Host Defense Mechanisms in Polyaromatic Hydrogen Carcinogenesis

多环芳烃致癌过程中的宿主防御机制

• 批准号: 8391636
• 负责人: Craig A Elmets
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391636
• 关键词: 3-Methylcholanthrene; Animals; Anthracenes; Antibodies; Antigens; Automobiles; Award; Benzo(a)pyrene; Biological Models; Bladder; Breast; Burn injury; CD8B1 gene; Cancer Etiology; Carcinogens; Carcinoma; Cell Line; Cellular Immunity; Charcoal; Chemicals; Clinical; Codon Nucleotides; Complex; Cutaneous; Dendritic Cells; Development; Effector Cell; Environmental Carcinogens; Evaluation; Event; Experimental Models; Exposure to; Food; Fossil Fuels; Funding; Generations; Goals; Gulf War; HRAS gene; Head and Neck Cancer; Health; Histocompatibility Antigens Class I; Host Defense Mechanism; Hydrocarbons; Hydrogen; Immune response; Immune system; Immunity; Individual; Interleukin-12; Kuwait; Malignant Neoplasms; Malignant neoplasm of lung; Methods; Modeling; Mus; Mutation; Occupational Malignant Neoplasm; Oncogenes; Papilloma; Pathway interactions; Persian Gulf; Play; Point Mutation; Population; Premalignant; Prevention; Procedures; Process; Proteins; Reagent; Research; Resistance; Role; Skin; Skin Cancer; Skin Carcinogenesis; Skin Neoplasms; Smoker; Staging; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tobacco smoke; Topical application; Ubiquitin; Vaccinated; Vaccination; Vaccines; Veterans; antigen processing; base; beneficiary; carcinogenesis; cell mediated immune response; chemical carcinogenesis; cigarette smoking; cytokine; design; dimethylbenzanthracene; environmental mutagens; genetic immunization strategies; interest; interleukin-23; multicatalytic endopeptidase complex; mutant; novel; prevent; prototype; response; tumor; tumor progression; tumorigenesis; vaccination strategy; vector

DESCRIPTION (provided by applicant): Polyaromatic hydrocarbons are ubiquitous environmental compounds that are the major carcinogenic moiety in cigarette smoke and were present in the burning oilfield emissions in the Persian Gulf War. There has been intense experimental interest in identifying the mechanisms by which they cause cancer. It is now known that the polyaromatic hydrocarbon 7,12- dimethylbenz(a)anthracene (DMBA) produces a specific point mutation in 61st codon of the H- ras oncogene and that this mutation is necessary for tumors to develop. While it is clear that the tumors caused by carcinogenic polyaromatic hydrocarbons elicit a partially protective immune response, the role that T-cell mediated immunity plays at earlier stages in the cutaneous carcinogenesis pathway is not well-understood. Our studies funded through a VA Merit Review Award have shown that administration of DMBA to the skin of mice results in an antigen specific T-cell mediated immune response that confers resistance to DMBA-induced tumor development. The T-cell response is directed, at least in part, at the H-ras mutation in the 61st codon and an immune response to the endogenous non-mutated ras does not occur. Based on these findings, we hypothesize that vaccination strategies resulting T-cell mediated immunity to oncogene mutations produced by polyaromatic hydrocarbons serves to protect individuals against the carcinogenic effects of these agents, and efforts to amplify that response will further reduce the formation of polyaromatic hydrocarbon-induced cancers. To test our hypothesis, we have prepared a genetic-immunization vector containing a ubiquitin-mutant ras fusion minigene sequence which provides superior proteosome targeting of the encoded protein. This promotes MHC class I antigen processing and thereby enhances the generation of CD8+ T-cells. We have developed stable dendritic cell lines transfected with our vector, and intend to us them to vaccinate animals to establish whether they will prevent the DMBA-induced skin tumors. We will also evaluate the effect of dendritic cell vaccination with our vector on activation of T-cell subsets and on their cytokine profiles. Studies are planned to assess the effect of dendritic cell vaccination with mutant H-ras on the presence of H-ras mutations in tumors and in non-tumor-bearing DMBA treated skin. Finally, we will determine the role of IL-12 and IL-23 in the T-cell response to mutant H-ras and whether administration of these cytokines or their neutralization through antibody treatment will alter the efficacy of the vaccination procedure. The long-term goal of these studies is to identify methods for the immunoprevention of tumors caused by carcinogenic polyaromatic hydrocarbons. Veterans are likely to be among the major beneficiaries of such methods because of the high proportion of smokers in this population and because of their exposure to these agents during the Persian Gulf War.

描述（由申请人提供）：