POTENTIAL FOR ENVIRONMENTAL AND THERAPEUTIC AGENTS TO INDUCE IMMUNOTOXICITY

本合同的目标是为国家毒理学计划(NTP)的危险识别活动提供支持，旨在预防因环境暴露于化学或物理制剂而导致的疾病或不良影响。该合同由四个部分组成，其中三个主要涉及环境化学品或治疗药物诱导免疫抑制、过敏反应和自身免疫能力的测试，以及一个研究和开发部分。在此期间，我们检查了服用环境污染物全氟十二酸、二水合钨酸钠、镜面赤铁矿和膳食补充剂黑升麻后的免疫功能。深入的研究继续探讨暴露于1，2，5，6二苯并菲后产生不同和高度生命阶段特异性免疫效应的潜在机制。此外，我们正在比较发育中的免疫系统和成人免疫系统在暴露于3，3‘，4，4’-四氯偶氮苯后的敏感性。我们正在进行分子和扩展的组织病理学研究，以进一步研究强致敏剂2，3-丁二酮和相关化合物2，5-戊二酮的作用模式，并评估这些化合物在皮肤暴露后的局部和系统免疫效果。此外，我们还评估了几种化合物诱导皮肤过敏的可能性，包括：1-丁基-1-甲基吡咯烷氯、N-丁基-氯化吡啶、1-乙基-3-甲基咪唑和1-丁基-3-甲基咪唑。正在进行的研究正在检测膳食补充剂白藜芦醇对1型糖尿病小鼠模型中自身免疫性疾病的发病和严重程度的影响。本合同中的研究和开发工作旨在开发新的方法，以获得更敏感的终点，以确定可能对免疫系统和炎症/免疫介导性疾病产生不利影响的环境或治疗剂，并进行旨在阐明化学物质可能在细胞和分子水平上改变免疫功能的机制的研究。与本报告所述期间合同的这一方面相关的项目侧重于开发额外的测试来评估巨噬细胞的活性，这将使我们能够在这些细胞从动物体内移除后评估它们的功能能力。在评估肺部等部位的局部免疫力时，这一点尤为重要。其他研究正在比较给药途径对局部和系统免疫反应的依赖性，以及暴露于特定化学品后感染的发展。我们继续评估区分潜在呼吸道致敏剂和接触性致敏剂的方法，优化替代抗原的使用，以评估抗体反应和延迟超敏反应，并检查发育中的免疫系统的潜在脆弱性窗口。此外，我们正在改进现有的模型，以便能够评估近交系和非传统品系啮齿动物免疫功能的变化，以帮助了解遗传学在宿主对炎症性疾病易感性中的作用。

The goal of this contract is to provide support of National Toxicology Program (NTP) hazard identification activities targeted toward the prevention of diseases or adverse effects caused by environmental exposure to chemical or physical agents. This contract consists of four components, three primarily involved in the testing of environmental chemicals or therapeutics for their ability to induce immunosuppression, hypersensitivity responses and autoimmunity, and a research and development component. During this period we have examined immune function following administration of the environmental contaminants Perfluorodecanoic acid, sodium tungstate dihydrate, specular hematite and the dietary supplement black cohosh. In depth studies continue to examine the underlying mechanisms by which differential and highly life stage specific immune effects occur following exposure to 1,2,5,6 dibenzanthracene. In addition, we are comparing the sensitivity of the developing versus adult immune system following exposure to 3,3',4,4'-Tetrachloroazobenzene. We are conducting molecular and extended histopathology studies to further examine the mode of action of the potent sensitizer 2,3-Butanedione and the related compound 2,5- pentanedione and evaluate both local and systemic immune effects of these compounds following dermal exposure. In addition, we have evaluated several compounds for their potential to induce dermal hypersensitivity including: 1-butyl-1-methylpyrrolidinium chloride, N-butyl-pyridinium chloride, 1-Ethyl-3-Methylimidazolium and 1-Butyl-3-Methylimidazolium. Ongoing studies are examining the potential of the dietary supplement resveratrol to influence the onset and severity of autoimmune disease in a murine model of type 1 diabetes. The research and development efforts in this contract are directed towards the development of new methods in order to obtain more sensitive endpoints for identifying environmental or therapeutic agents with the potential of having adverse effects on the immune system and inlammatory/immune mediated diseases, and studies aimed at elucidating the mechanisms by which chemicals may alter immune function at the cellular and molecular level. Projects associated with this aspect of the contract for this reporting period are focused on developing additional tests to evaluate macrophage activity, which will allow us to evaluate the functional capabilities of these cells after they are removed from the animal. This is particularly important when evaluating local immunity at sites such as the lung. Additional studies are comparing the dependency of route of administration on local and systemic immune responses, and the development of infections following exposure to specific chemicals. We continue to evaluate methods to discriminate between potential respiratory and contact sensitizing agents, optimizing the use of alternative antigens for evaluation of antibody responses and delayed hypersensitivity responses and examining potential windows of vulnerability in the developing immune system. In addition, we are refining existing models to be able to evaluate alterations in immune function in outbred and non-traditional strains of rodents to help understand the role of genetics in host susceptibility to inflammatory disease.