Immunosuppression indirect effects

Three lipids A have been more intensively studied in animal models, all of them having indirect effects, mediated in vivo by the immune system. For two of them, DT-5461 and ONO-4007, TNF-a is an important mediator acting at the vascular level that provokes tumor necrosis. For the third one, OM-174, the treatment induces the accumulation of IFN-y and EL-1 P in tumors, which activate NOS II transcription in tumor cells that produce autotoxic NO, which then provokes the apoptosis of tumor cells. At the same time this treatment inhibits the production of TGF-pi by tumor cells which reduces the TGF-pi induced immunosuppression and enhances NO production. Acquired immune response, probably completes the tumor regression started by the apoptosis process and, most probably induces specific memory. 

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. 

Some of these are involved in haematopoiesis (e.g. IL-1, -3, -5, -6 GM-, M-, G-CSF) their role is described in Chapter 2. Others (e.g. IL-1, -6, -8 TNF a- GM-, M-, G-CSF) are implicated in inflammation either directly (e.g. pure IL-1 can cause some symptoms of inflammation) or indirectly, via their ability to activate immune cells that participate in the inflammatory response (e.g. lymphocytes, neutrophils and macrophages) some of these effects are described in Chapters 2 and 3. Such cytokines as IL-4, interferon-a and IL-10 may be involved in immunosuppression others, such as IL-1, IL-6, TNF a and TGF j3, are involved in tissue remodelling. 

There is indirect evidence of sex differences in immunology. Women have a higher incidence of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. The influence of sex hormones on the immune system may provide insight into these immunological disorders. For example, estrogen stimulates both humoral and cell-mediated immunity, whereas testosterone has the opposite effect (126). Therefore, it is not surprising that there is sex-dependent variability in response to immunosuppressive agents. 

Adverse drug reactions can be induced by drugs of very diverse nature, including antibiotics, low molecular chemicals, or nucleic acids. Such reactions can be induced directly or indirectly in various ways. Direct effects on the immune system can result in immunosuppression, or in immune stimulation such as with some nucleic acid therapeutics siRNAs or AS ODNs. In contrast, indirect immune effects are caused by immune responses to a chemical or to selfdeterminants altered by a chemical such as with low molecular small molecules. 

The nature of the enhancement of antibody production by 3-butylazathioprine has not been established. Enhancement has been obtained in animals pretreated with 6-mercaptopurine and other commonly used immunosuppressive drugs (Schwartz, 1965). Schwartz proposed that the cytotoxic drugs resulted in cell damage with subsequent release of stimulatory polynucleotides. The observed effects of 3-butylazathioprine could be such an indirect result of cytotoxicity or alternatively may reflect a direct interaction of the drug with cells involved in the immune response. 

UV-B has various direct adverse effects on human health (skin cancer, immunosuppression, eye disorders), terrestrial plants and aquatic organisms [DNA alterations, photosynthesis inhibition, reduced growth, photoresponsiveness suppression (see Chapter 116)]. Moreover, due to the differences in UV-B sensitivity and adaptation among the various species, shifts in species composition may occur as a consequence of increased UV-B radiation, thus leading indirectly to alterations in ecosystems. ... 

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