The murine two stage skin carcinogenesis model was designed and used extensively to test the genotoxic potential and human exposure risk for specific chemicals. The 'two stage designation referred to both the temporal design and the inherent properties of the applied chemicals. A single application of an initiator (the mutagen) is followed by multiple repetitious applications of a tumor promoter the latter defined by the act that it alone is incapable of causing tumors. Over time, the model has evolved into a field of research that is aimed at identifying the factors and conditions responsible for the development of murine skin cancer. The 'two stage' designation also conveniently refers to the evolution of the skin lesions that develop: initial phase lesions present as benign papillomas that ultimately progress to the second phase squamous cell carcinomas. The emergence of transgenic mouse technology has impacted this field enormously by providing the means to isolate the specific consequences of the presence or absence of suspected players in the tumorgenesis pathway. From these numerous in vivo and in vitro studies an extensive database of information can be compiled; however, very few of these have focused on a potential role of the immune system in the susceptibility of mice to tumors induced by the two stage chemical model. To investigate this question, the susceptibility of immune-deficient mice has been tested. In preliminary experiments using recombinase-deficient mice (Rag2-/-), an increased sensitivity to tumorigenesis has been demonstrated, presumably attributable to an absence of mature T and/or B cells. Based on these results, this proposal hypothesizes that the immune system docs play a role in the pathogenesis of chemically induced tumors and that the specific involvement of the innate and acquired immune systems can be analyzed using the temporal and histological nature of the two 'stages' of lesions. The goals of the proposal include l) isolating the requirement of mature T and/or Bells in delaying papilloma formation and 2) identifying the specific T cell subset that may be involved in the progression of the skin disease of cancer. The approach will utilize the techniques of cell-type specific immune isolation and reconstitution of immune deficient mice. Successful demonstration of the feasibility of this approach is expected to open a broad based potential for studying the specific components of the immune system that are involved in the host response to chemical carcinogenesis. Ultimately, this may provide a means to understand and develop novel approaches to therapy for human skin cancer.
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