Abstract

The ultimate goal of these studies is to understand how exposing the skin of mice to ultraviolet radiation (UVR) leads to the production of suppressor T lymphocytes (Ts) that inhibit the rejection of UV-induced skin cancers. Considerable evidence suggests that the antigen presentation step of the immune response is the critical point at which UVR exerts its immunomodulatory effect. Therefore, these studies address the mechanism by which UVR alters the function of antigen presenting cells (APC) and the pathway by which altered APC function leads to Ts activation. The problem will be investigated using a model system of cutaneous immunity in which a contact sensitizing hapten (FITC) is used as the immunogen. We propose to test the following series of specific hypotheses concerning the sequence of events that leads to Ts induction: (1) DNA damage is the initiating event in Ts induction by UVR. (2) Epidermal cytokines are responsible for altered APC activity. (3) """"""""UV- altered"""""""" APC interact with different subsets of T lymphocytes than normal APC, resulting in a modified pattern of lymphokine secretion. (4) The modified pattern of lymphokine secretion is responsible for Ts induction. As these hypotheses are tested, we will attempt to assess their relevance for the induction of Ts in the UV carcinogenesis system.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA052457-05
Application #
2094738
Study Section
Pathology B Study Section (PTHB)
Project Start
1990-07-01
Project End
1997-04-30
Budget Start
1994-07-01
Budget End
1995-04-30
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

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

  Publications

Ma, Lisa J; Guzman, Esther A; DeGuzman, Ariel et al. (2007) Local cytokine levels associated with delayed-type hypersensitivity responses: modulation by gender, ovariectomy, and estrogen replacement. J Endocrinol 193:291-7
Maeda, Yutaka; Hwang-Verslues, Wendy W; Wei, Gang et al. (2006) Tumour suppressor p53 down-regulates the expression of the human hepatocyte nuclear factor 4alpha (HNF4alpha) gene. Biochem J 400:303-13
Ma, Lisa J; Guzman, Esther A; DeGuzman, Ariel et al. (2006) Unexpected effects of UVB in IL-10 transgenic mice: normalization of contact hypersensitivity response. Arch Dermatol Res 297:417-20
Guzman, E A; Chen, Y-H; Langowski, J L et al. (2005) Abrogation of delayed type hypersensitivity response to Candida albicans produced by a molecular mimic of phosphorylated prolactin. J Neuroimmunol 170:31-40
Nishigori, C; Yarosh, D; O'Connor, A et al. (1998) HindIII liposomes suppress delayed-type hypersensitivity responses in vivo and induce epidermal IL-10 in vitro. J Immunol 161:2684-91
Vink, A A; Moodycliffe, A M; Shreedhar, V et al. (1997) The inhibition of antigen-presenting activity of dendritic cells resulting from UV irradiation of murine skin is restored by in vitro photorepair of cyclobutane pyrimidine dimers. Proc Natl Acad Sci U S A 94:5255-60
Vink, A A; Yarosh, D B; Kripke, M L (1996) Chromophore for UV-induced immunosuppression: DNA. Photochem Photobiol 63:383-6
Vink, A A; Strickland, F M; Bucana, C et al. (1996) Localization of DNA damage and its role in altered antigen-presenting cell function in ultraviolet-irradiated mice. J Exp Med 183:1491-500
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
Kripke, M L; Cox, P A; Bucana, C et al. (1996) Role of DNA damage in local suppression of contact hypersensitivity in mice by UV radiation. Exp Dermatol 5:173-80

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