SKIN CANCER--IMMUNOTOXIC MECHANISMS

越来越多的人意识到，诱发皮肤癌 是一个多步骤的过程，需要启动和促进 物质的恶性肿瘤的充分发展。 最 研究免疫学对这一过程影响的策略， 专注于肿瘤的免疫反应。 然而，这代表着 对这种相互作用的调查在相当晚的阶段， 通路 这项建议的目的是审查 免疫学在皮肤癌变早期的作用 在通道中。 这将通过诱导接触来实现 小鼠对两种多环芳烃7，12- 二甲基苯并（a）蒽（DMBA）和苯并（a）芘（BP）。 这些 化合物已被广泛用于研究 皮肤癌形成。 动物将对这些试剂进行免疫接种 通过该化合物的表皮应用。 五天后， 将通过挑战他们的耳朵， 致敏化合物并测量随后的耳肿胀 反应 使用该模型系统，Ah位点的参与 在接触性超敏反应中， 高亲和力和低亲和力Ah受体。 细胞色素的作用 P450依赖性酶代谢在接触诱导中的作用 对这些药物的超敏反应将通过预处理 使用诱导或抑制药物的动物 细胞色素P450活性。 此外，各种致癌和非致癌物质， BP的致癌代谢物和非致癌PAH类似物 将通过测定它们的免疫原性来检测它们的免疫原性。 引发和引发接触性超敏反应的能力。 将尝试诱导对DMBA的免疫耐受性， BP通过利用耐受性诱导的方法， 成功应用于其他抗原。 DMBA和BP专用 将开发T细胞克隆以更全面地评估 抗原特异性T淋巴细胞对肿瘤发生的影响 这些化合物的活性。 最后，接触的影响 DMBA和BP免疫对这些诱导肿瘤的影响 将在皮肤致癌实验中检查试剂。 从这些研究中获得的知识可能有助于确定 细胞免疫对皮肤癌发生影响 提供了新的免疫皮肤病学方法， 治疗这种类型的皮肤癌。

There is an increasing awareness that the induction of skin cancer is a multistep process requiring both initiating and promoting substances for full development of the malignant tumor. Most strategies examining immunological influences on this process have focused on immune responses to tumors. This, however, represents an investigation of such interactions at a rather late stage in the pathway. The objective of this proposal will be to examine immunological influences on skin carcinogenesis at an early stage in the pathway. This will be accomplished by inducing a contact dermatitis reaction in mice to two polyaromatic hydrocarbons, 7,12- dimethylbenz(a)anthracene (DMBA) and benzo(a)pyrene (BP). These compounds have been widely employed to investigate mechanisms of skin cancer formation. Animals will be immunized to these agents by epicutaneous application of the compound. Five days later the response will be elicited by challenging their ears with the sensitizing compound and measuring the subsequent ear swelling response. Using this model system, participation of the Ah locus in contact hypersensitivity responses both in strains of mice with high an with low affinity Ah receptors. The role of cytochrome P450 dependent enzyme metabolism in induction of contact hypersensitivity to these agents will be assessed by pre-treating animals with pharmacologic agents which induce or inhibit cytochrome P450 activity. Also, various carcinogenic and non- carcinogenic metabolites of BP and non-carcinogenic PAH analogues will be tested for their immunogenicity by determining their ability to initiate and elicit contact hypersensitivity responses. Attempts will be made to induce immunological tolerance to DMBA and BP by utilizing methods of tolerance induction which have been successfully employed for other antigens. DMBA and BP-specific T cell clones will be developed to more fully evaluate the influence of antigen specific T lymphocytes on the tumorigenic activity of these compounds. Finally, the influence of contact immunization to DMBA and BP on the induction of tumors by these agents will be examined in skin carcinogenesis experiments. Knowledge obtained from these studies may help to define the influence of cell-mediated immunity on skin carcinogenesis and may offer new immunodermatologic approaches for the prevention and therapy of this type of skin cancer.