SKIN CANCER--IMMUNOTOXIC MECHANISMS

越来越多的人意识到皮肤癌的诱发 是一个既需要启动又需要推动的多步骤过程 促进恶性肿瘤充分发展的物质。多数 检查免疫对这一过程的影响的策略有 专注于对肿瘤的免疫反应。然而，这代表着 对这种相互作用的调查是在 路径。这项提案目标将是审查 免疫学对早期皮肤癌发生的影响 在这条路上。这将通过诱导接触来实现 小鼠对两种多环芳烃7，12-二恶英的皮炎反应 二甲基苯(A)、菲(DMBA)和苯并(A)芘(BP)。这些 化合物已被广泛用于研究其作用机制。 皮肤癌的形成。动物将对这些病原体进行免疫 通过皮下涂抹这种化合物。五天后， 通过挑战他们的耳朵来激发他们的反应 致敏化合物和随后的耳肿胀的测量 回应。使用这个模型系统，参与的ah轨迹 在接触超敏反应中，两种品系的小鼠 高AN与低亲和力的AH受体。细胞色素的作用 接触诱导中的P450依赖酶代谢 对这些药物的过敏反应将通过前处理进行评估 具有诱导或抑制药理作用的动物 细胞色素P450活性。此外，各种致癌和非致癌的 BP和非致癌多环芳烃类似物的致癌代谢产物 将通过确定其免疫原性来测试它们的免疫原性 启动和引发接触性过敏反应的能力。 将尝试诱导对DMBA的免疫耐受，并 BP通过利用已有的耐受诱导方法 成功地用于其他抗原。DMBA和BP特定 将开发T细胞克隆，以更全面地评估 抗原特异性T淋巴细胞在肿瘤发生中的作用 这些化合物的活性。最后，接触的影响 DMBA和BP免疫诱发肿瘤的实验研究 药物将在皮肤癌致癌实验中进行检测。 从这些研究中获得的知识可能有助于定义 细胞免疫在皮肤癌发生中的作用 为预防和预防疾病提供新的免疫皮肤学方法 这种皮肤癌的治疗方法。

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.