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Title: Chronic ultraviolet irradiation : effects on immune responses and tumour outgrowth
Author: Macve, Joanne C.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2003
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Exposure to solar ultraviolet (UV) radiation causes induction of skin cancers. Previous experiments using mice have demonstrated that the majority of these skin tumours are antigenic, and are rejected upon transplantation into immunocompetent, syngeneic recipients. However, prior irradiation of the recipients with subcarcinogenic doses of UV renders them susceptible to progressive tumour outgrowth, suggesting a role for UV in suppression of immune responses to skin tumours. Using a moderately immunogenic fibrosarcoma (FSA) cell line, the present study examines which UV wavebands are most effective in increasing susceptibility to tumour cell outgrowth; it also investigates the mechanisms by which UV exposure affects immune responses to injected tumour cells. To establish the most important wavebands for affecting the immunity to tumours, three different lamps were used: a broad-band UVB source (TL12), a narrow-band UVB source (TL01, 311-313 nm) and a UVA-I source (340-400 nm). A three week irradiation protocol was chosen as this has previously been shown to result in increased outgrowth of implanted tumours. The immunosuppressive properties of these lamps were assessed by irradiating mice twice a week for three weeks. All three sources were shown to reduce the number of epidermal Langerhans cells and the contact hypersensitivity response. Additionally, the numbers of dendritic cells in the draining lymph nodes of mice irradiated over 3 weeks with the broad-band UVB source were counted; a significant reduction in lymph node dendritic cell numbers was observed in irradiated mice compared with unirradiated controls, although the expression of MHC Class II and CD86 antigens on these cells was unaffected. The effects of the different lamps on tumour outgrowth were assessed by irradiating mice twice a week for three weeks on their shaved backs; the FSA cells were then injected subcutaneously into the irradiated site. Prior exposure of mice to 2 2 doses of 1200 J/m , but not 1000 J/m broad-band UVB resulted in increased growth of the injected cells, indicating a dose dependency of UVB-enhanced tumour outgrowth. No increase in tumour size was seen following injection of FSA cells into an unirradiated site on UV-irradiated mice, demonstrating that the effect of the UVB was a local one. Prior exposure of mice to narrow-band UVB or UVA-I did not result in increased tumour cell outgrowth. In unirradiated tumour-bearing mice, it was found that the in vitro spontaneous proliferation of cells from lymph nodes draining the sites of tumour cell injection was increased compared with the proliferation of cells from tumour-free mice. Taking lymph nodes at various time points after tumour cell inoculation showed that UVB-exposure prior to FSA cell injection resulted in a delay in the time at which an increase in the in vitro proliferation became apparent. Using flow cytometry, the expression of various cell surface markers on lymph node cells from tumour-bearing mice was assessed. Additionally, an attempt was made to identify any infiltrating host cells in the tumours using immunohistochemistry. CA-urocanic acid (UCA), formed from the naturally occurring trans-isomer on UVB-irradiation of skin, is a recognised initiator of UVB-induced immunosuppression, and has previously been implicated in photocarcinogenesis. In the present study, mice were treated twice a week for 3 weeks with cA-UCA prior to FSA cell injection; this treatment did not result in increased outgrowth of the resulting tumours. Similarly, injection of a monoclonal antibody with specificity for cA-UCA prior to each irradiation with broad-band UVB did not reverse the UVinduced increase in tumour growth. Thus no role for cA-UCA in UV-enhanced tumour outgrowth was established.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available