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We tested the hypothesis that DNA is a target for solar-simulated ultraviolet radiation (ssUVR)-induced suppression of the reactivation of memory immunity in humans. T4N5 liposomes contain the DNA repair enzyme T4 endonuclease V. This cleaves DNA at the site of ultraviolet radiation (UVR)-induced cyclobutane pyrimidine dimers (CPD), initiating DNA repair. It has previously been used to show that CPDs are a key molecular trigger for UVR-induced immunosuppression in mice. To determine whether CPD formation is involved in UVR immunosuppression in humans, nickel-allergic volunteers were irradiated with a range of doses of ssUVR. T4N5 or empty liposomes were then applied after irradiation. Nickel-induced recall immunity was assessed by reflectance spectrometry. T4N5 liposomes inhibited immunosuppression and prevented ssUVR from reducing the number of epidermal dendritic cells. T4N5 liposomes also reduced macrophage infiltration into irradiated epidermis. These studies show that enhanced removal of CPDs from human skin protects from immunosuppression, hence demonstrating that these photolesions are an important molecular event in ssUVR-induced immunosuppression in humans. CPDs also triggered loss of dendritic cells and infiltration by macrophages. It is possible that these changes to antigen presenting cells contribute to ssUVR induced suppression of recall immunity to nickel in humans.

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.

We have examined the mechanism by which solar-simulated ultraviolet radiation (ssUV) suppresses memory immunity to nickel in allergic humans. In initial studies, we used inbred mice to determine the contribution of different wavebands to sunlight-induced immunosuppression. We found that low dose UVA can enhance memory, medium dose UVA (half the amount in one minimum erythemal dose of ssUV) is immunosuppressive, but higher doses protect from UVB. This is genetically dependent, as it is not observed in all mouse strains. UVA caused a similar dose-related change in recall immunity in humans. ssUV dose responses determined the limits of protection provided by sunscreens from immunosuppression in humans. Immune protection factors calculated from these data correlated with UVA protection, but not with sun protection factor, showing that in commercial sunscreens that provide good UVB protection, UVA protection limits prevention of immunosuppression. N(G)-monomethyl-l-arginine acetate (l-NMMA) was used to inhibit nitric oxide (NO) production and T4N5 liposomes containing T4 endonuclease V to enhance DNA repair. Sub-erythemal ssUV caused a dose-related local suppression of recall immunity to nickel in humans. l-NMMA and the liposomes protected the nickel reaction, suggesting that NO and DNA damage are mediators of UV-induced immunosuppression in humans.

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.

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.

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.