19]][“Molecule P”

ICAM expression on human sk in cells is thought to be of critical importance for the elicitation of cellmediated immune responses in human sk in. In prev ious studies, the {|reasch {Endurobol|Amiodarone induction of ICAM expression in human cells, including keratinocy tes, has been shown to be suppressed upon exposure to sublethal doses of UVB radiation. This immunosuppressive ef fect of UVB irradiation was found to be dosedependent, and this assay system has therefore been used as a photoimmunological endpoint to assess the susceptibility of human sk in cells toward UVB radiationinduced immunosuppression. One consequence of this general immunosuppressive ability of UVB radiation is that exposure of human sk in to MED of UVB radiation ef fectively inhibited the elicitation phase of the delayedtype hypersensitiv ity reaction tonickel sulfate in sensitized indiv iduals. This immunosuppressive ef fect could be overcome through the topical application of photolyase and the subsequent exposure of treated sk in areas to photoreactivating radiation.These data indicate that DNA damage is linked to UVB radiationinduced suppression of the elicitation phase of allergic contact dermatitis.These results clearly link DNA damagewith the clin ical symptoms of immunosuppression and erythema.They extend obser vations made in the opposum that photoreactivation of py rimidine dimers reduced UV radiationinduced erythema. These data explain why the action spectrum for human erythema so closely parallels the action spectrum for the induction of cyclobutane dimers in DNA. Interestingly, this approach prov ided complete restoration of keratinocy te ICAM expression, whereas the number of epidermal thymine dimerswithin the same sk in areas was reduced by only. A possible explanation for this discrepancy might be that not all dimers are equal, but that repair of a fraction of dimers might. This hypothesis is supported by the recent obser vation that only photoproducts in actively transcribed DNA, which are preferentially repaired. Perhaps DNA regions involved in the transcriptional regulation of the human ICAM gene may be repaired more rapidly than others may.A lternatively, UVB radiation ef fects may require a critical number of cyclobutane py rimidine dimerswithin epidermal keratinocy tes, and if the number of dimers is reduced below this threshold, complete protection against UVB radiationinduced immunomodulation and apoptosis may be achieved.This would also imply that there is no linear correlation between the number of dimers and the development of immunosuppression.In support of thisview, UVB radiationinduced suppression of immune responses in human sk in was shown to be a function of biologically rather than physically equalized UVB radiation doses. Moreover, recent ev idence demonstrates that keratinocy te apoptosis induced by UV is mediated by DNA damage and can be prevented even if not all cyclobutane py rimidine dimers in DNA are repaired. In conclusion, the present study indicates that topical application of exogenous photolyase to human sk in is an approach that is highly ef ficient in protecting human sk in from the deleterious ef fects that result from the presence of UVB radiationinduced py rimidine dimers.Exogenous application of photolyase dif fers from conventional photoprotection through its ability to remove damage that has already occurred.

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