[CANCERRESEARCH54,6102-6105,December1, 1994]

Special Lecture

Ultraviolet Radiation and Immunology: Something New under the Sun

Presidential Address1

Margaret L. Kripke

Department of Immunology. The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Abstract

The carcinogenic activity of solar radiation has been known for nearlya century. However, within the past few years, we have realized thatexposing the skin to sunlight also has profound immunological effects onthe host and that these immunological changes can contribute to thedevelopment ofskin cancer and alter host resistance to infectious diseases.These findings have led to the development of a new field of research,termed photoimmunology, which is concerned with the effects of UVradiation on immunological processes.

Our interest in this field arose from studies on the antigenic propertiesof skin cancers induced in mice by chronic exposure to UV-B (280-320nm) radiation. These cancers are highly antigenic and many are immunologically rejected upon transplantation to normal syngeneic recipients.In studying how these cancers were able to survive and grow in theprimary host, we discovered that exposing the skin to UV radiation alteredsome types of immune responses, including the immune response againstskin cancers.

Studies on the nature and mechanism of the immunological alterationsbrought about by exposure to UV radiation suggested that UV-lnducedDNA damage triggers a cascade of events, leading ultimately to a state ofantigen-specific, systemic T lymphocyte-mediated immunosuppression.Key components of this cascade are epidermal cytokines, which modulatethe immune response to antigens introduced into the UV-irradiated hostand divert the response toward a state of specific lmmunosuppression.

The finding that UV radiation can redirect the immune response froman effector to a suppressor pathway has raised the possibility that immuneresponses to infectious diseases might also be influenced by exposure ofthe host to UV radiation. Interest in the health consequences of strataspheric ozone depletion, with its attendant increase in solar UV-B radiadon, has stimulated recent investigations on the effects of UV radiation onthe pathogenesis of infections in animal models and on immune responsesin humans. In addition, attempts are being made to use information aboutUV-induced specific immunosuppression to eliminate unwanted immuneresponses, such as transplant rejection and graft-versus-host reactions.

Thus, studies on the immunological effects of UV radiation are providing new information on how immune responses are regulated as well asimproving our understanding of the role of the immune system in skincancer induction. This information should facilitate the development ofmore effective measures for preventing the deleterious effects ofoverexposure to UV radiation.

Introduction

The fact that UV radiation has any effects on the immune system atall is both unexpected and remarkable. It is unexpected, because UVradiation has little power of penetration through living tissues, and

most is absorbed by the outer few mm of the skin. It is remarkablebecause life on earth has evolved in an environment containing UVradiation, and there is no obvious reason why the immune systemshould be accessible to it. Twenty years ago, no one would havepredicted that shining UV light on the skin would have immunological

Received 10/26/94; accepted 10/27/94.I Presented at the 85th Annual Meeting of the American Association for Cancer

Research, San Francisco, CA, April 10, 1994.

consequences, much less that this would turn into an entire field ofinvestigation. Nonetheless, the field of photoimmunology, which isthe study of the interactions between photons and the immune system,has become an important facet of both photobiology and dermatologyresearch.

The photons of most significance for photoimmunology are those inthe UV-B (280—320nm) region of the solar spectrum. These are thewavelengths that benefit human health by catalyzing the production ofvitamin D; they are also the primary wavelengths responsible forsunburn and skin cancer (1). Furthermore, it is this region of the solarspectrum that is affected by ozone depletion. Most UV-B radiationfrom the sun is filtered out by ozone in the stratosphere, and areduction in ozone concentration will permit an increase in the amountof UV-B radiation in sunlight (2). The threat of ozone depletion inrecent years has focused considerable attention on the potential immunological effects of UV-B radiation.

In my presentation I will first describe how our studies of UVinduced skin cancer led us into the realm of photoimmunology;second, I will summarize our current state of knowledge regarding themechanisms by which UV radiation modifies immune responses;finally, I will address the significance of these findings for humanhealth.

Historical Background

Many years ago, we set out to study the antigenic properties of skincancers induced in mice by UV radiation, using the approach ofclassical tumor immunology, namely tumor transplantation. Unexpectedly, while trying to propagate the tumors by transplantation, wefound that most failed to grow in normal, syngeneic hosts, but theygrew progressively in immunodeficient mice (reviewed in Refs. 3—6).This finding suggested that the tumors were highly antigenic, and itraised the question of why they were able to grow in the primary hostwithout succumbing to immunological rejection. The answer to thisquestion was equally unexpected; we found that exposing mice to UVradiation rendered them unable to reject these highly antigenic tumors.The alteration was systemic because tumors implanted anywhere inthe UV-irradiated hosts grew progressively.

The systemic alteration induced by UV radiation was immunological in nature because it could be transferred with T lymphocytes.Somehow, UV irradiation induced suppressor T cells that inhibited therejection of these highly antigenic tumors. The suppressor cells werespecific in that the recipients were still able to reject other types oftumors. We also demonstrated that the suppressor cells were important in the induction of primary skin cancers by showing that injectionof suppressor cells into mice early in carcinogenesis shortened thelatent period for tumor induction (7).

From these early studies, we learned that UV-induced tumors werehighly antigenic, that UV irradiation caused systemic immunosuppression, and that this immunosuppression contributed to the development of the primary skin cancers. Therefore, UV radiation seemedto play a multifaceted role in carcinogenesis: It transformed normal

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UV RADIA11ON AND IMMUNOLOGY

cells into cancer cells; it caused stable, heritable antigenic changes inthese cells; and it depressed the immune response to these antigeniccancers, thereby permitting their outgrowth. These findings raised two

important questions: (a) How does shining a light on the skin alter theimmune response? (b) Why does UV alter the immune response?

Mechanisms of UV-induced Immunosuppression

Most of what we know about how UV alters the immune responsecomes from studying other cell-mediated immune responses, ratherthan tumor rejection. Information on this topic has been contributedby many laboratories, as well as my own. Early on, we and otherslooked at the effects of UV irradiation on many immune responses(3—6). We found that early in the course of UV irradiation, some other

immune responses were also modified, particularly delayed hypersensitivity and CHS2 responses; other immune responses, such as graftrejection and antibody production, seemed to be unaffected.

The human prototype of the CHS response is poison ivy. In thisreaction, a chemical is applied to the skin, and antigen-presenting cells(mainly epidermal Langerhans cells) take up the antigen and migrateto the regional lymph nodes, where they interact with T helper cells toinitiate the response. After expansion and differentiation, these T cellsenter the circulation. When they contact the antigen in the skin, theyrelease cytokines (chemical mediators) and cause the local symptomsof redness, itching, and swelling. The DTH response is similar, exceptthat the antigen is introduced by the i.d. or s.c. route, and a differentpopulation of antigen-presenting cells is involved.

Local Immunosuppression. There are two models of UV-inducedimmunosuppression, termed local and systemic suppression (reviewedin Refs. 6, 8, and 9). In local suppression, the antigen is appliedtopically or i.d. in the site of UV irradiation. In the mouse, applicationof a contact sensitizing chemical to UV-irradiated skin induces adecreased CHS response, and one can find in the spleen of these miceantigen-specific T cells that inhibit the induction of CHS when transferred to another animal. Examination of the UV-irradiated skinreveals that epidermal Langerhans cells are morphologically alteredand reduced in number. These fmdings led to the hypothesis that UVirradiation was altering the function of cutaneous antigen-presentingcells and that this somehow changed the type of immune responseelicited.

To test this hypothesis, we used an in vivo approach in which thefluorescent antigen FITC is used as a contact sensitizer. This enabledus to follow the fate of the antigen-presenting cells in vivo. Eighteenh after painting FITC onto the skin of a normal mouse, the DLNcontain a small number of FITC+ dendritic cells. Characterization ofthese cells by sorting FITC+ cells demonstrated that they are Ia+ andF4/80+ and contain Birbeck granules, which are ultrastructural markers of epidermal Langerhans cells (10). Injection of the DLN cells intoa secondary host induces CHS because of the presence of theseFITC-bearing antigen-presenting cells (1 1). We used this model to askwhat happens to the activity of the DLN cells in mice that are firstexposed to UV radiation and then painted epicutaneously with FITC.DLN cells from unirradiated mice induce CHS when injected into thefootpads of normal syngeneic recipients. In contrast, DLN cells fromUV-irradiated mice fail to induce CHS; instead, they induce or transfer suppressor T cell activity (12).

One possible explanation for the decreased antigen-presenting activity is that the FITC+ dendritic cells never leave the skin after UVirradiation and thus are not present in the DLN. This is not the case,however; FACS analysis demonstrated that equivalent numbers of

2 The abbreviations used are: CHS, contact hypersensitivity; DLN, draining lymph

nodes; id., intradermal; DTH, delayed-type hypersensitivity; TNFa, tumor necrosis factora; IL, interleukin.

FITC+ cells are present in the DLN of normal and UV-irradiated mice(12).@ At least some of the FITC+ cells came from the skin of theUV-irradiated mice. This was demonstrated by sorting the FITC+cells and staining them with a monoclonal antibody specific forpyrimidine dimers; the dimers are present only in the DNA of cells

exposed directly to UV radiation. In the DLN of UV-irradiated mice,all of the dimer-containing cells were present in the FITC+ antigenpresenting cell population, indicating that they had been exposed toUv radiation in the skin and migrated into the DLN after sensitization.4 Recent experiments demonstrated that FACS-punfied, FITC+,Ia+ DLN cells have reduced antigen-presenting activity.3

Thus, our studies support the following model: UV irradiation altersantigen-presenting cells in the skin; these cells reach the DLN aftersensitization with F1TC; and their activity is altered. There is alsoevidence suggesting that inflammatory cells that have entered the skinin response to UV radiation may also function as antigen-presentingcells and thereby contribute to the altered immune response (13).Recent work from Verneer and Streilein suggests, in addition, thatcytokine mediators may also play a role in this form of UV-inducedimmunosuppression. Treating UV-irradiated mice with antibodyagainst TNFa can partially inhibit immunosuppression (14). There areprobably other contributors to the local suppressive milieu, such asprostaglandin E@, IL-i and IL-b, and cis-urocanic acid, all of which

are present in UV-irradiated skin. The net result is inhibition of theCHS pathway and activation of the suppressor pathway. Recent studies demonstrated that UV radiation has a similar effect in humans(15, 16).

Systemic Immunosuppression. UV irradiation can also suppressimmune responses initiated outside UV-irradiated skin. In this case,slightly more UV radiation is required, and the antigen can be paintedtopically or injected s.c. The result is the same as in the localsuppression model, however; instead of the DTH or CHS responsebeing induced, antigen-specific suppressor T cells are induced (6).Clearly, this form of suppression is not due to a direct effect of the UVon antigen-presenting cells in the skin, and it must involve solublemediators. Evidence for the participation of soluble mediators wasprovided by experiments demonstrating that exposing munne keratinocytes to UV radiation in vitro caused the production of solublefactors that mimicked whole-body UV irradiation: Injection of thesefactors into normal mice, followed by immunization, induced activesuppression, instead of CHS or DTH (17, 18). Recent studies demonstrated that IL-b is a mediator of suppression of the DTH response(19), whereas systemic suppression of CHS involves TNFa (20).

Molecular Mechanism of UV-induced Immunosuppression. Toinitiate a biological response, UV radiation must first be absorbed bymolecules in the skin (jthotoreceptor) and transform its energy into abiochemical event. Several pathways for the effect of UV radiation on

the immune response are possible. UV radiation can activate genesdirectly by causing structural alterations in DNA; it can also alterDNA indirectly by causing the formation of oxygen radicals, whichsecondarily damage DNA. UV radiation can cause lipid peroxidationin cell membranes, thereby activating genes by means of intracellularsignaling pathways, and it can isomerize a molecule in the stratum

corneum, urocanic acid, which has immunosuppressive properties.Recently, we used an approach developed by Dr. Daniel Yarosh

(Applied Genetics, Inc., Freeport, NY) to test the hypothesis thatdirect DNA damage, in the form of pyrimidine dimers, is involved inUV-induced immunosuppression. The approach involves the use of

3 5. Saijo, C. D. Bucana, K. M. Ramirez, M. L Kripke, and F. M. Strickland. Deficient

antigen presentation and Ts induction are separate effects of UV radiation, submitted forpublication.

4 A. Vink, F. Strickland, L. Ross, and M. Kripke, unpublished data.

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Uv RADIATIONAND IMMUNOLOGY

liposomes to deliver an excision repair enzyme to cells in the skin invivo. BacteriophageT4 endonucleaseV, an excisionrepair enzymespecific for pyrimidine dimers in DNA, is encapsulated in acid-labileliposomes and applied topically to murine skin. There, it is taken up

by keratinocytes and Langerhans cells and reaches the nucleus ofthese cells (21). Previous studies demonstrated that these T4N5 liposomes increased the repair of pyrimidine dimers in mouse skin in vivoand human keratinocytes in vitro (22, 23).

In these studies, we wished to determine whether reducing theamount of DNA damage by application of the T4N5 liposomeswould also reduce the amount of immunosuppression induced byUv irradiation. C3H mice were exposed to FS4O sunlamp irradiation and immunized 3 days later at an unexposed site with a

contact sensitizing chemical to induce CHS or with Candida albicans to induce DTH. Both responses were inhibited in UV-irradi

ated mice. Application of T4N5 liposomes immediately after UVirradiation abrogated the immunosuppressive effects of the irradiation, whereas application of liposomes containing heat-denaturedenzyme had no effect. The T4N5 liposomes were effective onlywhen applied to the UV-irradiated skin, not to distant, unexposedskin, and only when applied immediately after the irradiation (24).

In subsequent studies, we demonstrated that T4N5 liposomes alsoreduce UV-induced damage to epidermal Langerhans cells (25).These studies and others (26) strongly suggest that DNA damage isthe primary mechanism by which UV radiation triggers its immunosuppressive effects and that the formation of pyrimidine dimersis likely to be an essential first step in the pathway leading toimmunosuppression. Since TNFa and IL-lO have been demonstrated to play a role as soluble mediators of UV-induced immu

nosuppression (14, 19, 20), our current studies are directed towarddetermining whether application of T4N5 liposomes reduces the

amount of these cytokines in UV-irradiated skin.Our working model for systemic immunosuppression is that tJV

induced DNA damage activates transcription of cytokine genes, therebyinitiating the release of immunosuppressive cytokines. These cytokinesshift the balance of the immune response away from a DTH (T helper 1)

type of response toward a suppressive (T helper 2) type of response, so

that antigens introduced during a critical period after UV irradiationinduce active suppression instead of immunity. There is growing sentiment that the suppressor T cells associated with UV irradiation maysimply be T helper 2 cells, which produce cytokines, such as IL-lO, thatdown-regulate T helper 1 cells (27, 28).

To put together the models for both local and systemic suppression,we propose that with low doses of UV radiation, antigen-presentingcells in the irradiated skin are modified, either directly by the actionof UV or indirectly by the influx of inflammatory cells or by the localrelease of cytokines that modify their activity. Larger doses of UVradiation may bring about the release of these cytokines systemically,causing an alteration in the activity of antigen-presenting cells indistant lymphoid organs and activation of the T helper 2 pathway. Ofcourse, we speculate that this is the mechanism by which UV irradiation suppresses the immune response to skin cancers, although there

is as yet no direct evidence for this.

Significance

These studies may have significance for DNA repair deficiencydiseases. If DNA damage is responsible for triggering immunosup

pression through alterations in epidermal cytokine production, thenpersons who are unable to repair UV-induced DNA damage may havecytokine imbalances, in addition to a high incidence of skin cancer.This may help to explain some of the secondary manifestations of

xeroderma pigmentosum and other sun sensitivity syndromes which

could arise from cytokine dysregulation.These studies clearly have significance for preventing the deleteri

ous effects of sunlight exposure. Understanding the mechanisms ofimmunosuppression is suggesting new approaches for preventing UVmediated damage. In addition to preventing DNA damage, the approach used by all current sun-blocking agents, it may be possible toreverse DNA damage by increasing DNA repair; to inhibit the activityof specific cytokines, such as TNFa; and to prevent the release ofcytokines from epidermal cells. All of these approaches may serve toreduce the immunological effects of UV irradiation. On the otherhand, we may be able to use this information to induce specificimmunosuppression to prevent undesirable immune responses, suchas transplant rejection or graft-versus-host disease (29).

If immunology is important in the induction of human skincancer, then one might expect that sensitivity to UV-inducedimmunosuppression should correlate with skin cancer risk. Evidence supporting this idea was provided by Yoshikawa et al. (15),who demonstrated that under certain experimental conditions,about 40% of the normal human population is highly susceptible tolocal suppression of the CHS response by UV radiation; however,nearly 100% of persons who have had one or more skin cancers arehighly sensitive to UV-induced immunosuppression. These resultsare consistent with the hypothesis that sensitivity to immunosuppression by UV is an additional risk factor for skin cancer

development in susceptible individuals.With regard to immunology, these studies illustrate that the immune

system is important in skin cancer development and that immunological mechanisms may play a determining role in the outcome of the

host-tumor interaction. They also make another point. Because theimmune system is so intimately connected to the skin, it is accessibleto external influences, and such seemingly superficial events as shining a light on the skin may have profound systemic immunological

consequences. Therefore, what we put on our skin or encounter in ourenvironment may influence our systemic immune response.

These studies also have environmental significance. Because thetypes of immune responses affected by UV radiation are important indefense against infectious diseases, this has raised the question ofwhether UV irradiation can impair immunity to infectious agents.Studies from our laboratory and others have demonstrated that notonly can UV irradiation of mice interfere with the induction ofimmunity to certain infectious agents (reviewed in Ref. 30), but insome instances, UV irradiation can also increase the duration andseverity of the disease process. This is illustrated in experiments inwhich mice were exposed once to UV radiation and then infected withMycobacterium lepraemurium in the footpad (31). This bacteriumcauses a slow, progressive infection that ultimately results in deathafter about 1 year. A single dose of UV radiation decreased the DTHresponse, decreased the rate of clearance from lymphoid tissues, andaccelerated the rate of death from this organism. These studies illustrate that the condition of the immune system during the first encounter with an infectious agent may be critical to the outcome of disease.

Such findings have raised a concern that increased solar UV radiation, resulting from ozone depletion, may alter the balance of thehost-disease relationship in favor of the pathogen for some diseases.For example, infection of some mouse strains with Leishmania actiyates a T helper 2 response and results in a progressive, lethalinfection; in others, a T helper 1 response is activated, the infection isself-limiting, and the animals develop immunity (32). Therefore, ashift from the T helper 1 to the T helper 2 type of response by UVirradiation could have serious consequences for infectious diseases.Thus, ozone depletion may result not only in more cases of skincancer but also in an increase in the incidence, severity, or duration of

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UV RADIATION AND IMMUNOLOGY

some infectious diseases, particularly in countries where infectiousdiseases constitute a major public health problem.

What, then, is the evolutionary significance of UV-induced immunosuppression? Why would UV exposure, which is necessary for life,cause immunosuppression? The answer is, of course, unknown, butthe popular immunological answer, suggested first by Dr. GeorgeKlein (Karolinska Institute, Stockholm, Sweden), is that because UVradiation is mutagenic and causes antigenic changes in cells of theskin, immunosuppression is a protective response designed to keep usfrom rejecting our skin every time we develop a sunburn. However,the recent findings on DNA damage and epidermal cytokines raiseanother possibility: we now know that keratinocytes can producemany cytokines; some of these, like IL-lO, are involved in immunosuppression, but others, like granulocyte-macrophage colony-stimulating factor, IL-i, IL-4, and IL-6, are involved in hematopoiesis andlymphoid differentiation. Perhaps epidermal cytokine production represents an “SOS―type of response to DNA damage in general and isdesigned to restore hematopoietic balance following exposure to

DNA-damaging agents. Because of coordinate regulation of cytokinesor pleiotropic activity of cytokines, this response is accompanied by abrief period of immunosuppression. Thus, UV irradiation may prod

uce a small gap in immune surveillance in exchange for rapid mobilization of hematopoietic cells in response to DNA-damaging agents.Regardless of the evolutionary function of UV-induced immunosuppression, however, it seems fair to conclude that studies of UVradiation and immunology have indeed provided us with somethingnew under the sun.

Acknowledgments

I would like to thank all those who participated in these studies, whichspan nearly two decades. In particular, I would like to thank my currentresearch group, headed by Dr. Cherrie Donawho, who helped immeasur

ably with the preparation of this presentation and who have kept theresearch going during my tenure as President of the American Associationfor Cancer Research. Special thanks are also due to my long-standingcollaborator, Dr. Corazon Bucana, who directs the Ultrastructural ResearchLaboratory for the Departments of Cell Biology and Immunology at theUniversity of Texas M. D. Anderson Cancer Center, and Dr. Daniel

Yarosh, Applied Genetics, Inc., Freeport, NY, whose collaboration hashelped add a new dimension to our work.

References

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11. Thomas, W. R., Edwards, A. J., Watkins, M. C., and A.sherson, G. L. Distribution ofimmunogenic cells after painting with the contact sensitizers fluorescein isothiocyanate and oxazolone. Different sensitizers form immunogenic complexes with differentcell populations. Immunology, 39: 21—27,1980.

12. Okamoto, H., and Kripke, M. L. Effector and suppressor circuits of the immuneresponse are activated in vito by different mechanisms. Proc. NatI. Acad. Sci. USA,84: 3841—3845,1987.

13. Cooper, K. D., Fox, P., Neises, G., and Katz, S. I. Effects of ultraviolet radiation onhuman epidermal cell alloantigen presentation: initial depression of Langerhanscell-dependent function is followed by the appearance of T6—Dr+cells that enhanceepidermal alloantigen presentation. J. lmmunol., 134: 129—137,1985.

14. Vermeer, M., and Streilein, J. W. Ultraviolet-B-light induced alterations in epidermalLangerhanscells are mediatedin part by tumornecrosisfactor-a.Pholodermatol.Photoimmunol. Photomed., 7: 258—265, 1990.

15. Yoshikawa, T., Rae, V., Bruins-Slot, W., Van den Berg, J-W., Taylor, J. R., andStreilein, J. W. Susceptibility to effects of UVB radiation on induction of contacthypersensitivity as a risk factor for skin cancer in humans. J. Invest. Dermatol., 95:530—536,1990.

16. Cooper, K. D., Oberhelman, L., Hamilton, T. A., Baadsgaard, 0., Terhune, M.,LeVee, G., Anderson, 1., and Koren, H. UV exposure reduces immunization rates andpromotes tolerance to epicutaneous antigens in humans: relationship to dose, CD1a—DR+ epidermal macrophage induction, and Langerhans cell depletion. Proc. Natl.Acad. Sci. USA, 89: 8497—8501,1992.

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18. Kim, T-Y., Kripke, M. L., and Ullrich, S. E. Immunosuppression by factors releasedfrom UV-irradiated epidermal cells: selective effects on the generation of contact anddelayed hypersensitivity after exposure to UVA or UVB radiation. J. Invest.Dermatol., 94: 26—32,1990.

19. Rivas, J., and Ullrich, S. E. Systemic suppression of delayed-type hypersensitivity bysupernatants from UV-irradiated keratinocytes: an essential role for keratinocytederived interleukin-lO. J. Immunol., 149: 3865—3871, 1992.

20. Rivas, J. M., and Ullrich, S. E. The role of IL-4, IL-b, and TNFa in the immunesuppression induced by ultraviolet radiation. J. Leuk. Biol., in press, 1994.

21. Yarosh, D., Bucana, C., Cox, P., Alas, L., Kibitel, J., and Kripke, M. L. Localizationof liposomes containing a DNA repair enzyme in murine skin. J. Invest. Dermatol.,103:461—468,1994.

22. Yarosh, D. B., Tsimis, J., and Yee, V. Enhancement of DNA repair of UV damage inmouse and human skin by liposomes containing a DNA repair enzyme. J. Soc.Cosmetol. Chem., 41: 85—91,1990.

23. Ceccoli, J., Rosales, N., Tsimis, J., and Yarosh, D. B. Encapsulation of the UV-DNArepair enzyme T4 endonuclease V in liposomes and delivery to human cells. J. Invest.Dermatol., 93: 190—194,1989.

24. Kripke, M. L., Cox, P. A., Alas, L. G., and Yarosh, D. B. Pyrimidine dimers in DNAinitiate systemic immunosuppression in UV-irradiated mice. Proc. NatI. Acad. Sci.USA, 89: 7516—7520,1992.

25. Wolf, P., Cox, P., Yarosh, D. B., and Kripke, M. L. Sunscreens and T4N5 liposomesdiffer in their ability to protect against UV-induced sunburn cell formation, alterationsof dendritic epidermal cells, and local suppression of contact hypersensitivity.J. Invest. Dermatol., in press, 1994.

26. Applegate, L. A., Lay, R. D., Alcalay, J., and Kripke, M. L. Identification of themolecular target for the suppression of contact hypersensitivity by ultraviolet radiation. J. Exp. Med., 170: 1117—1131,1989.

27. Simon, J. C., Tigelaar, R. E., Bergstresser, P. R., Edelbaum, D., and Cruz, P. D.Ultraviolet B radiation converts Langerhans cells from immunogenic to tolerogenicantigen-presenting cells. J. Immunol., /46: 485—491, 1991.

28. Ullrich, S. E. Mechanism involved in the systemic suppression of antigen-presentingcell function by UV irradiation: keratinocyte-derived IL-b modulates antigen-presenting cell function of splenic adherent cells. J. Immunol., 152: 3410—3416, 1994.

29. Ullrich, S. E., and Magee, M. J. Mechanisms in the suppression of allograft rejectionafter treatment of recipient mice with UV radiation and allogeneic spleen cells.Transplantation (Baltimore), 46: 115—119, 1988.

30. Jeevan, A., and Kripke, M. L. Impact of ozone depletion on immune function. WorldResource Rev., 5: 141—155,1993.

3 1. Jeevan, A., Gilliam, K., Heard, H., and Kripke, M. 1. Effects of ultraviolet radiationon the pathogenesis of Mycobacterium !epraemurium infection in mice. Exp.Dermatol., I: 152—160,1992.

32. Scott, P. The role ofThl and Th2 cells in experimental cutaneous leishmaniasis. Exp.Parasitol., 68: 369—372,1989.

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