Immunotoxicology immunosuppression

The majority of early publications that can be reasonably identified as comprising immunotoxicology reported altered resistance to infection in animals exposed to various environmental or industrial chemicals. Authors logically concluded that xenobiotic exposure suppressed immune function since the immune system is ultimately responsible for this resistance to infection. Subsequent studies demonstrated that suppression of various cellular and functional endpoints accompanied or preceded increased sensitivity to infection, and that administration of known immunosuppressants likewise decreased host resistance. The human health implications of these studies, that chemical exposure reduced resistance to infection, drove the initial focus of many immunotoxicologists on functional suppression, and provided the theoretical and practical underpinnings of immunotoxicity testing. 

While profound immunosuppression can lead to an increased incidence of infectious or neoplastic diseases, interpreting data from experimental immunotoxicology studies or epidemiological studies for quantitative risk assessment purposes can be problematic. This is because inadvertent exposures to immunotoxic agents may often be expressed as a mild-to-moderate change, reflected, for example, by a 15 to 25% decrement in an immune parameter compared to control values. To help address the clinical consequences of mild-to-moderate immunosuppression, we examined available experimental, clinical and epidemiological studies that examined the association between suppression of immune function and infectious disease, independent of the etiology of suppression. 

One of the critical features of any discussion of the mechanisms of immune suppression must be the appreciation that robust changes in immune function can be mediated by either direct or indirect effects (or both) of a xenobiotic. Direct effects can be associated with distinct types of cells. Perhaps the best examples are cyclosporin A and related immunosuppressive drugs, such as rapamycin and FK-506, which specifically target T cells via an interaction with cytosolic and/or nuclear proteins to disrupt antigen-induced activation of transcription. To date, despite the tremendous evolution of the discipline of immunotoxicology, no other xenobiotic associated... 

Immunotoxicological impacts include molecular and structural effects in immune tissues and organs, cellular pathology, reductions in immune cell numbers, retarded maturation of immune system cells, and altered immune system antibody production. These adverse effects are manifest by two types of reaction immunosuppression and immunostimulation. 

Hypersensitivity and immunosuppression are considered the primary focus for developing in vitro methods in immunotoxicology. Nevertheless, in vitro assays to detect immunostimula-tion and autoimmunity are also needed. Although developmental immunotoxicity is an emerging concern, there are no in vitro test models available at this time. 

An initial evaluation of myelotoxicity should be performed. If a compound is myelotoxic, there may be no need to proceed with additional evaluation. The methodology for bone marrow culture systems is published and well characterized. In vitro bone marrow culture systems are commercially available, and they would probably have to be modified slightly to accommodate in vitro exposure to test material. Assays of immunosuppression have been validated to predict the maximum tolerated dose (MTD) in humans. Their suitability for use in immunotoxicology should be determined and would require prevalidation. These assays are relatively expensive if human cells are used, and the standardized nature of commercial systems should provide good feasibility. 

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