Ultraviolet radiation-induced immune modulation: potential consequences for infectious, allergic, and autoimmune disease.

Both the U.S. Environmental Protection Agency (EPA) and the World Health Organization (WHO) are concerned with potential health effects that might result from increased exposure to ultraviolet radiation (UVR) as a result of depletion of stratospheric ozone by anthropogenic chemicals such as chlorofluorocarbons and halons. Major targets for UVR effects include the skin, eye, and immune system. A thorough review of effects of UVR on these tissues was published recently by WHO (1). In 1989, the EPA's Health Effects Research Laboratory (HERL, predecessor of NHEERL, the National Health and Environmental Effects Laboratory) convened an expert panel to identify research needs to improve health risk assessments with respect to UVR exposure. At that time there were sufficient data to make quantitative estimates of the risks of skin cancer and cataract development associated with depletion of stratospheric ozone. Studies also indicated that some immune functions were compromised by exposure to UVR and that this might influence the incidence and severity of infectious diseases as well as vaccine effectiveness. However, data necessary to quantitate the risk to the immune system were not available. As a result of recommendations from the expert panel, HERL initiated a small, focused research effort to improve this data base. The need to accurately assess the risk of UVR exposure to the immune system is critical, since these effects are expressed immediately, in contrast to skin cancer and cataracts, which take years to develop. In 1994, HERL and the UV Monitoring and Assessment Program, an industrial group, held a workshop that focused on potential effects UVRinduced immune suppression might have on infectious disease in humans and concluded that quantitative predictions were not possible (2). The subject of this report is a workshop jointly sponsored by the EPA and WHO on 12-13 December 1995, "UVR-Induced Immune Modulation: Potential Consequences for Infectious, Allergic, and Autoimmune Disease," in Chapel Hill, NC. The aims of the workshop were 1) to review currently available studies relevant to assessing risks associated with UVR effects on the immune system, 2) to identify needs for further research to improve the risk assessment process, and 3) to recommend and prioritize specific research projects for which WHO should actively seek funding. Two of the most problematic areas for risk assessment are extrapolating from immune function data obtained in laboratory rodents to humans, and extrapolating from effects on human immune functions to potential effects on infectious diseases and/or vaccine effectiveness. These issues were addressed in sessions one and two, respectively. Session three dealt with the possibility that UVR immune modulation may impact allergic and autoimmune disease as well. Session 1: Quantitative comparisons between human and mouse studies: applications to the development of risk assessment models. Dr. Noonan reviewed experimental evidence for dose and wavelength-dependent UVR-induced modulation of contact hypersensitivity (CH) and delayed-type hypersensitivity (DTH) in mice. Suppression of these immune responses appears to play a critical role in the growth of skin cancers and enhances the progression of certain infections in mice. Dose-response data from a study (3) of 18 strains of inbred mice demonstrated three phenotypes for suppression of CH (Table 1). The total dose required for immune suppression is much less than that required for skin cancer induction and, unlike cancer induction, is independent of dose-rate and dose fractionation. Dr. Assaf then presented studies done by Cooper et al. (in collaboration with the EPA) showing dose-response curves for UVR-induced suppression of CH in humans [K.D. Cooper, personal communication; (4)]. Subjects (ranging from light skinned to heavily pigmented) were grouped according to UVR sensitivity based on minimal erythemal dose, and doses of UVR causing 50% immunosuppression were determined for each skin type (Table 1). These doses could easily be achieved at midday in temperate latitudes under summer sun and were less than that required to achieve 50% suppression in the most sensitive mice in Noonan's studies. Hence, the responses of mice and humans to UVRinduced suppression of CH are quantitatively similar (Table 1). Dr. Selgrade described a parallelogram model (Fig. 1) at has been used to make comparisons between effects in laboratory rodents and humans, and between deficits in immune function and increased susceptibility to disease (5). In such models, dose-response data from Drs. Noonan and Assaf would correspond to the upper corners of the parallelogram. Dose-response data on host resistance to infection in mice and the potential for assessing vaccine effectiveness in humans presented in session two would correspond to the lower corners. Quantitative comparisons could then be made between the corners of the parallelogram, which would indicate how well CHS predicts effects on response to infectious disease and how well mouse data predicts human effects. Session 2: Potential impact of UVR on infectious disease and vaccine effectiveness. Dr. Jeevan reviewed studies in which UVR exposure increased the incidence and/or severity of infection in mice challenged with viral, parasitic, fungal, and bacterial agents. She presented data with Mycobacterium bovis BCG (the vaccine strain for tuberculosis) and M. lepraemurium (a mouse leprosy model). The UVR dose required for 50% suppression of the DTH response to these two agents (Table 1) resulted in approximately a threefold increase in the number of BCG bacteria in spleen and lymph nodes of infected mice (6). Dr. van Loveren described similar studies in rats in which there was a strong relationship between suppression of the in vitro lymphoproliferative response to bacterial antigen following in vivo UVR exposure and increased susceptibility to challenge with bacteria. Also, he reported a 3.8fold difference in the dose required to suppress the skin-mixed lymphocyte response by 50% in humans and rats and indicated that his data could be applied in a parallelogram model to predict effects on resistance to bacterial infection in humans. (Table 1) (7). Dr. Ward described three opportunities for field studies to assess effects of UVR exposure on vaccine effectiveness in humans. First, vacci-