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M Norval

Publications and source records attributed to M Norval.

At least 73 records · Page 4Linked to original sources
PubMed1995

The role of cis-urocanic acid in UVB-induced suppression of contact hypersensitivity.

Ultraviolet light B (UVB) is well recognized to suppress the contact hypersensitivity (CHS) response and it has been postulated that cis-urocanic acid (UCA) is a mediator of the immunosuppression. This study was designed to examine the effect of UCA on CHS and to clarify its role in UVB-induced immunosuppression in C57BL/6 mice. Intradermal injection of 0.5-50 micrograms cis-UCA into the ear 2 h before DNFB sensitization resulted in a 60-70% reduction of CHS assessed by ear swelling, whereas trans-UCA did not have a significant effect on CHS except at a high dose (50 micrograms) which showed a 20-40% suppression. Intraperitoneal injection of anti-cis-UCA antibody before administration of cis-UCA abrogated the suppression. To examine the effect of UCA on UVB-induced immunosuppression, some mice were pre-treated with anti-cis-UCA antibody and then exposed to UVB (960 J/m2). After 3 days the mice were sensitized either on the irradiated abdominal skin or on the unirradiated dorsal surface of the right ear followed by the challenge on the left ear. The CHS response was significantly suppressed in UVB-irradiated mice both locally (abdominal sensitization, suppression was 45%, P < 0.001) and systemically (ear sensitization, suppression was 53%, P < 0.0025). The CHS response was partially restored in both abdominal sensitized mice and ear sensitized mice by pre-treatment with anti-cis-UCA antibody. These results confirmed the immunosuppressive effects of cis-UCA on CHS and suggest that cis-UCA plays a role in UVB-induced local and systemic immunosuppression.

Animals↗
PubMed1995

A monoclonal antibody to cis-urocanic acid prevents the ultraviolet-induced changes in Langerhans cells and delayed hypersensitivity responses in mice, although not preventing dendritic cell accumulation in lymph nodes draining the site of irradiation and contact hypersensitivity responses.

Ultraviolet B (UVB) irradiation of C3H mice causes suppression of delayed hypersensitivity and contact hypersensitivity (CH) to antigens encountered following exposure, and is accompanied by a reduction in Langerhans cell (LC) numbers in the epidermis, loss of epidermal antigen-presenting cell function, and accumulation of dendritic cells in lymph nodes draining the site of irradiation. Various photoreceptors and mediators of these changes have been proposed, one of which is cis-urocanic acid (cis-UCA) formed from the naturally occurring trans-UCA in the epidermis on UV irradiation. A monoclonal antibody that reacts with cis-UCA has become available recently and has been used in this study to clarify the role of UCA. Pretreatment of C3H mice with the monoclonal antibody abrogated the UVB-induced and cis-UCA-induced reduction in epidermal LC numbers. It also prevented the UV-induced suppression of epidermal antigen-presenting cell ability as measured by the mixed skin lymphocyte response. However, it had no effect on the accumulation of dendritic cells in lymph nodes draining the site of UV exposure. With regard to hypersensitivity responses, it did not prevent UV-induced suppression of CH to oxazolone at a range of concentrations but it restored to normal the UV-suppressed delayed hypersensitivity to herpes simplex virus, if administered before exposure. Thus cis-UCA is involved in some UV-induced changes in murine skin but not in others, where alternative mediators, such as tumor necrosis factor-alpha, may be more important.

Animals↗
PubMed1995

Urocanic acid isomers in human skin: analysis of site variation.

Urocanic acid (UCA) is found in the stratum corneum as the trans-isomer and, on ultraviolet (UV) irradiation, photoisomerization into cis-UCA takes place. Cis-UCA has been suggested to play a part in UV-induced immunosuppression. In the present study, the concentration of UCA and the percentage as cis-UCA at 10 different body sites of 20 normal volunteers were analysed. A large interindividual variation in total UCA concentration was found, but the mean UCA concentration in each site was similar, other than at the sole of the foot. There was little variation in the UCA content between sites normally exposed, and not exposed, to light, but the percentage of UCA in the cis form was clearly higher at exposed areas.

Adult↗
PubMed1995

Immunomodulation at the initiation of phototherapy and photochemotherapy.

The numbers and function of circulating lymphocyte subsets are within normal ranges in patients with psoriasis and are not affected by 4 weeks of ultraviolet (UV) therapy, except for a suppression in natural killer (NK) cell activity. However, it is possible that immunomodulation might occur at the initiation of phototherapy with a return to control values on more prolonged UV exposure. Thus, in this study the responses of 15 patients with chronic plaque psoriasis undergoing broad-band UVB therapy, 10 narrow-band (311-313 nm) UVB therapy and 10 PUVA therapy were compared. In each case, samples were taken immediately before starting treatment and 1 week later. Broad-band UVB and PUVA therapy had no effect on NK activity, but a significant reduction was found in the group receiving narrow-band UVB. In vitro lymphoproliferative responses to mitogens and to herpes simplex virus antigens did not alter with therapy, except there was a significant increase in mitogen responses (at optimal mitogen concentrations only) in the narrow-band UVB group. Generally no alterations in overall percentages of circulating mononuclear cells were found in any group. Samples were taken from the epidermis of the forearm and back of the patients receiving narrow-band UVB for the quantification of urocanic acid (UCA) isomers. The total UCA concentration remained unchanged after 1 week of therapy, while the percentage of cis-UCA increased significantly at both sites in the majority of patients. However, this rise did not correlate with the decrease in NK cell activity and the two parameters may not be related causally.

Adult↗
PubMed1995

The role of urocanic acid in UV-induced immunosuppression: recent advances (1992-1994).

Cis-urocanic acid (UCA), formed in the epidermis by UV irradiation of trans-UCA, has been implicated as a mediator of the immunosuppression induced by UV exposure of the skin. This review covers recent work in which the wavelength dependence of cis-UCA formation, the interaction of UCA isomers with DNA, the effects of UCA isomers on the immune system and their interaction with histamine are examined. Results are frequently conflicting, particularly when considering the possible mode of action of cis-UCA but, overall, a multifaceted role for UCA in immunomodulation by UV radiation is substantiated.

Animals↗
PubMed1995

The effect of chronic low-dose UVB radiation on Langerhans cells, sunburn cells, urocanic acid isomers, contact hypersensitivity and serum immunoglobulins in mice.

C3H mice were irradiated three times a week for up to 6 weeks with either 500 J/m2 or 1000 J/m2 broadband UVB (270-350 nm) or 3000 J/m2 narrowband UVB (311-312 nm; TL01 source). Each dose was suberythemal to the mouse strain used. The number of Langerhans cells (LC) in the epidermis was reduced by over 50% after 2 weeks of irradiation with the UVB source and by 20% following TL01 irradiation. Continued irradiation for up to 6 weeks resulted in no further decrease in LC numbers in the case of the UVB source but a steady decline to 40% in the case of the TL01 source. Sunburn cells were detected following irradiation with both sources but the numbers were very low in comparison with acute exposure. Ultraviolet-B exposure resulted in doubling of the thickness of the epidermis throughout the 6 weeks of irradiation while TL01 exposure did not alter epidermal thickness. Conversion of trans- to cis-urocanic acid (UCA) was observed with both UVB and TL01 sources. The percentage of cis-UCA started to return to normal after 4 weeks of TL01 exposure despite continued irradiation. As observed following a single exposure, the contact hypersensitivity (CH) response was significantly reduced following 6 weeks of UVB irradiation but was unaffected by TL01 exposure, indicating no correlation between cis-UCA levels and CH response. Total serum immunoglobulin levels remained unchanged throughout the 6 weeks of UVB or TL01 irradiation but IgE titers significantly increased in all cases in the first 2 weeks of irradiation, indicating a possible shift to a TH2 cytokine profile.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Immune responses of patients to orf virus infection.

Orf is a disease of sheep and goats which is caused by a parapox virus. It can be transmitted to humans, and is considered an occupational hazard by those handling sheep. In this paper we present the first report of both cell-mediated and humoral immune responses to naturally acquired orf virus infection in humans. Lymphoproliferative responses of peripheral blood mononuclear cells of patients to an orf virus antigen were vigorous soon after infection, but rapidly declined. Orf virus antibody levels, detected by ELISA, were shown to rise during infection. Western blot analysis confirmed this, and demonstrated that the antibody produced in response to the infection was directed against the 40-kDa viral surface tubule protein. Where direct comparisons were possible, the immune response of humans to orf virus infection was similar to that previously reported for sheep. Evidence was obtained suggesting that prior exposure to vaccinia virus (smallpox vaccination) provided no protection from subsequent orf virus infection. In addition, orf virus infection did not enhance immune responses to vaccinia virus antigens.

Adolescent↗
PubMed1994

The effects of ultraviolet light irradiation on viral infections.

Exposure to ultraviolet radiation is associated with the development of cutaneous carcinomas, and with suppression of immune responses to a variety of antigens, including those of fungal, bacterial and parasitic origin, and contact sensitizers. UV irradiation also influences viral infections. It can affect viral mutation, the photolocalization of viral exanthems, viral oncogenesis, activation of viral genomes, and the suppression of immune responses to viruses. The evidence for, and mechanisms involved in, each of these categories is presented, and the effect of UV radiation on the virus-host interaction, particularly during persistent infections, is discussed.

Genes, Viral↗
PubMed1994

Comparative potency of different UV sources in reducing the density and antigen-presenting capacity of Langerhans cells in C3H mice.

Although broadband UV-B irradiation has been shown to induce selective immunosuppression in a variety of experimental systems, the wavelength dependence of the immunomodulation and the initial events in the skin remain unclear. In the present study three UV lamps were used at suberythermal doses on C3H mice: a conventional broadband UV-B source (270-350 nm), a narrowband UV-B source (311-312 nm) and a UV-A source (320-400 nm). Their effects on the photoisomerization of the naturally occurring trans-isomer of urocanic acid (UCA) to cis-UCA, on the density of Langerhans cells and on the ability of epidermal cells to stimulate allogeneic lymphocytes in the mixed skin lymphocyte reaction (MSLR) were ascertained. Broadband UV-B irradiation was more efficient than narrowband UV-B at reducing the density and function of Langerhans cells, while UV-A irradiation was least effective. These changes were most pronounced immediately following irradiation, were dose dependent and were only detected in UV-exposed areas of skin. There was a close correlation between the UV-induced reduction in Langerhans cell density and the formation of cis-UCA in the epidermis. This correlation was not detected between the reduction in the MSLR response following UV irradiation in vivo and cis-UCA formation.

Adenosine Triphosphatases↗
PubMed1994

Role of tumour necrosis factor-alpha in ultraviolet B light-induced dendritic cell migration and suppression of contact hypersensitivity.

Irradiation with ultraviolet B light (UVB) is known to suppress contact and delayed hypersensitivity response to a variety of antigens encountered within a short period following exposure. Such irradiation results in loss of Langerhans' cells and in synthesis of tumour necrosis factor-alpha (TNF-alpha) in the epidermis. In the present study the effect of broad-band (270-350 nm) and narrow-band (311-312 nm) UVB on the induction of contact hypersensitivity (CH) and on dendritic cell (DC) numbers in draining lymph nodes (DLN) of mice was examined. Broad-band UVB induced the accumulation of DC in DLN and this increase was substantially abrogated by treatment of mice with neutralizing antibody to TNF-alpha before irradiation. In addition, irradiation before sensitization with oxazolone resulted in a suppressed CH response. The suppression was negated to a considerable extent by TNF-alpha antibodies, administered before irradiation. Thus, one of the major effects of broad-band UVB is likely to be the synthesis of epidermal TNF-alpha which, in turn induces the migration of Langerhans' cells to DLN and leads to an impairment of their activity or function. Conversely narrow-band UVB did not result in an accumulation of DC in DLN or in a suppressed CH response. Such irradiation does, however, cause the isomerization from trans to cis-UCA in the epidermis. Cis-UCA has been proposed as a photoreceptor for UV and suppresses immune responses in a variety of experimental systems. Thus cis-UCA does not act through TNF-alpha induction or by influencing DC migration, and other studies indicate that histamine-like receptors in the skin may be involved.

Animals↗
PubMed1993

Effect of phototherapy and urocanic acid isomers on natural killer cell function.

Ultraviolet (UV) radiation suppresses a variety of immune responses but it is uncertain whether this action contributes to the effectiveness of phototherapy. Urocanic acid (UCA) has been proposed as a mediator of the immunologic effects of UV. On exposure the naturally occurring trans-isomer of UCA in the skin changes into the cis-isomer, which has been demonstrated to mimic many of the immunomodulatory effects of UV irradiation. Natural killer (NK) cells play an important role in several immunologic processes and published evidence indicates that their activity is altered by UV irradiation. To ascertain the effect on NK cells of phototherapy used in the treatment of psoriasis, modulation of NK activity in psoriatic patients undergoing broad-band UVB, narrow-band UVB, or psoralen plus (PUVA) regimens was examined. This was compared with NK cell activity in psoriatic patients treated with topical coal tar and in normal subjects receiving broad band UVB. The NK cell activity of psoriatic and normal subjects was the same over a wide range of effector to target cell ratios. Almost all patients undergoing phototherapy exhibited depressed NK cell activity during or after irradiation, although the timing of the depression varied between the lamps used and may be related to dose. However, patients treated with topical coal tar showed unchanged NK cell activity throughout the therapy. The effect of UCA isomers on NK cell activity in vitro was also determined. It was found that cis-UCA induced a dose-dependent suppression of NK cell activity in both patients and normal subjects, whereas trans-UCA had hardly any effect in either group. Thus it is possible that there may be a correlation between cis-UCA formation in the epidermis and the modulation of NK cell activity that occurs during phototherapy.

Adult↗
PubMed1993

The effect of UV therapy on immune function in patients with psoriasis.

Ultraviolet radiation (UVR) is known to suppress some cell-mediated immune responses to antigens encountered during or soon after exposure. Phototherapy is widely used in psoriasis, and this study was undertaken to monitor changes in a range of immunological parameters during standard courses of treatment, with the aim of ascertaining whether such modulations contribute to the effectiveness of therapy. The responses of 17 patients with psoriasis undergoing UVB therapy, and four receiving PUVA therapy, were compared with 15 patients receiving coal tar treatment and four normal subjects undergoing UVB irradiation. In each case, samples were taken before starting therapy, after 4 weeks of therapy, and 4 weeks after completion of treatment. Serum immunoglobulin isotypes and complement components were within normal ranges in most of the psoriasis patients, and remained unchanged throughout therapy. Similarly, percentages of subsets of peripheral blood mononuclear cells (PBMC) were normal, and were unaltered by treatment. Patients who were already infected with herpes simplex virus (HSV), as demonstrated by a positive lymphoproliferation test in vitro, were monitored for asymptomatic HSV shedding and HSV recrudescences during therapy. There was little evidence that phototherapy caused reactivation of the virus. No significant alteration in lymphoproliferative response to HSV and to the mitogen concanavalin A was observed during therapy. Epidermal cells and blood adherent cells were used to present HSV to PBMC, depleted of adherent cells and enriched for T cells, in a lymphoproliferative assay. The functional antigen-presenting ability of adherent cells remained unchanged throughout therapy, whereas that of epidermal cells was suppressed during UVB irradiation and recovered, in most instances, after UVB therapy had been completed. The epidermis of patients with psoriasis contained about three times the quantity of urocanic acid (UCA) of normal subjects, whereas the UCA concentration in suction blister fluid did not differ between the two groups. During UVB irradiation, the percentage of cis-UCA rose in both the epidermis and suction blister fluid of all subjects, and it remained elevated in the blister fluid after therapy had finished. Tumour necrosis factor-alpha was measured in suction blister fluid, and its concentration did not alter consistently as a result of therapy. Whether any of the immunological parameters measured, and the changes noted, contribute to the effectiveness of phototherapy in the treatment of psoriasis remains uncertain.

Adult↗
PubMed1993

Action spectra for the trans to cis photoisomerisation of urocanic acid in vitro and in mouse skin.

Urocanic acid (UCA) is a major UV chromophore in the upper layers of the skin where it is found predominantly as the trans isomer. UV irradiation induces photoisomerisation of trans-UCA to cis-UCA which has been shown to mimic some of the immunosuppressive properties of UV exposure. We examined the wavelength dependence for trans-UCA to cis-UCA photoisomerisation in vitro and in mouse skin in vivo over the spectral range 270-340 nm. The resulting action spectra were very similar with maximal effectiveness at 300-315 nm and equal activity at 270 nm and 325-330 nm, demonstrating that UVA-II radiation (320-340 nm) is efficient at UCA photoisomerisation. These action spectra differed markedly from the trans-UCA absorption spectrum in vitro and also the reported action spectrum for UV suppression of contact hypersensitivity in mice. These findings suggest that the relationship between cis-UCA formation in skin and UV-induced immunosuppression may be complex.

Animals↗
PubMed1993

Comparative potency of broad-band and narrow-band phototherapy sources to induce edema, sunburn cells and urocanic acid photoisomerization in hairless mouse skin.

The Philips TL01 narrow-band (311-313 nm) fluorescent lamp provides effective phototherapy for psoriasis and atopic eczema while emitting less erythemogenic radiation than conventional broad-band (e.g. Philips TL12; 270-350 nm) sources. We studied the potency of TL01 and TL12 radiation to induce edema and sunburn cells (SBC) and to photoisomerize naturally occurring trans-urocanic acid (UCA) to cis-UCA in hairless mouse skin. Cis-UCA has immunosuppressive properties and is a putative mediator of UV-induced suppression of immune responses. For each source, there was UV dose dependence for all three responses. Within the dose ranges used, the potency ratio of TL12:TL01 radiation to induce equivalent edema and SBC was about 6:1. However, the potency ratio to induce cis-UCA was less than 2.3:1. Therefore, at a given level of edema or SBC induction, TL01 was more efficient than TL12 at UCA photoisomerization. The TL01 induction of immunomodulating cis-UCA, while causing minimal skin injury, may relate to the therapeutic efficacy of this source in skin conditions with an immunological component.

Albinism↗
PubMed1993

Characterization of a monoclonal antibody to cis-urocanic acid: detection of cis-urocanic acid in the serum of irradiated mice by immunoassay.

Cis-urocanic acid (cis-UCA), which is formed from the naturally occurring trans-isomer on ultraviolet (UV) irradiation, has been suggested as a photoreceptor for and mediator of the suppressive effects of UV irradiation on systemic immune responses. Trans-UCA is located predominantly in the stratum corneum, and the extent of isomerization to cis-UCA may be analysed by high-performance liquid chromatography (HPLC) of skin extracts. Such an analysis is not suitable for other tissues. In this study a murine monoclonal antibody to cis-UCA was prepared and tested by ELISA using UCA isomers conjugated to protein as antigens. The interaction of the antibody with structural analogues of UCA was assessed by competitive inhibition ELISA which indicated that the antibody had a high specificity for cis-UCA. Screening of sera at various times after UVB irradiation of mice by competitive inhibition ELISA using the monoclonal antibody showed that cis-UCA was present, probably in an unbound form, for at least 2 days after the exposure. Thus, cis-UCA produced in the epidermis following UVB irradiation reaches the serum a few hours later. The implications of this finding for the generation of suppressed immune responses are discussed.

Animals↗
PubMed1992

Lymphoproliferative responses to human papillomaviruses in patients with cutaneous warts.

In vitro lymphoproliferative responses of peripheral blood mononuclear cells (PBMC) from patients with cutaneous warts, caused by infection with human papillomavirus type 1 (HPV-1) or type 2 (HPV-2), were assayed during the course of treatment. Purified HPV-1 and HPV-2 were used as antigens, as well as herpes simplex virus (HSV) and concanavalin A (Con A). All patients had normal percentages of subsets within the PBMC population and normal lymphoproliferative responses to Con A, and those with a clinical history of HSV infections had positive lymphoproliferative responses to HSV. Responses to both HPV antigens were poor. Only 10 of 100 assays of PBMC from 26 patients showed a stimulation index greater than 2. Addition of interleukin 2 made little difference in most cases. No correlation of clinical status of warts, i.e. improving, unchanged or resolved, with lymphoproliferation was found. When the PBMC were depleted of plastic-adherent cells and enriched for T cells, some samples which had not shown a lymphoproliferative response to HPV-1 or HPV-2 became positive; this response was abolished when the adherent cells were re-added. Thus it is possible that the adherent cell population from a proportion of patients contains cells which suppress lymphoproliferation, or that an immunoregulatory network is present so that lymphoproliferation does not take place in vitro without prior activation and cloning of T cells.

Adolescent↗