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 1,2:5,6 dibenzanthracene and tetrachloroazoxybenzene, the nanomaterial C60 fullerenes, the dietary supplement resveratrol, a polyphenol found in grapes, peanuts and a number of other plants, as well as the antiviral therapeutic used in the treatment of HIV, Nelfinavir. In depth studies are examining the underlying mechanisms by which differential and highly life stage specific immune effects occur following exposure to 1,2,5,6 dibenzanthracene. We are conducting molecular and extended histopathology studies to further examine the mode of action of the potent sensitizer 2,3-Butanedione and evaluate both local and systemic immune effects of this compound following respiratory exposure. In addition, we have evaluated several compounds for their potential to induce dermal hypersensitivity including: dimethylamine borane, 1,5-naphthalene-diisocyanate and tert-butyl hydroperoxide, heptachlor and o-cresol. Ongoing studies are examing the potential of the phytoestrogen genistein to influence the onset and severity of autoimmune disease in several murine models. 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. New 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.
