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Background: The immune suppressive effects of topical photodynamic therapy (PDT) are potential contributors to treatment failure after PDT for nonmelanoma skin cancer. Nicotinamide (vitamin B(3) ) prevents immune suppression by ultraviolet radiation, but its effects on PDT-induced immunosuppression are unknown., Objectives: To determine the effects of topical and oral nicotinamide on PDT-induced immunosuppression in humans., Methods: Twenty healthy Mantoux-positive volunteers received 5% nicotinamide lotion or vehicle to either side of the back daily for 3 days. Another group of 30 volunteers received 500 mg oral nicotinamide or placebo twice daily for 1 week in a randomized, double-blinded, crossover design. In each study, methylaminolaevulinate cream was applied to discrete areas on the back, followed by narrowband red light irradiation (37 J cm(-2) ) delivered at high (75 mW cm(-2) ) or low (15 mW cm(-2) ) irradiance rates. Adjacent, nonirradiated sites served as controls. Delayed-type hypersensitivity (Mantoux) reactions were assessed at treatment and control sites to determine immunosuppression., Results: High irradiance rate PDT with vehicle or with placebo caused significant immunosuppression (equivalent to 48% and 50% immunosuppression, respectively; both P < 0·0001); topical and oral nicotinamide reduced this immunosuppression by 59% and 66%, respectively (both P < 0·0001). Low irradiance rate PDT was not significantly immunosuppressive in the topical nicotinamide study (15% immunosuppression, not significant), but caused 22% immunosuppression in the oral study (placebo arm; P = 0·006); nicotinamide reduced this immunosuppression by 69% (P = 0·045)., Conclusions: While the clinical relevance of these findings is currently unknown, nicotinamide may provide an inexpensive means of preventing PDT-induced immune suppression and enhancing PDT cure rates., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

Ultraviolet A (UVA) radiation is immunosuppressive and mutagenic in humans and carcinogenic in animals. UVA suppresses immunity with a bell-shaped dose response. At doses equivalent to 15-20 minutes of sun exposure at noon, UVA contributes to approximately 75% of sunlight-induced immunosuppression. A recent action spectrum, indicating that 360-380 nm but not 320-350 nm UVA suppresses immunity in humans, suggests an important role for reactive oxygen species. UVA also causes an energy crisis in cells, and normalization of adenosine triphosphate with nicotinamide prevents UVA immunosuppression. UVA activation of the alternative complement pathway and defects in memory T-cell development are also involved. Human skin cancers contain mutations in the p53 and BRM genes that are consistent with being induced by UVA. UVA is also mutagenic in human skin equivalents. The basal layer of human skin is more susceptible to UVA-induced mutations than the upper layers. Because skin cancers arise from these basal proliferating cells, this finding is likely to be important and could be attributable to low levels of the DNA repair enzyme OGG1 in basal cells. UVA is therefore likely to make a larger contribution to UVA-induced skin carcinogenesis in humans than is predicted by small animal models as the result of being immunosuppressive and mutagenic for basal keratinocytes., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The immune-suppressive effects of sunlight play a central role in skin carcinogenesis. Ultraviolet (UV) B radiation is highly immunosuppressive even at suberythemal doses, and longwave UVA is now also recognized to cause immunosuppression in humans. The relative contributions of UVA and UVB to immunosuppression by incidental daily sun exposure are, however, unclear., Objectives: We previously determined wavelength dependencies for immunosuppression by UVB and UVA wavebands in humans. We now aimed to calculate relative and solar immune-suppressive effectiveness across the UVB and UVA spectra., Methods: We used the nickel model of recall contact hypersensitivity to determine UV immunosuppression dose responses and minimum immune suppression doses (MISDs) at 11 narrowbands from 289 to 392 nm. The relative immune-suppressive effectiveness of each narrowband was then determined as 1/MISD vs. wavelength. This curve was multiplied by the solar spectrum to show the relative immune-suppressive effectiveness of each waveband in sunlight., Results: We found peaks of immune-suppressive effectiveness in the UVB waveband at 300 nm and in the UVA at 370 nm. Because of the far greater amount of longwave UVA in sunlight, the relative solar immune-suppressive effectiveness of UVA was threefold higher than that of UVB at doses equivalent to sun exposure from normal daily activities., Conclusions: Longwave UVA, which abuts the visible light spectrum and is less effectively filtered by sunscreens than UVB, is likely to be the largest contributor to immunosuppression resulting from incidental daily sun exposure., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists.)

Background: Ultraviolet (UV) A radiation, which has both mutagenic and immune suppressive effects on the skin, is increasingly recognised as a key contributor to cutaneous carcinogenesis. Whilst short wavelength UVB (290-320 nm) is well-recognised as an environmental health hazard, the dangers of UVA (320-400 nm) are relatively unexplored., Objective: Using the nickel model of recall immunity in healthy human volunteers, we determined the wavelength dependency for UV-induced immunosuppression across the UVA spectrum., Methods: Dose-response curves were established for local suppression of contact hypersensitivity responses to nickel at 7 wavelengths between 331 and 392 nm., Results: We found a broad peak of UVA immune suppressive effectiveness at 364-385 nm. Whilst we had previously found linear dose-responses for UVB-induced immunosuppression in this model, long wavelength UVA caused bell-shaped, Gaussian dose-responses, suggesting different chromophores and mechanisms of immunosuppression for UVB and UVA., Conclusion: The immunosuppressive peak induced by longwave UVA has not been described previously for any species and being close to the border with visible light indicates an unexpected role for these long wavebands in human health and disease., (Copyright 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

UVB radiation is a potent environmental carcinogen that not only causes mutations in the skin but also profoundly suppresses skin immune responses. Although this UVB-induced suppression of antitumor immunity has a key role in skin cancer development, the wavelengths within UVB causing greatest in vivo immunosuppression in humans are as yet unknown. We have identified a wavelength dependency for immunosuppression in humans across the UVB spectrum. We established linear dose-response curves for UV-induced local suppression of recall contact hypersensitivity responses at four wavelengths between 289 and 322 nm and found peak immune suppressive effectiveness at 300 nm and no detectable suppression at 322 nm within a physiologically relevant dose range.

Background: Riboflavin (vitamin B(2)) plays a key role in cellular energy metabolism. We have observed previously that nicotinamide (vitamin B(3)), which is also centrally involved in cellular energy restoration after UV irradiation, is highly immune protective in humans. We thus hypothesized that riboflavin might also confer immune protection., Methods: We irradiated healthy, nickel-allergic volunteers with narrowband UVA (385 nm) and UVB (300 nm) at separate sites on the lower back. These areas were treated with riboflavin solution or vehicle at 24 h and again at 30 min before UV exposure. Forty-eight hours after irradiation, volunteers were patch tested with nickel-containing Finn chambers, at both irradiated and nonirradiated sites, with and without prior riboflavin treatment. The resulting contact hypersensitivity reactions at each site were then measured 72 h later with a reflectance erythema meter in order to determine and compare the immune suppressive effects of each intervention., Results: We observed that low doses of both UVB and longwave UVA1 were immune suppressive in humans. Topical riboflavin conferred immune protection against both wavebands., Conclusions: Riboflavin is immune protective in humans, and this may reflect the role of the B group vitamins in cellular energy restoration after UV exposure.

Background: Visible light irradiation after application of a photosensitizer (topical photodynamic therapy; PDT) is increasingly used to treat nonmelanoma skin cancers and premalignant actinic keratoses. PDT can provide a cosmetically superior alternative to surgery, but carries failure rates of 10-40%. While some murine studies have suggested immune enhancement by PDT, others reported immunosuppressive effects, which may indicate impaired antitumour immunity and thus compromised tumour clearance., Objectives: This study aimed to determine the in vivo immune effects of PDT in humans., Methods: Using healthy, Mantoux-positive volunteers, we irradiated discrete areas of the back with narrowband red light (630 nm; 37 J cm(-2)), with and without prior application of 5-aminolaevulinic acid (ALA) or methyl aminolaevulinate (MAL). Adjacent, untreated areas served as immunologically intact control sites. Delayed-type hypersensitivity responses to tuberculin purified protein derivative (Mantoux reactions) were then elicited in each of the irradiated, unirradiated and control sites, and the intensity of the reactions was quantitated with an erythema meter and by measurement of Mantoux diameter. By comparing Mantoux intensity at treated and control sites, immunosuppression was determined in each volunteer for each intervention., Results: We found that both MAL-PDT and ALA-PDT significantly suppressed Mantoux erythema (by 30% and 50%, respectively) and diameter (41% and 38%). Red light alone significantly suppressed diameter (22%) but not erythema (13%)., Conclusions: Topical PDT induced significant immune suppression, which could impair local antitumour immune responses and may thus contribute to treatment failure.

Cutaneous immunity, which is a key defence against the development of skin cancers, is suppressed by even small doses of ultraviolet (UV) radiation. Preventing this UV-induced immunosuppression may therefore reduce the incidence of skin cancer. Nicotinamide (vitamin B3) has immune-protective and cancer-preventive effects against UV radiation in mice, and we have shown previously that topical nicotinamide is immune protective in humans. Using the Mantoux model of skin immunity in healthy volunteers, we compared oral nicotinamide to placebo (both administered for 1 week) in a randomized, double-blinded, crossover design against the effects of solar-simulated ultraviolet (ssUV) radiation on delayed-type hypersensitivity to tuberculin purified protein derivative. Discrete areas of the back were irradiated with low doses of ssUV daily for three consecutive days. Immunosuppression, calculated as the difference in Mantoux-induced erythema of irradiated sites compared with unirradiated control sites, was determined in volunteers taking oral nicotinamide and placebo. Significant immunosuppression occurred in an UV dose-dependent manner in the presence of placebo. Oral nicotinamide, at doses of either 1500 or 500 mg daily, was well tolerated and significantly reduced UV immunosuppression with no immune effects in unirradiated skin. Oral nicotinamide is safe and inexpensive and looks promising as a chemopreventive supplement for reducing the immunosuppressive effects of sunlight.

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.

Relatively few studies have examined the effects of low-dose ultraviolet (UV) radiation on in vivo human cutaneous immunity, or the ability of sunscreens to prevent UV-induced immunosuppression. We have studied the effects of solar-simulated UV radiation on nickel contact hypersensitivity (CHS) in nickel-allergic volunteers, and on delayed type hypersensitivity responses in Mantoux-positive volunteers. Nickel CHS and Mantoux responses were significantly suppressed by acute, suberythemal UV exposures equivalent to less than 8 min summer sunlight. Both UVA and UVB wavebands were immunosuppressive, but UVA-induced immunosuppression was transient, whereas UVB had a more sustained effect. Dose-responses for UV immunosuppression were determined using the nickel method, enabling calculation of in vivo sunscreen immune protection factors in a manner analogous with sun protection factor measurement. Sunscreens were found to confer significantly less protection against UV-induced immunosuppression than against UV-induced erythema.

The effects of low dose ultraviolet (UV) radiation on delayed type hypersensitivity responses to tuberculin purified protein derivative were investigated in 17 healthy, Mantoux-positive volunteers. Suberythemal and erythemal doses of solar simulated UV from a fluorescent lamp source were delivered to the subjects' lower backs daily for five consecutive days. Mantoux testing with intradermally injected purified protein derivative was then performed at both the irradiated sites and an adjacent, unirradiated site, and the Mantoux induced erythema was quantitated 72 h later with a reflectance erythema meter. In comparison with the unirradiated Mantoux sites, Mantoux induced erythema was significantly reduced at the irradiated test sites. In six subjects, we compared the effects of chronic versus short term UV irradiation on the Mantoux reaction. These volunteers were irradiated on one side of their lower backs with the 5 d UV protocol, and on the other side of their backs for 4 or 5 wk. In all but one subject, the short irradiation protocol induced greater suppression of Mantoux responses than prolonged UV exposure. We conclude that even suberythemal doses of UV significantly reduce delayed type hypersensitivity responses to purified protein derivative, and that an adaptive mechanism appears to counteract the immunosuppressive effects of chronic irradiation.