Evidence collected during the last decade has indicated that the skin is a functional and specialized immunologic organ. Epidermal antigen-presenting cells can initiate an immune reaction by presenting antigen to elements of the immune system. Immunocompetent T cells migrate to the skin where they can play a role in immunosurveillance. Keratinocytes release a wide variety of lymphokines and cytokines that can amplify and drive the immune response, both locally and at distant sites. In addition, it is clear that physical and chemical agents that interact with the skin can modulate and at times compromise immune function. One prominent example is the systemic immunosuppression resulting from exposure to ultraviolet radiation (UVR). Exposure to relatively large doses of UVR interferes with the ability of the immune system to respond to antigens or allergens injected or applied at distant unirradiated sites. The immunosuppression is associated with defects in splenic antigen-presenting cell function and the appearance of splenic suppressor T cells. How UVR, which has limited penetration, can induce these systemic immunological defects is not entirely clear. The hypothesis that has been proposed, and one that will be tested during the course of these studies, is that keratinocyte-derived suppressive cytokines are involved. Data published from this laboratory support the hypothesis by demonstrating that the suppression seen following the injection of a suppressive glycoprotein from ultraviolet(UV)-irradiated keratinocyte cultures closely mimics that seen following in vivo exposure to UV radiation. However, formal proof of the hypothesis is dependent upon the use of chemically pure material and showing that this glycoprotein does indeed induce suppression. Thus, the specific aims of the proposed research are to purify the suppressive cytokine, to demonstrate that this glycoprotein can be found in the serum of UV-irradiated animals, and to demonstrate that neutralizing the function of the suppressive cytokine will neutralize the immunosuppression found following in vivo UV exposure. Understanding the signals involved in the induction of systemic immunosuppression following trauma to the skin may have important practical ramifications. For example, the systemic immunosuppression following exposure to UVR has been shown to be a co-factor for the development of skin cancer in experimental animals. Understanding how UVR induces suppression may provide new approaches for the treatment and prevention of skin cancer. Furthermore, the systemic immunosuppression seen in burn patients is a major factor contributing to the demise of the patient. Here again a better understanding of how systemic suppression is induced may provide new insights into overcoming the suppression and improving the prognosis of the patient. Studying the role of the keratinocyte-derived suppressive cytokine in the induction of systemic suppression following UV exposure may provide a better understanding of how immunological signals are transmitted from the skin to the rest of the immune system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR040824-03
Application #
2080273
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1991-09-30
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1995-08-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
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Huang, S; Ullrich, S E; Bar-Eli, M (1999) Regulation of tumor growth and metastasis by interleukin-10: the melanoma experience. J Interferon Cytokine Res 19:697-703
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Nishigori, C; Yarosh, D B; Ullrich, S E et al. (1996) Evidence that DNA damage triggers interleukin 10 cytokine production in UV-irradiated murine keratinocytes. Proc Natl Acad Sci U S A 93:10354-9
Ullrich, S E (1996) Does exposure to UV radiation induce a shift to a Th-2-like immune reaction? Photochem Photobiol 64:254-8
Jeevan, A; Ullrich, S E; De Gracia, M et al. (1996) Mechanism of UVB-induced suppression of the immune response to Mycobacterium bovis bacillus Calmette-Guerin: role of cytokines on macrophage function. Photochem Photobiol 64:259-66
O'Connor, A; Nishigori, C; Yarosh, D et al. (1996) DNA double strand breaks in epidermal cells cause immune suppression in vivo and cytokine production in vitro. J Immunol 157:271-8
Moodycliffe, A M; Bucana, C D; Kripke, M L et al. (1996) Differential effects of a monoclonal antibody to cis-urocanic acid on the suppression of delayed and contact hypersensitivity following ultraviolet irradiation. J Immunol 157:2891-9
Ullrich, S E (1995) The role of epidermal cytokines in the generation of cutaneous immune reactions and ultraviolet radiation-induced immune suppression. Photochem Photobiol 62:389-401
Schmitt, D A; Owen-Schaub, L; Ullrich, S E (1995) Effect of IL-12 on immune suppression and suppressor cell induction by ultraviolet radiation. J Immunol 154:5114-20

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