Ultraviolet radiation (UVR) is a complete carcinogen, inducing skin cancer via DNA photodamage that can lead to mutagenesis, and promoting its growth via photoimmunosuppression (PI). The omega-3 polyunsaturated fatty acid (n-3 PUFA) eicosapentaenoic acid was shown in murine studies to protect against PI and UV-induced skin cancer although the mechanism is uncertain. The principal objectives of this thesis were to (i) examine whether n-3 PUFA can protect against a clinical model of PI in healthy humans and (ii) explore whether the underlying mechanism could be abrogation of UV-induced depletion of antigen-presenting Langerhans cells (LC) from the epidermis, and/or impact on immunomodulatory cytokines. Nickel (Ni) allergic females (n=79) were randomized to 3 months of daily supplementation with 5g n-3 PUFA (70% eicosapentaenoic acid, EPA; 10% docosahexaenoic acid, DHA) or the placebo medium chain triglyceride, GTCC. Local PI was clinically assessed post supplementation using the nickel contact hypersensitivity (Ni CHS) model. In each volunteer, Ni patches were applied to 3 skin sites that were irradiated for 3 consecutive days with UV-doses of 1.89, 3.82 & 7.59J/cm2 respectively. CHS responses were measured and compared to responses of control patches applied on unirradiated skin using a reflectance erythema meter. In the same subjects, assessments of cellular and biochemical mediators of PI were made pre and post supplementation. At 24hr post irradiation with an erythemal UV-dose (4 minimal erythemal doses) to upper buttock skin, half the subjects (n=39) had skin punch biopsies taken and the other half (n=40) had suction blisters raised on this irradiated skin and on unirradiated skin of the contralateral buttock. Epidermal sheets were prepared from the punch biopsies and immunohistochemically stained to assess UV-induced LC numbers. Levels of immunomodulatory cytokines were analysed in the suction blister fluid using Luminex multiplex assay kits. To evaluate compliance and bioavailability, blood samples were taken from all volunteers, pre and post supplementation and EPA% weight in red blood cell membranes was examined using gas chromatography. Post supplementation, EPA %wt was significantly higher in the active group compared to control: mean 3.61% ± 0.22% (SEM) vs. 0.93% ± 0.06% (p<0.001). 3 volunteers showed evidence of non-compliance and were excluded from further analysis. Compared to placebo, evidence for protection against local PI of Ni CHS was apparent post n-3 PUFA at all UV doses, reaching statistical significance at the UV-dose of 3.8J/cm2 (p<0.05). No significant difference in post-UV epidermal LC numbers after supplementation was seen between active and placebo groups, with a % fall following UV of 76.61 ± 3.39% (SEM) in the active group and 73.52 ± 5.24% (SEM) in the control group. When intragroup comparisons were made pre vs. post supplementation, a similar increase in UV-induced LC depletion from the epidermis was seen in both groups, reaching statistical significance following n-3 PUFA (p=0.018). Levels of interleukins IL-10 and IL-8, and of TNF-α, increased post-UVR in both active and control groups pre-supplementation, with no changes occurring following supplementation. In conclusion, supplemental EPA was bioavailable and evidence of protection against clinical PI of Ni CHS was seen in the actively treated group. However, no evidence was found that this abrogation of PI was mediated through a reduced effect of UV on migration of epidermal LC or the immunomodulatory cytokines examined. This original study gives the first evidence that dietary n-3 PUFA may protect against clinical PI, and potentially skin cancer promotion, in humans. Further research is needed to confirm this finding, and to examine the underlying mechanisms, which could involve other immunoregulatory cells of the skin, such as dermal dendritic cells and T regulatory cells and other mediators of UV-immunosuppression including the prostanoids, which may be modified by n-3 PUFA.

No / Background: Skin cancer is a major public health concern, and the majority of cases are caused by solar ultraviolet radiation (UVR) exposure, which suppresses skin immunity. Omega-3 (n−3) PUFAs protect against photoimmunosuppression and skin cancer in mice, but the impact in humans is unknown. Objectives: We hypothesized that EPA-rich n−3 PUFA would abrogate photoimmunosuppression in humans. Therefore, a nutritional study was performed to assess the effect on UVR suppression of cutaneous cell-mediated immunity (CMI) reflected by nickel contact hypersensitivity (CHS). Design: In a double-blind, randomized controlled study, 79 volunteers (nickel-allergic women, 22–60 y old, with phototype I or II) took 5 g n−3 PUFA–containing lipid (70% EPA plus 10% DHA) or a control lipid daily for 3 mo. After supplementation, nickel was applied to 3 skin sites preexposed on 3 consecutive days to 1.9, 3.8, or 7.6 J/cm2 of solar-simulated radiation (SSR) and to 3 unexposed control sites. Nickel CHS responses were quantified after 72 h and the percentage of immunosuppression by SSR was calculated. Erythrocyte [red blood cell (RBC)] EPA was measured by using gas chromatography. Results: SSR dose-related suppression of the nickel CHS response was observed in both groups. Photoimmunosuppression appeared less in the n−3 PUFA group than in the control group (not statistically significant [mean difference (95% CI): 6.9% (−2.1%, 15.9%)]). The difference was greatest at 3.8 J/cm2 SSR [mean difference: 11% (95% CI: 0.5%, 21.4%)]. Postsupplementation RBC EPA was 4-fold higher in the n−3 PUFA group than in the control group (mean difference: 2.69% (95% CI: 2.23%, 3.14%), which confirmed the EPA bioavailability. Conclusion: Oral n−3 PUFAs appear to abrogate photoimmunosuppression in human skin, providing additional support for their chemopreventive role; verification of study findings is required.