Immune suppression indirect effects

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... 

A number of chemicals with demonstrable suppression of immune function produce this action via indirect effects. By and large, the approach that has been most frequently used to support an indirect mechanism of action is to show immune suppression after in vivo exposure but no immune suppression after in vitro exposure to relevant concentrations. One of the most often cited mechanisms for an indirect action is centered around the limited metabolic capabilities of immunocompetent cells and tissues. A number of chemicals have caused immune suppression when administered to animals but were essentially devoid of any potency when added directly to suspensions of lymphocytes and macrophages. Many of these chemicals are capable of being metabolized to reactive metabolites, including dime-thylnitrosamine, aflatoxin Bi, and carbon tetrachloride. Interestingly, a similar profile of activity (i.e., suppression after in vivo exposure but no activity after in vitro exposure) has been demonstrated with the potent immunosuppressive drug cyclophosphamide. With the exception of the PAHs, few chemicals have been demonstrated to be metabolized when added directly to immunocompetent cells in culture. A primary role for a reactive intermediate in the immune suppression by dimethylnitrosamine, aflatoxin Bi, carbon tetrachloride, and cyclophosphamide has been confirmed in studies in which these xenobiotics were incubated with suspensions of immunocompetent cells in the presence of metabolic activation systems (MASs). Examples of MASs include primary hepatocytes, liver microsomes, and liver homogenates. In most cases, confirmation of a primary role for a reactive metabolite has been provided by in vivo studies in which the metabolic capability was either enhanced or suppressed by the administration of an enzyme inducer or a metabolic inhibitor, respectively. 

Indirect response models were also used for the effect of somatotropin on endogenous IGF-1 concentration, as well as the immune suppressive activity of the monoclonal antihody mAh 5c8 [86, 87]. 

IFN-y is produced by THi cells and shifts the response toward a THi phenotype. This is accomplished by activation of NK cells that promotes innate immunity, augmenting specific cytolytic response and induction of macrophages. The induction of cytotoxic immunity can be direct or indirect via suppression of TH2 response. Another direct effect of IFN-y is the differentiation of naive CD4+ lymphocytes toward a THi phenotype. The cytokines present are very important in this differentiation process. Furthermore, induction of IL-12 and suppression of IL-4 by IFN result in differentiation toward a THi phenotype. 

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