Search PubMed⌕ Search

Biomedical subjects

Gary M Halliday

Publications and source records attributed to Gary M Halliday.

34 records · Page 2Linked to original sources
PubMed2004

Natural products as aids for protecting the skin's immune system against UV damage.

Modern sun-protection products reduce the risk for erythema and DNA damage, but even those products with a very high sun protection factor (SPF) and full-spectrum UVB and UVA protection may not prevent UV radiation (UVR)-induced immunomodulation. Formulating sunscreens with a high SPF, as well as a high immune protection factor, is necessary for preventing skin cancer and maintaining effective immune responses to infectious disease after sun exposure. Supplementing current sun-protection products with immunoprotective compounds may help fill the gap between erythema protection and immunoprotection. Animal and now human studies have shown that a class of agents known as oligosaccharins--complex carbohydrates found in plants--protect the cutaneous immune system from UVB-induced and UVA-induced immunomodulation. This immunoprotective effect occurs independently from erythema and DNA damage protection, and these agents, particularly tamarind xyloglucan, may become important adjunctive ingredients to sunscreens.

Aloe↗
PubMed2003

Phase I/II study of treatment with dendritic cell vaccines in patients with disseminated melanoma.

Previous studies have suggested that immunotherapy with dendritic cell (DC) vaccines may be effective in treatment of patients with AJCC stage IV melanoma. We examined this treatment in phase I/II studies in 33 patients with good performance status and low volume disease. Nineteen patients received DCs plus autologous lysates and 14 patients DCs plus peptides from the melanoma antigens MAGE-3.A2, tyrosinase, gp100, and MART-1. Keyhole limpet hemocyanin (KLH) was used as a helper protein and influenza peptide was given as a positive control. DCs were produced from adherent cells in blood lymphocytes (monocytic DCs), grown in IL-4 and GM-CSF without a maturation step. The DCs were injected into inguinal lymph nodes at weekly intervals (x4), 2 weeks (x1), and 4-weekly intervals (x2). There were 3 responses (3 partial responses) and 1 mixed response in the 19 patients treated with DCs plus autologous lysates. No responses were seen in the group treated with DCs plus peptides. Stable disease (defined as no progression over a period of 3 months) was seen in 4 patients in group 1 and 5 patients in group 2. Treatment was not associated with significant side effects. We examined whether DTH skin tests or assays of IFN-gamma cytokine production may be useful predictors of clinical responses. Twenty-two of 30 patients had DTH responses to KLH and 12 of 13 patients had DTH responses to the influenza peptide. Five of 15 DTH responses were seen against autologous lysates. This was strongly correlated with clinical responses. Approximately half the patients had responses to MART-1 peptide and a third to the other melanoma peptides. Similarly, cytokine production assays showed responses to influenza in 7 of 13 patients, and approximately one third of patients had responses to the other peptides. No IFN-gamma responses were seen in 5 patients against their autologous lysates. There was no correlation between assays of IFN-gamma production and clinical responses. The present studies suggest that autologous lysates may be more effective than the melanoma peptides used in the study as the source of antigen for DC vaccines. DTH responses to autologous lysates appear useful predictors of clinical responses, but further work is needed to identify other measures associated with clinical responses.

Adult↗
PubMed2003

Phagocytosis by dendritic cells rather than MHC IIhigh macrophages is associated with skin tumour regression.

Dendritic cells (DC) are important for the induction of anti-tumour immunity and are currently being used in clinical trials. Whether DC in tumours behave the same as DC in normal tissues or whether the tumours subvert DC phenotype and function remains unknown. To address this, we have used a unique animal tumour model to compare the DC infiltrating regressing tumours with the DC infiltrating progressing skin tumours. Compared to progressor tumours, the regressor tumours were infiltrated by greater numbers of DC that were also less mature, based on MHC II expression. Apart from this, the phenotype of DC in both tumours was similar. However, compared to various control DC, they could not be classed as either mature or immature. Similar to terminally maturated DC but in contrast to fresh DC, tumour-derived DC did not express CCR5 or CXCR4, suggesting that they most closely resembled terminally matured DC. Macrophages that expressed high MHC II levels were found infiltrating progressor but not regressor tumours and in vivo were the major phagocytic cell. In contrast, DC were found to be the major phagocytic cell in regressor tumours. The results show that immune destruction and eventual regression of skin tumours occurs if DC rather than MHC II(high) macrophages are the major phagocytic cell.

Animals↗
PubMed2003

High levels of Fas ligand and MHC class II in the absence of CD80 or CD86 expression and a decreased CD4+ T cell Infiltration, enables murine skin tumours to progress.

It is still not clear why some tumours will be recognized and destroyed by the immune system, and others will persist, grow, and eventually kill the host. It has been hypothesized that tumour cells might evade immunological destruction by expressing Fas ligand (FasL), a molecule which induces apoptosis in Fas(+) target cells. However, the role of FasL in creating an immune privileged status within a tumour remains controversial. To determine whether FasL is associated with skin tumour progression, we developed a tumour model enabling us to compare two squamous cell carcinomas (SCC). One is a regressor SCC which spontaneously regresses after injection into syngeneic mice. The other is a progressor SCC which evades immunological destruction. Detailed flow cytometric analysis was used to study tumour cell expression of FasL, Fas, CD80, CD86 and MHC class II. We also analysed the percentage of apoptotic tumour cells in vivo using annexin V and correlated skin tumour progression with CD4 and CD8 T cell infiltration. Progressor tumours expressed high levels of FasL in vivo, which was virtually absent from regressor tumours. The percentage of progressor tumours expressing MHC II was significantly greater than regressor tumours, while neither tumour expressed CD80 or CD86 costimulatory molecules. Consistent with a regressor phenotype, the percentage of viable tumour cells was significantly lower for regressor compared to progressor tumours which coincided with a significantly larger CD4(+) T cell infiltrate into the tumour mass. The results suggest that progression of skin tumours occurs if tumour cells express high levels of MHC II but not costimulatory molecules such as CD80 or CD86. This implies that tumours may induce anergy in CD4(+) T cells via MHC II antigen presentation in the absence of costimulation. To ensure escape from the immune system, tumours may then kill these T cells via a FasL-dependent mechanism.

Animals↗
PubMed2003

Prevention of immunosuppression by sunscreens in humans is unrelated to protection from erythema and dependent on protection from ultraviolet a in the face of constant ultraviolet B protection.

Sunscreens have been advocated as an important means of preventing skin cancer. Ultraviolet radiation induced immunosuppression is recognized as an important event in skin cancer development, yet the effectiveness of sunscreens in protecting the human immune system from ultraviolet radiation (i.e. ultraviolet radiation) is still unclear. The only currently accepted method of sunscreen rating is the sun protection factor system based on the prevention of erythema. We determined immune protection factors for six commercially available sunscreens using a nickel contact hypersensitivity model in humans. Both sun protection factor and immune protection factor testing was performed using the same solar simulated ultraviolet radiation source and dose-responses were used to determine endpoints both with and without sunscreens. We found that the immune protection factor did not correlate with the sun protection factor; however, immune protection factor was significantly correlated to the ultraviolet A protective capability of the sunscreens, indicating that sunscreen protection from ultraviolet A is important for the prevention of ultraviolet immunosuppression, when there is constant ultraviolet B protection. We recommend that sunscreens should be rated against their immune protective capability to provide a better indication of their ability to protect against skin cancer.

Adolescent↗
PubMed2003

Nitric oxide appears to be a mediator of solar-simulated ultraviolet radiation-induced immunosuppression in humans.

Topical application of NG-methyl-L-arginine and 2,2'-dipyridyl were used to examine the respective roles of nitric oxide and reactive oxygen species in solar-simulated ultraviolet radiation-induced immunosuppression in humans in vivo. Immunosuppression was studied using a nickel contact hypersensitivity recall model. Ultraviolet radiation dose-responses were generated to determine the extent to which NG-methyl-L-arginine and 2,2'-dipyridyl affected the immune response. NG-methyl-L-arginine but not 2,2'-dipyridyl protected the immune system from ultraviolet radiation-induced suppression. Both NG-methyl-L-arginine and 2,2'-dipyridyl inhibited nitrite production. Nitrite is a degradation product of peroxynitrite, a cytotoxic mediator resulting from reactions between nitric oxide and reactive oxygen species. This suggests that nitric oxide, not its downstream product peroxynitrite, was likely to be responsible for solar-simulated ultraviolet radiation-induced immunosuppression. In contrast, both nitric oxide and reactive oxygen species were mediators of solar-simulated ultraviolet radiation-induced apoptosis and loss of dendritic S-100+ cells (probably Langerhans cells) from the epidermis. It is likely that different mechanisms are involved in these ultraviolet-induced endpoints and that events in addition to Langerhans cell depletion are important for local immune suppression to recall antigens in humans. Understanding the mechanisms of cutaneous ultraviolet-induced oxidative stress will assist in the future design of novel products that protect skin from photoaging and skin cancer.

2,2'-Dipyridyl↗
PubMed2003

Objective measurement of minimal erythema and melanogenic doses using natural and solar-simulated light.

Very little information exists on the amount of natural and artificial UV light required to cause sunburn and tanning in individuals with very pale skin who are at the greatest risk of developing skin cancer. We have investigated minimal erythema dose (MED) and minimal melanogenic dose (MMD) in a group of 31 volunteers with Fitzpatrick skin types I and II using an Oriel 1000 W xenon arc solar simulator and natural sunlight in Sydney, Australia. We measured the erythemal and melanogenic responses using conventional visual scoring, a chromameter and an erythema meter. We found that the average MED measured visually using the artificial UV source was 68.7 +/- 3.3 mJ/cm2 (3.4 +/- 0.2 standard erythema doses [SED]), which was significantly different from the MED of sunlight, which was 93.6 +/- 5.6 mJ/cm2 (P < 0.001) (11.7 +/- 0.7 SED). We also found significant correlations between the solar-simulated MED values, the melanin index (erythema meter) and the L* function (chromameter). The average MMD (obtained in 16 volunteers only) using solar-simulated light was 85.6 +/- 4.9 mJ/cm2, which was significantly less than that measured with natural sunlight (118.3 +/- 8.6 mJ/cm2; P < 0.05). We mathematically modeled the data for both the chromameter and the erythema meter to see if we were able to obtain a more objective measure of MED and differentiation between skin types. Using this model, we were able to detect erythemal responses using the erythema index function of the erythema meter and the a* function of the chromameter at lower UV doses than either the standard visual or COLIPA methods.

Adolescent↗
PubMed2002

Nitric oxide-mediated depletion of Langerhans cells from the epidermis may be involved in UVA radiation-induced immunosuppression.

Ultraviolet A (UVA) irradiation of the dorsal skin of mice reduced the contact hypersensitivity (CHS) response and the density of epidermal Langerhans cells (LC). The roles of nitric oxide (NO) and reactive oxygen species (ROS) in these biological effects of UVA were investigated. Topical application of N(G)-monomethyl-L-arginine acetate, an inhibitor of NO production, 2,2'-dipyridyl, an iron chelater, or 4-hydroxy-tempo, a superoxide dismutase mimicking agent, inhibited UVA-induced suppression of the CHS response. N(G)-monomethyl-L-arginine acetate but not the ROS inhibitors prevented UVA from reducing LC numbers in the epidermis. This suggests that NO but not ROS produced in response to UVA mediates a depletion of LC from the epidermis, probably by signaling these cells to migrate from the skin. This could be responsible for UVA-induced immunosuppression. UVA-induced ROS can also cause immunosuppression, but by a different mechanism. Agents that inhibit or modulate NO or ROS production may be useful for preventing damage caused by the UVA component of sunlight to the skin immune system.

2,2'-Dipyridyl↗
PubMed2002

Measurement of ultraviolet radiation-induced suppression of recall contact and delayed-type hypersensitivity in humans.

This article describes methodology used for assessment of ultraviolet radiation-induced suppression of recall responses in humans. Nickel allergy is common in the general population and patch testing of nickel-allergic volunteers provides a convenient model of contact hypersensitivity. Similarly, Mantoux-positive volunteers, recruited from within hospital staff, are used as a model for delayed-type hypersensitivity. Use of secondary rather than primary immune responses allows placement of multiple test sites on each volunteer. Further, each volunteer acts as his or her own unirradiated control. This enables UV immunosuppression to be studied with relatively few human volunteers, and makes determination of UV immunosuppression dose responses feasible in human subjects. The method can also be used for assessment of the level of immune protection afforded by agents such as sunscreens or biologically active substances.

Dermatitis, Contact↗
PubMed2002

Dendritic cells: making progress with tumour regression?

Due to their potent ability to activate the immune system, dendritic cells (DC) are showing promise as potential adjuvants for tumour immunotherapy of cancer patients. However, little is known about the effect tumour cells can have on DC function. Indeed, the discovery of different DC subsets with different immunological functions indicates that the relationship between tumour cells and tumour-infiltrating DC subtypes is likely to be complex. There remains a lot to be understood about the effects of tumours on DC before we can expect to benefit from DC-based tumour immunotherapy of cancer patients. Here we review the recent advances being made in understanding DC phenotype and function in relation to interactions with different types of tumours.

Animals↗
PubMed2002

Ultraviolet a irradiation of C57BL/6 mice suppresses systemic contact hypersensitivity or enhances secondary immunity depending on dose.

Ultraviolet radiation is the most common environmental carcinogen humans are exposed to. It is now known that in order for skin cancers to develop, both genetic damage and immunosuppression is required. Ultraviolet-induced immunosuppression is therefore a key contributor to the development of skin cancer. Little is known about the relative contributions of the different ultraviolet spectra (A and B), however. Therefore detailed ultraviolet dose-response curves for systemic suppression of contact hypersensitivity in two mouse strains were determined to examine the relative contributions of each of these spectral components of sunlight to primary and secondary immunity. Whereas ultraviolet B caused a linear dose-related immunosuppression in both C57BL/6 and Balb/c mice, only C57BL/6 mice were immunosuppressed by medium doses of ultraviolet A. At higher ultraviolet A doses, C57BL/6 mice were protected from immunosuppression, suggesting a genetic predisposition to ultraviolet-A-induced immunomodulation. Surprisingly, we found that, in contrast to primary immunosuppression, low dose ultraviolet A enhanced the secondary immune response, whereas ultraviolet B caused antigen-specific tolerance. When ultraviolet A and ultraviolet B were combined to mimic sunlight (solar-simulated ultraviolet), immunosuppression and tolerance were only observed over a narrow dose range as the memory-enhancing effect of low dose ultraviolet A and the immunoprotective effect of higher dose ultraviolet A prevented the suppressive effects of ultraviolet B. These studies suggest that complex relationships between ultraviolet dose, immunomodulation, spectra, and genetic background are likely to be important for skin cancer induction. We also describe for the first time that low doses of ultraviolet A are able to enhance secondary immunity, which has important implications for vaccination strategies.

Animals↗
PubMed2002

Ultraviolet a augments solar-simulated ultraviolet radiation-induced local suppression of recall responses in humans.

Many studies support the role of ultraviolet B in sunlight-induced alteration of the cutaneous immune system. The role of ultraviolet A is less clear, particularly in humans. The aim of this study was to determine the effect of additional ultraviolet A on solar-simulated ultraviolet-induced suppression of recall responses to nickel in humans. Immuno suppression dose-responses were induced in volunteers by exposure to solar-simulated ultraviolet radiation for four consecutive days. The ultraviolet A radiation dose was increased daily by providing additional high-dose ultraviolet A either before, or after the solar-simulated ultraviolet radiation. These ultraviolet A doses can be readily achieved through a sunscreen. Two different ultraviolet A spectra were used; 320-400 nm and 330-400 nm. Ultraviolet A alone did not cause significant immunosuppression, but augmented solar-simulated ultraviolet radiation-induced immunosuppression. Additional ultraviolet A reduced the minimum dose of solar-simulated ultraviolet radiation that was immunosuppressive. Both ultraviolet A spectra had this effect, although photoaugmentation was less pronounced with the 330-400 nm spectrum. Ultraviolet A-induced immediate pigment darkening did not protect from solar-simulated ultraviolet radiation-induced immuno suppression.

Adult↗
PubMedDate not supplied

The topical isoflavonoid NV-07alpha reduces solar-simulated UV-induced suppression of Mantoux reactions in humans.

UV radiation suppresses delayed-type hypersensitivity responses to intradermally injected tuberculin purified protein derivative in Mantoux-positive individuals. The effect of the topically administered isoflavonoid NV-07alpha, a synthetic derivative of the isoflavonoid equol, on UV-induced suppression of Mantoux reactions was assessed in 18 healthy Mantoux-positive volunteers. A single, fixed dose of solar-simulated UV radiation was delivered to the volunteers' lower backs. Different concentrations of NV-07alpha or its vehicle were applied to different sites within the irradiated field immediately after UV exposure and again 24 h later. Forty-eight hours after irradiation, Mantoux testing was performed at both the irradiated sites and adjacent, unirradiated sites. The intensity of Mantoux reactions was measured 72 h later with a reflectance erythema meter and by measuring the diameter of each reaction. Although lower concentrations of NV-07alpha (0.5 and 2 mM) did not prevent UV immunosuppression, 4 mM NV-07alpha partially but significantly attenuated UV-induced suppression of Mantoux-induced erythema. Minimal erythema doses were also determined for sites treated with NV-07alpha or its vehicle immediately after UV exposure. NV-07alpha had no significant effects on UV erythema. We conclude that 4 mM NV-07alpha prevented the suppressive effects of UV radiation on Mantoux responses in humans but did not affect UV-induced erythema at the concentrations used.

Administration, Topical↗
PubMedDate not supplied

UV-A fingerprint mutations in human skin cancer.

This review of our work, presented at the Photocarcinogenesis Symposium of the 14th International Congress on Photobiology, shows that UV-A causes a similar number of gene mutations as UV-B in human skin cancer. Areas of about 20 keratinocytes from solar keratoses and squamous cell carcinomas, which are benign and malignant skin cancers, respectively, were sampled by laser capture microdissection. Automated sequencing of the p53 gene was used to detect mutations in these tumor areas, and the cause of the mutations was attributed on the basis of previously published studies. UV-A and UV-B caused similar numbers of p53 gene mutations in both benign and malignant human skin tumors, with UV-B-induced mutations being restricted to the upper areas of the tumors and UV-A-induced mutations predominating at the basal layer. Furthermore, each microdissected region within a tumor had distinct mutations showing that the skin tumors consisted of different clones of cells. This is not consistent with how human skin carcinogenesis is currently understood, and hypotheses to explain our data are presented. We propose that the UV-A waveband of sunlight is as important as UV-B in causing skin cancer in humans.

Genes, p53↗
PubMedDate not supplied

Ultraviolet B but not A radiation activates suppressor B cells in draining lymph nodes.

Immunosuppressive doses of solar-simulated UV radiation activate lymph node B cells that can suppress primary immunity by inhibiting the function of dendritic cells. The aim of this study was to determine the waveband responsible for activation of these suppressor B cells. We exposed C57BL/6 mice to various doses of either UVA or UVB radiation and analyzed the number and activation state of lymph node antigen-presenting cells (APC). Immunosuppressive doses of UVB but not UVA activated B cells as assessed by major histocompatibility complex II (MHC II) expression and doubled their numbers in draining lymph nodes. Higher doses of UVA that were not immunosuppressive actually suppressed B cell activation. Our results show that UVA and UVB suppress systemic immunity via different mechanisms. Lymph node B cells are activated in response to immunosuppressive doses of UVB but not UVA. Thus, the activation state of lymph node APC appears to be important for UV immunomodulation.

Animals↗