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UVB-induced inflammation and carcinogenesis in immunosuppressed mice

Hatton, Jennifer L
http://rave.ohiolink.edu/etdc/view?acc_num=osu1117221148

Abstract Details

2005, Doctor of Philosophy, Ohio State University, Medical Science.
Ultraviolet light B (UVB) is a ubiquitous complete carcinogen of the skin. Due to their immunosuppressive therapy, organ transplant recipients have a 60-250 fold increased likelihood to develop aggressive, highly metastatic UVB-induced squamous cell carcinomas (SCC) compared to the general population. This thesis examines both UVB-induced cutaneous inflammation and UVB-induced skin tumor models mimicking transplant immunosuppression by depleting systemic CD4+ or CD8+ T lymphocytes. Our hypothesis is that a systemic decrease of CD4+, but not CD8+ T lymphocytes will increase the amount of UVB-induced DNA damage in acute UVB exposure and result in increases in tumor number following chronic UVB exposure.In the UVB-induced inflammation model, a decrease in systemic CD4+ but not CD8+ T lymphocytes increased UVB-induced neutrophil number and activity in the skin. Both T lymphocyte depletion groups showed increased DNA damage through increased levels of p53+ epidermal cells. This increase in DNA damage was not due to an increase in direct UVB-induced damage, as seen by immunohistochemical analysis of cyclobutane pyrimidine dimers (CPDs). Increased UVB-induced DNA damage could increase the amount of UVB-induced skin cancer that develops. The anti-inflammatory, anti-angiogenic drug, celecoxib, was able to almost completely abate the exacerbated UVB-induced inflammatory reaction in the CD4-depleted animals.In the chonic UVB-induced skin tumor model, a decrease in systemic CD4+ but not CD8+ T lymphocytes significantly increased tumor numbers. Tumors isolated from CD4-depleted mice also showed increased invasive properties and increased numbers of p53 point mutations. Topical treatment with the anti-inflammatory drug celecoxib significantly decreased tumor numbers in control, CD4- and CD8-depleted mice. Based upon our findings, it appears that there are multiple mechanisms by which systemic immunosuppression can cause an increase in tumor number and aggressiveness in transplant recipients. Our studies suggest that clinically blocking increased levels of inflammation in the skin via the topical application of celecoxib as a chemo-preventative agent might be one potential mechanism to decrease the increased risk of skin cancer observed in immunosuppressed patients.
Tatiana Oberyszyn (Advisor)
189 p.
UVB; skin; immunosuppression; transplant recipients; inflammation; carcinogenesis; T lymphocytes

Recommended Citations

Citations

  • Hatton, J. L. (2005). UVB-induced inflammation and carcinogenesis in immunosuppressed mice [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1117221148

    APA Style (7th edition)

  • Hatton, Jennifer. UVB-induced inflammation and carcinogenesis in immunosuppressed mice. 2005. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1117221148.

    MLA Style (8th edition)

  • Hatton, Jennifer. "UVB-induced inflammation and carcinogenesis in immunosuppressed mice." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1117221148

    Chicago Manual of Style (17th edition)

osu1117221148
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© 2005, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.