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Abstract

Ultraviolet radiation (UVR) causes mutagenic DNA damage to skin cells and
suppression of the skin immune system (SIS) that contributes to skin cancer
development. UVR in the UVB range also causes the beneficial production of vitamin
D3 by keratinocytes. Keratinocytes also contain the enzymes required for the two-step
hydroxylation of vitamin D3 is to its biologically active form: 1α,25 dihydroxyvitamin
D3 (1α,25 (OH)2D3). 1α,25 (OH)2D3 has been demonstrated to modulate the SIS and
its response to UVB irradiation. Topical application of 1α,25 (OH)2D3 suppresses the
SIS and protects against UV-induced DNA damage. This thesis investigates the
hypothesis that dietary vitamin D3 similarly suppresses the SIS response via modulation
of the SIS and protects against UVB induced immunosuppression via a reduction in
UVB induced DNA damage.
To assess the influence of vitamin D3 on the development and function of the SIS, and
the skins response to UVR, a vitamin D3 deficient mouse population was developed.
Breeding pairs of vitamin D3 replete and vitamin D3 deficient mice were formed and
the off-spring of these mice were used in experiments. The contact hypersensitivity
(CHS) response was used to assess the SIS function in vitamin D3 replete and vitamin
D3 deficient mice. In this model the application of the contact sensitiser to the skin of
neonatal mice leads to suppression of the CHS response upon subsequent resensitisation
and elicitation of the CHS in adulthood. The suppression of the CHS
response is termed ‘neonatal tolerance’.
Vitamin D3 enhanced neonatal tolerance in male but not female mice. The enhanced
neonatal tolerance induction related to an increase in the proportion of CD4+CD25+
cells in vitamin D3 replete neonatal male mice and this cell population could transfer
tolerance in this mouse group. Vitamin D3 suppressed the CHS response in adult male
but not adult female mice. An investigation of DC function in adult mice revealed no
modulation by vitamin D3 in antigen carriage or co-stimulatory molecule expression,
suggesting that these cells were not modulating the reduced CHS response in adult male
mice. However, dietary vitamin D3 was associated with a higher proportion of CD4+CD25+ cells in the SDLN after contact sensitiser application in male but not
female mice, implying that vitamin D3 was modulating the induction of these cells.
The level of UVB-induced immunosuppression was assessed in vitamin D3 replete and
deficient mice in C57BL/6 and BALB/c mice. Vitamin D3 protected C57BL/6, but not
BALB/c mice against UVB-induced immunosuppression. The protection against UVBinduced
immunosuppression may relate to a reduction in UVB-induced DNA damage in
C57BL/6 mice, not identified in BALB/c mice. In BALB/c mice female gender
protected against UVB-induced immunosuppression and was associated with a subtle
lowering of UVB-induced DNA damage in comparison to male mice at low UVR
exposures. These results indicate that the protection against UVB-induced
immunosuppression by vitamin D3 varies with genetic background and the modulation
of UVB-induced DNA damage.
If these mouse studies are extended to humans, the ability of vitamin D3 to suppress the
SIS and the limited protection against UVB-induced DNA damage in males, depending
on their genetic background, may contribute to the greater burden of skin cancer in
males than in females.

Item Type:	Thesis - PhD
Authors/Creators:	Malley, RC
Additional Information:	Copyright © the Author
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