Margaret L. Kripke

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.

Dendritic cells require T cells for functional maturation in vivo

We examined dendritic cell (DC) status in SCID and RAG2 -/- mice to assess the influence of T cells on DC development and function in vivo. These mice have reduced numbers of DC in the epidermis and lymph nodes draining hapten-sensitized skin. Epidermal DC in these mice were defective in presenting antigen in vivo to adoptively transferred, hapten-sensitized T cells from normal mice. Likewise, draining lymph node DC were deficient in their capacity to stimulate naive T cells in vitro and in vivo. DC numbers as well as the impaired ability to present antigen in vivo, were corrected by reconstituting these animals with normal T lymphocytes, suggesting that T cells are crucial for normal DC maturation and function in vivo.

Health effects from stratospheric ozone depletion and interactions with climate change

The potential health effects of elevated levels of ambient UV-B radiation are diverse, and it is difficult to quantify the risks, especially as they are likely to be considerably modified by human behaviour. Nevertheless epidemiological and experimental studies have confirmed that UV radiation is a definite risk factor for certain types of cataract, with peak efficacy in the UV-B waveband. The causal link between squamous cell carcinoma and cumulative solar UV exposure has been well established. New findings regarding the genetic basis of skin cancer, including studies on genetically modified mice, have confirmed the epidemiological evidence that UV radiation contributes to the formation of basal cell carcinomas and cutaneous melanomas, For the latter, animal models have demonstrated that UV exposure at a very young age is more detrimental than exposure in adulthood. Although suppression of certain immune responses has been recognised following UV exposure, the impact of this suppression on the control of infectious and autoimmune diseases is largely unknown. However, studies on several microbial infections have indicated significant consequences in terms of symptoms or reactivation of disease. The possibility that the immune response to vaccination could be depressed by UV-B exposure is of considerable concern. Newly emerging possibilities regarding interactions between ozone depletion and global climate change further complicate the risk assessments for human health but might result in an increased incidence of cataracts and skin cancer, plus alterations in the patterns of certain categories of infectious and other diseases.

Sun and malignant melanoma

The incidence and mortality rates of malignant melanoma in Caucasians are increasing rapidly in many countries worldwide. Considerable circumstantial evidence suggests that exposure to solar radiation may play a role in this substantial rise in malignant melanoma. This evidence comes primarily from epidemiologic studies and from the identification of susceptible phenotypes. Despite the increasing data that implicate sunlight as an important factor in the development of certain types of malignant melanomas in humans, the role of solar electromagnetic radiation in the pathogenesis of human malignant melanomas is yet to be determined.

WAVELENGTH DEPENDENCE AND DOSE‐RATE INDEPENDENCE OF UV RADIATION‐INDUCED IMMUNOLOGIC UNRESPONSIVENESS OF MICE TO A UV‐INDUCED FIBROSARCOMA

Irradiation of BALB/c mice with FS40 sunlamps induces susceptibility to challenge with syngeneic UV‐induced fibrosarcomas that otherwise would be rejected immunologically. Plastic filters were used to remove various wavelengths from the radiation source to identify the active waveband. Wavelengths above 315 nm (those transmitted through a mylar filter) were ineffective in producing tumor susceptibility, even when the total amount of energy applied was the same as that emitted by the unfiltered FS40 sunlamps. Removal of wavelengths below 275 nm (with a polystyrene filter) did not reduce the activity of the radiation. Alteration of the dose‐rate of the radiation by as much as a factor of 10. by irradiating animals through neutral density filters, did not change the proportion of tumor‐susceptible mice, suggesting that there is reciprocity with regard to dose‐rate and time of UV exposure. Cell transfer studies were used to test whether similar immunologic mechanisms were responsible for the equal susceptibility to tumor challenge of mice given continuous UV exposure (one 12‐h treatment) or fractionated exposures (twelve 1‐h treatments). With both treatment regimens, tumor susceptibility could be transferred to X‐irradiated recipients with lymphoid cells, provided that sufficient time had elapsed after the single treatment.

Systemic Alteration Induced in Mice by Ultraviolet Light Irradiation and Its Relationship to Ultraviolet Carcinogenesis

Chronic irradiation of mice with ultraviolet (UV) light produces a systemic alteration of an immunologic nature. This alteration is detectable in mice long before primary skin cancers induced by UV light begin to appear. The alteration results in the failure of UV-irradiated mice to reject highly antigenic, transplanted UV-induced tumors that are rejected by unirradiated syngeneic recipients. The immunologic aspect of this systemic alteration was demonstrated by transferring lymphoid cells from UV-irradiated mice to lethally x-irradiated recipients. These recipeints were unable to resist a later challenge with a syngeneic UV-induced tumor, whereas those given lymphoid cells from normal donors were resistant to tumor growth. Parabiosis of normal mice with UV-irradiated mice, followed by tumor challenge of both parabionts with a UV-induced tumor, resulted in the growth of the challenge tumors in both UV-irradiated and unirradiated mice. Splenic lymphocytes from tumor-implanted UV-treated mice were not cytotoxic in vitro against UV-induced tumors, whereas under identical conditions cells from tumor-implanted, unirradiated mice were highly cytotoxic. Our findings suggest that repeated UV irradiation can circumvent an immunologic mechanism that might otherwise destroy nascent UV-induced primary tumors that are strongly antigenic.

Mechanisms of depressed reactivity to dinitrochlorobenzene and ultraviolet-induced tumors during ultraviolet carcinogenesis in BALB/c mice☆

Abstract Chronic treatment of BALB/c mice with ultraviolet (uv) radiation produces two distinct immunologic deficiencies. These deficiencies are apparent long before visible skin tumors are induced by the uv irradiation. One is reflected in a transient inability to develop delayed hypersensitivity to dinitrochlorobenzene and appears to be due to a defect in antigen processing. The other is expressed by the failure of mice to reject syngeneic uv-induced tumors, which are highly antigenic. This lack of tumor rejection can be passively transferred with lymphoid cells and seems to be due to the presence of specific suppressor lymphocytes.

EXPOSURE OF MICE TO UV‐B RADIATION SUPPRESSES DELAYED HYPERSENSITIVITY TO Candida albicans

Abstract

p53 Tumor Suppressor Gene: A Critical Molecular Target for UV Induction and Prevention of Skin Cancer†

The relationship between exposure to UV radiation and development of skin cancer has been well established. Several studies have shown that UVB induces unique mutations (C→T and CC→TT transitions) in the p53 tumor suppressor gene that are not commonly induced by other carcinogens. Our studies have demonstrated that UV‐induced mouse skin cancers contain p53 mutations at a high frequency and that these mutations can be detected in UV‐irradiated mouse skin well before the appearance of skin tumors. This observation suggested that it might be possible to use p53 mutations as a biologic endpoint for testing the efficacy of sunscreens in photoprotection studies. Indeed, application of SPF 15 sunscreens to mouse skin before each UVB irradiation resulted in reduction in the number of p53 mutations. Because p53 mutations represent an early essential step in photocarcinogenesis, these results imply that inhibition of this event may protect against skin cancer development. This hypothesis was confirmed by our finding that sunscreens used in p53 mutation inhibition experiments also protected mice against UVB‐induced skin cancer.

PHOTOBIOLOGY SCHOOL.: PHOTOIMMUNOLOGY*

As the name implies, photoimmunology is the study of the effects of photons on the immune system. As a scientific discipline, it is only a little more than 10 years old, and thus it represents one of the more recent subspecialties in photobiology. Photoimmunology combines certain elements of three scientific disciplines, namely photobiology, immunology, and dermatology. Dermatology is included because all of the known effects of photons on the immune system are initiated in the skin, either from a direct effect of UV radiation on immune cells within the skin or by means of indirect effects of UV radiation on other components of the skin that secondarily affect immune cells. The photons of most interest in photoimmunology are those with wavelengths in the UV region of the spectrum, particularly in the UV-B (28c320 nm) range. Wavelengths in the UVC (20@280 nm) range are also immunologically active, but they have received much less attention because of their absence from natural sunlight. The second component of photoimmunology, the immune system, is the primary defense mechanism that protects the body against infectious disease. Its importance in this regard is easily visualized by considering the unfortunate fate of people who lack one or more components of the immune system, such as those with AIDS or other immunodeficiency diseases. The immune system is a complex, interactive system of checks and balances designed to rid the body of foreign substances and maintain homeostasis.