Pyrimidine dimers in DNA initiate systemic immunosuppression in UV-irradiated mice.
Exposing the skin of mice to UV radiation interferes with the induction of delayed and contact hypersensitivity immune responses initiated at nonirradiated sites. The identity of the molecular target in the skin for these immunosuppressive effects of UV radiation remains controversial. To test the hypothesis that DNA is the target for UV-induced systemic immunosuppression, we exposed C3H mice to UV radiation and then used liposomes to deliver a dimer-specific excision repair enzyme into the epidermis in situ. The application of T4 endonuclease V encapsulated in liposomes to UV-irradiated mouse skin decreased the number of cyclobutane pyrimidine dimers in the epidermis and prevented suppression of both delayed and contact hypersensitivity responses. Moreover, the formation of suppressor lymphoid cells was inhibited. Control, heat-inactivated endonuclease encapsulated in liposomes had no effect. These studies demonstrate that DNA is the major target of UV radiation in the generation of systemic immunosuppression and suggest that the primary molecular event mediating these types of immunosuppression by UV radiation is the formation of pyrimidine dimers. Furthermore, they illustrate that the delivery of lesion-specific DNA repair enzymes to living skin after UV irradiation is an effective tool for restoring immune function and suggest that this approach may be broadly applicable to preventing other alterations caused by DNA damage.
Kripke
M L
ML
Department of Immunology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Cox
P A
PA
Alas
L G
LG
Yarosh
D B
DB
D000704:Analysis of Variance; D000818:Animals; D002175:Candida / Q000276:immunology; D004247:DNA / Q000378:metabolism / Q000528:radiation effects*; D004249:DNA Damage; D004260:DNA Repair; D043224:Deoxyribonuclease (Pyrimidine Dimer); D004307:Dose-Response Relationship, Radiation; D004337:Drug Carriers; D004706:Endodeoxyribonucleases / Q000378:metabolism; D005260:Female; D006968:Hypersensitivity, Delayed; D007165:Immunosuppression Therapy; D016219:Immunotherapy, Adoptive; D008081:Liposomes; D051379:Mice; D008809:Mice, Inbred C3H; D011740:Pyrimidine Dimers; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D012867:Skin / Q000276:immunology* / Q000528:radiation effects*; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014466:Ultraviolet Rays; D014764:Viral Proteins
D004337:Drug Carriers; D008081:Liposomes; D011740:Pyrimidine Dimers; D011994:Recombinant Proteins; D014764:Viral Proteins; D004247:DNA; D004706:Endodeoxyribonucleases; C470698:endonuclease V, phage T4; D043224:Deoxyribonuclease (Pyrimidine Dimer)