POTENTIAL FOR ENVIRONMENTAL AND THERAPEUTIC AGENTS TO INDUCE IMMUNOTOXICITY

该合同的目的是为国家毒理学计划（NTP）的危害识别活动提供支持，这些活动旨在预防因环境暴露于化学或物理制剂而引起的疾病或不良影响。该合同包括四个部分，三个主要涉及测试环境化学品或治疗剂诱导免疫抑制、超敏反应和自身免疫的能力，以及一个研究和开发部分。在此期间，我们已经检查了免疫功能管理的环境污染物全氟癸酸，钨酸钠二水合物，镜面赤铁矿和膳食补充剂黑升麻。在深入的研究中，继续检查暴露于1，2，5，6二苯并蒽后发生差异和高度生命阶段特异性免疫效应的潜在机制。此外，我们正在比较暴露于3，3 '，4，4'-四氯偶氮苯后发育中与成人免疫系统的敏感性。我们正在进行分子和扩展的组织病理学研究，以进一步检查强效致敏剂2，3-丁二酮和相关化合物2，5-戊二酮的作用模式，并评估皮肤接触后这些化合物的局部和全身免疫效应。此外，我们还评价了几种化合物诱导皮肤超敏反应的潜力，包括：氯化1-丁基-1-甲基吡咯烷鎓、氯化N-丁基吡啶鎓、1-乙基-3-甲基咪唑鎓和1-丁基-3-甲基咪唑鎓。正在进行的研究正在检查膳食补充剂白藜芦醇对1型糖尿病小鼠模型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方法，以获得更敏感的终点，用于识别可能对免疫系统和炎症/免疫介导的疾病产生不利影响的环境或治疗剂，以及旨在阐明化学品可能在细胞和分子水平上改变免疫功能的机制的研究。在本报告所述期间，与合同这方面相关的项目重点是开发额外的测试来评估巨噬细胞活性，这将使我们能够评估这些细胞从动物体内取出后的功能能力。这在评估肺部等部位的局部免疫力时尤为重要。其他研究正在比较给药途径对局部和全身免疫反应的依赖性，以及接触特定化学品后感染的发展。我们继续评估方法，以区分潜在的呼吸道和接触致敏剂，优化使用替代抗原的抗体反应和迟发型超敏反应的评价和检查潜在的窗口脆弱性在发展中的免疫系统。此外，我们正在完善现有的模型，以便能够评估远系繁殖和非传统啮齿动物品系的免疫功能改变，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.