specific T cells capable of regulating immunity. The consequences of the UV-induced changes in the skin immune system for the control of skin cancers, infectious diseases including vaccination, and autoimmune diseases are considered. Finally, the effects of active vitamin D, synthesised in the epidermis following UVR, are discussed in the context of the skin immune response.

Animals↗
PubMed2005

Jaagsiekte sheep retrovirus-specific immune responses induced by vaccination: a comparison of immunisation strategies.

Jaagsiekte sheep retrovirus (JSRV) is the aetiological agent of ovine pulmonary adenocarcinoma (OPA). No JSRV-specific immunological responses have been detected in clinical cases of OPA or in experimentally infected lambs. The aim of the present study was to induce immune responses in sheep against JSRV proteins using several immunisation strategies. The vaccines were administered subcutaneously and intradermally, or intranasally, in adjuvant. Antibodies were measured by ELISA and immunoblotting, and T cell responses by lymphoproliferation assay. Antibodies specific for JSRV-capsid protein were induced by inoculation of recombinant proteins in adjuvant, and transient JSRV-specific T cell responses by intranasal inoculation with inactivated virus. These results will help in the design of a protective vaccine against JSRV infection and the development of OPA.

Adjuvants, Immunologic↗
PubMed2005

Adaptation to the UV-induced suppression of phagocytic activity in murine peritoneal macrophages following chronic exposure to solar simulated radiation.

Exposure of certain strains of mice to ultraviolet radiation (UVR) is known to suppress both local and systemic immune responses, including a reduction in the phagocytic activity of peritoneal macrophages. However, in many instances, the immunological effects have been observed following a single or a limited number of doses of UVR from sources containing a higher proportion of UVB than that emitted by the sun. The first aim of the present study was to establish whether a single exposure of C3H/HeN mice to solar simulated radiation (SSR) suppressed the ability of the peritoneal macrophages to phagocytose opsonised sheep red blood cells. The mice were irradiated with SSR from Cleo Natural lamps and a single dose of 31.9 J cm(-2) was found to be the minimal dose for significant suppression of macrophage phagocytic activity. Such a dose did not modulate the surface expression of I-A(k), CD11b, CD86 or FcgammaRII/III (CD32/16) on the macrophages. The second aim was to assess whether repeated SSR exposures with a dose below the minimal immunosuppressive dose affected macrophage activity and, if so, to test for photoadaptation by repeated exposures followed by a single, normally immunosuppressive dose of SSR, and then assaying the macrophage activity. Groups of mice were irradiated on each of 2, 10 and 30 days with 14.9 J cm(-2) SSR, followed in some instances by a single additional exposure of 31.9 J cm(-2) on the same day as the last irradiation. The phagocytic activity of the peritoneal macrophages was tested 24 h later. It was reduced by 32%, 18% and 4% respectively after 2, 10 and 30 repeated exposures to SSR, and by 39%, 21% and 7% respectively after 2, 10 and 30 repeated exposures plus the additional higher dose at the end. Thus, although the macrophage activity was initially suppressed by the SSR, photoadaptation of this immune parameter occurred following repeated exposures.

Adaptation, Physiological↗
PubMed2005

Suppression of contact hypersensitivity after repeated exposures of humans to low doses of solar simulated radiation.

Although it is generally recognised that UV radiation (UVR) can induce suppression of contact hypersensitivity (CHS) in human subjects, most protocols to date have not tested the effect of low daily doses of solar simulated radiation (SSR). In the present study, healthy individuals, divided into four groups each consisting of approximately 34 subjects, were whole-body irradiated with 1.2 standard erythema doses of SSR for 2, 10 or 30 consecutive days, or were unirradiated. They were sensitised with diphenylocyclopropenone (DPCP) on one exposed body site 24 h after the final UVR. The occurrence and severity of the primary allergic response were noted, and both parameters were shown to be significantly lowered in the group irradiated for 30 days compared with the unirradiated group. Elicitation of CHS was undertaken 3 weeks after the sensitisation, using a range of concentrations of DPCP on a UV-protected body site. The extent of the CHS at 48 h was assessed by the clinical score, by an erythema meter and by histological examination of a biopsy taken from the site challenged with one selected concentration of DPCP. Although erythema and pigmentation did not differ between the groups, a significant negative correlation was found between the clinical CHS score and the number of days of UV exposure, at the lowest challenge dose of DPCP. In addition a significant negative correlation was revealed between the intensity of spongiosis (intraepidermal oedema and vesicles, as evaluated by histology) and the number of days of UV exposure. Thus small daily doses of SSR induce suppression of CHS in human subjects and the effect is cumulative, indicating that there is no adaptation to the immunomodulating effects of UVR, at least over the test period of 30 days.

Cyclopropanes↗
PubMed2005

An action spectrum for the production of cis-urocanic acid in human skin in vivo.

Urocanic acid (UCA) is present at millimolar concentrations in mammalian epidermis and undergoes photoisomerization from the naturally occurring trans-isomer to the cis-isomer on exposure to ultraviolet radiation (UVR). Cis-UCA causes downregulation of various immune responses in mouse and human experimental models and has been proposed as both a chromophore and a mediator of UV-induced immune suppression. In this study, the wavelength dependence from 260-340 nm for trans to cis-UCA photoisomerization in human skin was analyzed in five healthy volunteers. The resulting action spectrum demonstrated maximal cis-UCA production in the UVB spectral region of 280-310 nm. This spectral peak is red-shifted to longer wavelengths compared with the erythemal action spectrum. The cis-UCA action spectrum can be used to predict the ability of sunscreens to protect against UVR-induced cis-UCA formation and may assist in explaining discrepancies between sunscreens' abilities to protect against erythema and photoimmunosuppression.

Adult↗
PubMed2005

Lack of effect of repeated suberythemal ultraviolet-B exposures on human blood dendritic subtypes.

BACKGROUND/PURPOSE: Dendritic cells (DC) play a major role in the afferent immune response. They are found as a minor cell population in the blood as three main subtypes that can be distinguished phenotypically: plasmacytoid DC (PDC), and myeloid DC1 and 2 (MDC1 and 2). The aim of the study was to examine the effect of repeated whole-body suberythemal ultraviolet (UV) B irradiation on the percentages of DC subsets in the blood and skin, and to test for photoadaptation by the subsequent administration of a local erythemal UV dose. METHODS: Thirty subjects in each group were irradiated with either 0.7 personal minimal erythema dose (MED) UVB daily for 10 days (whole body), or for the 10 days followed by a single three MED UVB exposure of a local body site, or with the single three MED UVB exposure of a local body site only. Blood was collected before and after the exposures and the percentage of DC and DC subtypes assessed by flow cytometry. Skin biopsies were collected at the same times, and the number and position of the DC subsets examined by immunofluorescent microscopy. RESULTS: The whole-body repeated UVB irradiations did not result in a change in the blood DC (BDC) or the subsets percentages in the blood, except that there was a small but significant rise in the percentage of the MDC2 subset. No alteration occurred following the local erythemal UVB exposure. The total number of BDC in the skin was small, with the PDC being located mainly in the dermis and the myeloid subtypes mainly in the epidermis. No change in cutaneous numbers or distribution was revealed following the irradiation protocols. CONCLUSIONS: Repeated whole-body suberythemal UVB irradiation does not cause a change in BDC or BDC subsets in the blood or skin, except for a small increase in the percentage of MDC2 in the blood. Local erythemal UVB irradiation does not alter the BDC subsets in blood or skin.

Adult↗
PubMed2003

Exposure to multiple doses of UVB radiation reduces the numbers of epidermal Langerhans cells and lymph node dendritic cells in mice.

Immune suppression following UVB irradiation is partly attributed to the effects of the exposure on antigen-presenting cells. Following a single UVB irradiation, there is a decrease in epidermal Langerhans cell numbers; this is accompanied by an increase in the number of dendritic cells (DC) in lymph nodes draining the irradiated site. We investigated whether a similar effect occurred following multiple UVB exposures. Mice were irradiated on their ears and shaved dorsal skin twice a week for 3 weeks. After the final exposure, the number of ATPase(+) Langerhans cells in epidermal sheets prepared from the ears was found to be decreased by 33% compared to unirradiated controls. The number of DC in the draining lymph nodes (DLN) did not increase as might have been expected; rather, a significant decrease of approximately 30% in DC numbers in the DLN of UVB-irradiated mice compared with unirradiated controls occurred. This decrease in antigen-presenting cells in both the epidermis and the DLN may be an important contributing factor to the immune suppression that follows multiple UVB exposures.

Animals↗
PubMed2003

Health effects from stratospheric ozone depletion and interactions with climate change.

The potential health effects of elevated levels of ambient UV-B radiation are diverse, and it is difficult to quantify the risks, especially as they are likely to be considerably modified by human behaviour. Nevertheless epidemiological and experimental studies have confirmed that UV radiation is a definite risk factor for certain types of cataract, with peak efficacy in the UV-B waveband. The causal link between squamous cell carcinoma and cumulative solar UV exposure has been well established. New findings regarding the genetic basis of skin cancer, including studies on genetically modified mice, have confirmed the epidemiological evidence that UV radiation contributes to the formation of basal cell carcinomas and cutaneous melanomas, For the latter, animal models have demonstrated that UV exposure at a very young age is more detrimental than exposure in adulthood. Although suppression of certain immune responses has been recognised following UV exposure, the impact of this suppression on the control of infectious and autoimmune diseases is largely unknown. However, studies on several microbial infections have indicated significant consequences in terms of symptoms or reactivation of disease. The possibility that the immune response to vaccination could be depressed by UV-B exposure is of considerable concern. Newly emerging possibilities regarding interactions between ozone depletion and global climate change further complicate the risk assessments for human health but might result in an increased incidence of cataracts and skin cancer, plus alterations in the patterns of certain categories of infectious and other diseases.

Cataract↗
PubMed2003

Dietary selenium levels determine epidermal langerhans cell numbers in mice.

Selenium (Se) is a dietary trace element that is essential for effective immunity and protection from oxidative damage induced by ultraviolet radiation (UVR). Langerhans cells (LC) represent the major antigen-presenting cells resident in the epidermis; a proportion migrate from the skin to the draining lymph nodes in response to UVR. Because it is known that Se deficiency impairs immune function, we determined what effect this has on LC numbers. CH3/HeN mice were weaned at 3 wk and placed on diets containing <0.005 ppm of Se (Se deficient) or 0.1 ppm of Se (Se adequate, control mice). After 5 wk on the diet, the epidermal LC numbers in the Se-adequate group were 966 +/- 51 cells/mm2 and LC counts in the epidermis of the Se-deficient mice were 49% lower (p<0.05). Glutathione peroxidase- I (GPx) activity was measured in the epidermis, lymph nodes, and liver. In the epidermis, the activity of GPx in the Se-deficient mice was only 39% (p<0.01) of that seen in epidermis from Se-adequate mice (1.732 U/mg protein). The mice were then irradiated with one dose of 1440 J/m2 of broadband UVB or mock irradiated. After 24 h, the decrease in LC number after UVB was greater in the Se-adequate mice, (40% decrease) compared to the Se-deficient group (10%). Thus, Se deficiency reduces epidermal LC numbers, an effect that might compromise cutaneous immunity.

Adenosine Triphosphatases↗
PubMed2003

Viability of the antigen determines whether DNA or urocanic acid act as initiator molecules for UV-induced suppression of delayed-type hypersensitivity.

UV radiation suppresses the immune response, and UV-induced immune suppression contributes to UV-induced photocarcinogenesis. For UV-induced immune suppression to occur, electromagnetic energy (i.e. UV radiation) must be converted to a biological signal. Two photoreceptors have been identified in the skin that serves this purpose, epidermal DNA and trans-urocanic acid (UCA). Although compelling evidence exists to support a role for each pathway (UV-induced DNA damage or photoisomerization of UCA) in UV-induced immune suppression, it is not clear what determines which photoreceptor pathway is activated. To address this question, we injected UV-irradiated mice with a monoclonal antibody with specificity for cis-UCA or applied liposomes containing DNA repair enzymes to the skin of UV-irradiated mice. The effect that each had on UV-induced suppression of delayed-type hypersensitivity was measured. We asked whether the light source used (FS-40 sunlamps vs solar-simulated UV radiation) altered whichever pathway of immune suppression was activated. Different doses of UV radiation and the viability of the antigen were also considered. Neither the dose of UV nor the light source had any influence on determining which pathway was activated. Rather, we found that the viability of the antigen was the critical determinant. When live antigens were used, UV-induced immune suppression was blocked with monoclonal anti-cis-UCA but not with T4 endonuclease V-containing liposomes. The reverse was observed when formalin-fixed or killed antigens were used. Our findings indicate that antigen viability dictates which photoreceptor pathway predominates after UV exposure.

Animals↗
PubMed2002

The potentially insecticidal Narcissus pseudonarcissus lectin demonstrates age-related mitogenicity.

Lectins from monocotyledonous plants such as Narcissus pseudonarcissus (NPA) possess insecticidal properties and have the potential to increase pest resistance in transgenic crops. Therefore it is of interest to investigate the mitogenic properties of such lectins. Mononuclear cells purified from human umbilical cord and adult peripheral blood samples were stimulated with NPA and compared to phytohaemagglutinin as an example of a lectin from a dicotyledonous plant. Here we report that NPA is slightly mitogenic for adult human lymphocytes but mitogenicity is increased more than sevenfold for lymphocytes from umbilical cord blood. Similarly, NPA was found to be mitogenic for peripheral blood mononuclear cells (PBMC) from lambs and not adult sheep, supporting the age-related mitogenicity and indicating that further examination of the younger human population is warranted.

Adult↗
PubMed2002

Studies to determine the immunomodulating effects of cis-urocanic acid.

Exposure to ultraviolet (UV) radiation, particularly the UVB wavelengths, leads not only to DNA damage but also to suppression of cell-mediated immunity to antigens encountered shortly after the irradiation. One initiator of this complex process is cis-urocanic acid (cis-UCA), which is formed from the naturally occurring trans isomer in the epidermis on absorption of UV. cis-UCA has been shown to have immunomodulating properties in a variety of in vivo and in vitro experimental systems, although its mechanism of action is not yet clear. This article covers methods of preparing cis-UCA and of analyzing UCA isomers in various human and mouse tissues. Experiments that demonstrate that cis-UCA is immunosuppressive are described. The final section deals with the preparation and characterization of a monoclonal antibody with specificity for cis-UCA.

Animals↗
PubMed2002

Application of a systemic herpes simplex virus type 1 infection in the rat as a tool for sunscreen photoimmunoprotection studies.

The application of a novel model for sunscreen photoimmunoprotection studies was assessed using a systemic infection of rats with herpes simplex virus type 1 (HSV-1). Rats were irradiated daily with 1 minimal erythemal/oedematous dose of UVB for 7 consecutive days on their shaved backs with or without application of a broad-spectrum sunscreen (containing TiO2) with a sun protection factor of 10. Subsequently, rats were infected intranasally with HSV. UV exposure prior to HSV infection induced increased severity and incidence of clinical signs of disease, suppression of cellular immune responses as assessed by delayed type hypersensitivity and increased viral load in the brain. The sunscreen provided protection against all these UV-induced effects. We conclude that this novel model is a promising way of testing the immunoprotective qualities of sunscreens, based on the response to a common infectious agent of human subjects.

Animals↗
PubMed2002

The effects of UV waveband and cis-urocanic acid on tumour outgrowth in mice.

Immunogenic murine tumours that are normally rejected upon transplantation into syngeneic hosts grow progressively if the hosts are UV-irradiated prior to tumour implantation. Using three sources of UV we investigated the most effective waveband and dose for increased outgrowth of injected fibrosarcoma (FSA) cells in mice, compared with unirradiated controls. The animals were exposed on their shaved dorsal skin twice a week for 3 weeks to either broad-band (TL12) or narrow-band (TL01) UVB, or UVA-I radiation; FSA cells were then injected subcutaneously into the UV-irradiated skin. Exposure to TL12 at doses higher than 1000 J m(-2), but not TL01 or UVA-I, caused increased outgrowth of the injected tumour cells. The effect of the UV irradiation seemed to be local as injection of the FSA cells into the unirradiated ventral skin of mice irradiated with TL12 on the dorsal surface did not result in increased outgrowth of the tumours. Cis-urocanic acid, a recognised initiator of UV-induced immunosuppression, applied topically or intradermally for 3 weeks prior to FSA cell injection, had no effect on the rate of tumour outgrowth. Similarly, injection of a monoclonal antibody with specificity for cis-urocanic acid, prior to each irradiation with TL12, did not reverse the increased growth of FSA cells injected into the UV-irradiated skin. Thus wavelengths within the broad-band UVB range are the most effective for inducing increased outgrowth of FSA cells; cis-urocanic acid is not an important mediator in this UV-enhanced growth of tumours.

Animals↗
PubMed2002

Systemic immune responses following infection with Jaagsiekte sheep retrovirus and in the terminal stages of ovine pulmonary adenocarcinoma.

Jaagsiekte sheep retrovirus (JSRV) is the aetiological agent of ovine pulmonary adenocarcinoma (OPA). To monitor changes in cellular immune function during JSRV infection, lymphoproliferation in response to various mitogens was measured in the blood of conventionally housed and specific-pathogen-free lambs experimentally infected with JSRV until the development of OPA and compared with uninfected control lambs. In addition, blood samples collected from adult field cases in the terminal stages of OPA and control adult sheep were compared. No difference in the proliferative response to phytohaemagglutinin and pokeweed mitogen between the animal groups was detected. In contrast, reduced responses to concanavalin A stimulation were demonstrated in the JSRV-inoculated lambs, prior to the onset of clinical disease, and also in the terminally ill adult sheep. Peripheral blood leukocytes were monitored to identify phenotypic frequency alterations. The CD4 lymphocytopaenia and neutrophilia reported previously in adult OPA cases were demonstrated but similar phenotypic changes were not identified during experimental infection.

Animals↗