SUPPRESSION OF CONTACT HYPERSENSITIVITY BY UV RADIATION AND ITS RELATIONSHIP TO UV-INDUCED SUPPRESSION OF TUMOR IMMUNITY

Abstract— In this study, we examine some of the photobiologic and immunologic characteristics of the suppression of contact hypersensitivity (CHS) by UV radiation. BALB/c mice were irradiated on the shaved dorsal skin with FS40 sunlamps and sensitized 5 days later by applying a contact sensitizer lo the shaved abdomen. The suppression of CHS resulting from exposure to a given total dose of UV radiation was unaffected by changes in dose fractionation over a 5-day period and by changes in dose-rate over a 10-fold range. Elimination of wavelengths below 315 nm with a mylar filter abrogated the suppressive effect of the sunlamps, even when the same total energy was administered. Irradiation of unshaved mice required 14 times more energy to produce 50% suppression than was required for shaved mice, suggesting that the exposed skin is the primary target of this effect. Contact sensitization of UV-irradiated, but not unirradiated, mice induced the appearance of antigen-specific suppressor T lymphocytes in their spleen. The photobiologic and immunologic similarities between the suppression of CHS by UV radiation and the UV-mediated suppression of tumor rejection that we described previously suggest that these two immunosuppressive effects of UV exposure share certain steps in their pathways.     

SUPPRESSION OF THE INDUCTION OF DELAYED-TYPE HYPERSENSITIVITY REACTIONS IN MICE BY A SINGLE EXPOSURE TO ULTRAVIOLET RADIATION

Abstract— After a single exposure of mice to UV radiation, their ability to generate a contact hypersensitivity (CHS) response to contact sensitizers applied epicutaneously to distant, unirradiated skin is severely impaired. It is not clear, however, if the classic delayed type hypersensitivity (DTH) reponse to exogenous antigens, injected into the subcutaneous (s.c.) space, can also be modulated by UV radiation. We report here that a single exposure of mice to UV radiation suppressed the induction of DTH to both erythrocyte and soluble protein antigens injected s.c., but did not suppress the elicitation of the response. The suppressive effect was abrogated by cyclophosphamide treatment. In addition, antigen-specific suppressor cells were found in the spleens of the mice with a decreased DTH response. Since the ability to mount a DTH response has been linked with the resistance to certain pathogenic microorganisms, we suggest that the suppression of DTH by UV radiation may have the potential to compromise host resistance to such infectious agents.     

Viability of the antigen determines whether DNA or urocanic acid act as initiator molecules for UV-induced suppression of delayed-type hypersensitivity

UV radiation suppresses the immune response, and UV-induced immune suppression contributes to UV-induced photocarcinogenesis. For UV-induced immune suppression to occur, electromagnetic energy (i.e. UV radiation) must be converted to a biological signal. Two photoreceptors have been identified in the skin that serves this purpose, epidermal DNA and trans-urocanic acid (UCA). Although compelling evidence exists to support a role for each pathway (UV-induced DNA damage or photoisomerization of UCA) in UV-induced immune suppression, it is not clear what determines which photoreceptor pathway is activated. To address this question, we injected UV-irradiated mice with a monoclonal antibody with specificity for cis-UCA or applied liposomes containing DNA repair enzymes to the skin of UV-irradiated mice. The effect that each had on UV-induced suppression of delayed-type hypersensitivity was measured. We asked whether the light source used (FS-40 sunlamps vs solar-simulated UV radiation) altered whichever pathway of immune suppression was activated. Different doses of UV radiation and the viability of the antigen were also considered. Neither the dose of UV nor the light source had any influence on determining which pathway was activated. Rather, we found that the viability of the antigen was the critical determinant. When live antigens were used, UV-induced immune suppression was blocked with monoclonal anti-cis-UCA but not with T4 endonuclease V-containing liposomes. The reverse was observed when formalin-fixed or killed antigens were used. Our findings indicate that antigen viability dictates which photoreceptor pathway predominates after UV exposure.     

The Monodelphis melanoma model: initial report on large ultraviolet A exposures of suckling young

The objective of this study was to determine whether exposure of early suckling young of the opossum Monodelphis domestica to ultraviolet A (UVA) radiation (320-400 nm) can lead to the development of melanocytic lesions similar to those induced after exposure to ultraviolet B (UVB) radiation (280-320 nm) to total doses as low as 380 J/m2. A total of 576 sucklings received nine exposures of 0.6, 2.6 or 15.5 kJ/m2 per dose (total doses approximately 6, 23 and 140 kJ/m2, respectively) from a Blak Ray lamp source with a narrow range emission at 365 nm. A further 280 sucklings were exposed in the same way to doses of 2.6 kJ/m2 per dose (total approximately 23 kJ/m2) broad-band UVA with visible wavelengths from a Dermalight lamp. Frequency of litter loss following all of the UVA-exposure protocols was similar to that within the same stocks in the colony at large. Only one of the 856 UVA-exposed individuals possessed a melanocytic lesion at the 5 month assessment point. No radiation-induced lesions of any type were evident on the skin of the other animals exposed as sucklings. The affected male was from a group of 70 individuals exposed to the highest total dose (140 kJ/m2) from the Blak Ray light source. The melanocytic hyperplasia was provisionally identified as a potential melanoma but it slowly regressed as the animal aged. We conclude that in the opossum suckling exposure system, the potency of UVA for melanoma induction is extremely low compared with that of UVB. Possible explanations, amenable to further investigations, are given for the low UVA sensitivity of the suckling model compared to the adult exposure model of Ley (Ley, R. D. [1997] Cancer Res. 57, 3682-3684).     

Growth rate and chromosome number of tumor cell lines with different metastatic potential

We investigated whether the metastatic potential of various tumor cell lines was related to chromosome counts or to rate of growth in vitro or in vivo. Clones of known metastatic potential derived from a C3H- fibrosarcoma induced by UV radiation (UV-2237) and from C57BL/6 B16 melanoma were tested for these characteristics. No correlation was found between the growth rate of these clones in monolayer culture or at a subcutaneous site and their ability to produce metastases. The cells from clones of UV-2237 were mainly in the diploid range with only one exception, and the B16 clones were all hyperploid. Thus, there was also no correlation between malignant behavior of the clones and gross changes in chromosome number.     

EFFECT OF UV IRRADIATION ON LETHAL INFECTION OF MICE WITH Candida albicans

Exposure of mice to UV radiation inhibits the induction and elicitation of the delayed-type hypersensitivity (DTH) response to Candida albicans. To determine whether UV irradiation also affects the pathogenesis of systemic C. albicans infection, C3H mice were exposed to a single dose of 48 kJ/m² UV-B radiation from FS40 sunlamps 5 days before or 5 days after sensitization with formalin-fixed C. albicans and challenged intravenously (i.v.) with a lethal dose of viable fungi 6 days after sensitization (11 or 1 days after UV irradiation). Exposing unsensitized mice to UV radiation 11 days before lethal challenge had no effect on survival, but the survival time of mice exposed to UV radiation 1 day before challenge was reduced by more than 50%. In the latter group, decreased survival time correlated with persistence of C. albicans in the brain and progressive growth of C. albicans in the kidneys. Sensitization of unirradiated mice with formalin-fixed C. albicans extended their survival time following lethal i.v. challenge with viable C. albicans. Exposing the mice to UV radiation 5 days before sensitization did not abrogate this beneficial effect of sensitization on survival, even though it significantly reduced the DTH response. Thus, immunity to systemic infection did not depend on the ability of the mice to exhibit a DTH response to C. albicans. The beneficial effect of sensitization on survival after lethal infection was abrogated, however, in mice exposed to UV radiation 1 day before lethal challenge with C. albicans. Furthermore, these mice were unable to contain the progressive growth of C. albicuns in the kidneys, in contrast to sensitized, unirradiated mice. The induction of cutaneous inflammation with turpentine had no effect on the survival rate of mice lethally infected with C. albicans, suggesting that inflammation alone is not sufficient to decrease the survival time of C. albicans-infected mice.     

INHIBITION OF THE IMMUNE RESPONSE TO ALLOANTIGEN IN THE RAT BY EXPOSURE TO ULTRAVIOLET RADIATION

Exposure of mice to ultraviolet radiation (UV) followed by alloantigen sensitization can suppress the immune response to that alloantigen. In order to assess the applicability of using UV-induced immunosuppression in organ transplantation, the effectiveness of UV in prolonging the survival of vascularized organ allografts must be determined. Because, for technical reasons, rats are better suited than mice for such experiments, we first wanted to determine whether UV suppresses the immune response of inbred rats to alloantigens. The data presented here demonstrate that exposure of rats to UV (115-129 kJ/m2) prior to alloantigenic sensitization decreases the mixed lymphocyte response to alloantigen. The depression of the proliferative response to alloantigen was selective in that spleen cells from the UV-treated rats could respond to mitogenic stimulation. In contrast to previous results with mice, suppressor cells could not be demonstrated in the spleens of the UV-treated rats. In addition, UV treatment after sensitization inhibited the response to alloantigen. These data suggest that treatment of the recipient with UV before or after alloantigenic sensitization may provide a novel method of inhibiting immune responses to allogeneic antigens.     

Suppression of Delayed and Contact Hypersensitivity Responses in Mice Have Different UV Dose Responses

Although acute exposure to UV radiation suppresses the induction of delayed-type (DTH) and contact (CHS) hypersensitivity in mice, it is not clear whether the photo-biological mechanism(s) involved in suppressing these closely related immune reactions is the same. A careful examination of the UV dose responses and wavelength dependencies involved in suppressing CHS and DTH may provide important insights into the mechanisms involved. We compared the UV dose-response curves for suppressing four closely related immune reactions, local and systemic suppression of CHS to dinitrofluorobenzene, systemic suppression of DTH to Candida albicans and systemic suppression of DTH to alloantigen using three different UV spectra (FS40 sunlamps, Kodacel-filtered FS40 sunlamps and solar-simulated light). For each immune response studied, the amount of UVB radiation required to induce 50% immune suppression was lowest when FS40 sunlamps were used, highest with solar-simulated light and intermediate when Kodacel-filtered FS40 sunlamps were used, but the differences observed were not statistically significant. The UV dose-response curves for immune suppression differed significantly depending on the assay used, the site of antigenic sensitization and the antigen used. These findings suggest that the mechanisms by which UV radiation induces immune suppression differ for the four immunological reactions studied.     

LOCAL SUPPRESSION OF CONTACT HYPERSENSITIVITY IN MICE BY A MONOFUNCTIONAL PSORALEN PLUS UVA RADIATION

Monofunctional psoralens, plus UVA radiation are not erythemogenic and are less mutagenic than bifunctional psoralens plus UVA radiation. Thus, they have received considerable attention in recent years as potential therapeutic agents for various skin diseases. The purpose of this study was to examine the immunologic side effects following treatment of mice with a monofunctional psoralen plus UVA radiation. We report that angelicin plus UVA radiation suppressed the induction of contact hypersensitivity to dinitrofluorobenzene. This decreased immune response was associated with the presence of splenic suppressor cells that transferred suppression to normal recipients. Treatment with angelicin and UVA radiation also decreased the number of Thy-1+ and Ia+ dendritic epidermal cells in the treated site. We conclude that although this monofunctional psoralen is not phototoxic, it has immunosuppressive activity in mice.