Immunosuppression direct effects

In its acute stages, benzene toxicity appears to be due primarily to the direct effects of benzene on the central nervous system, whereas the peripheral nervous system appears to be the target following chronic low-level exposures. In addition, because benzene may induce an increase in brain catecholamines, it may also have a secondary effect on the immune system via the hypothalamus-pituitary-adrenal axis (Hsieh et al. 1988b). Increased metabolism of catecholamines can result in increased adrenal corticosteroid levels, which are immunosuppressive (Hsieh et al. 1988b). 

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. 

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... 

Glucocorticoids Osteoporosis occurs in Cushing s disease and in patients treated with glucocorticoids for immunosuppression. Glucocorticoids are used in the treatment of hypercalcemia. Decrease intestinal Ca + absorption may antagonize 1,25-(0H)2D or PTH may directly stimulate parathyroids may have direct effects on intestine and bone independent of PTH and 1,25-(0H)2D. 

Breasts Breast fibroadenomas may result from exposure to ciclosporin. After renal transplantation, fibroadenomas either developed or progressed in eight women taking ciclosporin-based immunosuppression [14 ]. They were converted from ciclosporin to tacrolimus after a mean of 64 months 8 of 21 fibroadenomas resolved and the others either reduced in size or remained stable. These changes were occurred within 1 year after conversion to tacrolimus. Fibroadenoma development is promoted either by a direct effect of ciclosporin or by a blockade of prolactin receptors on T lymphocytes. 

Corticosteroids have various effects on immune and inflammatory response systems, although their exact mechanism of immunosuppression is not fully understood. It is generally believed that at high doses, the agents are directly lymphotoxic, and at lower doses, the corticosteroids act by inhibiting the production of various cytokines that are necessary to amplify the immune response.11... 

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. 

The mechanisms of the influence of the SNS on the induction of CD8+ Tregs are likely directed towards both the activation and function of these cells (fig. 2). Sympathetic neurons are a source of (i) norepinephrine that has strong immunoregulatory effects [35] including the proliferation of liver NKT cells necessary for the initiation of contact sensitivity reactions (ii) immunomodulatory NPY [38] that may promote the production of IFN-y necessary for the function of CD8+ suppressor T cells (see below), and (hi) tissue plasminogen activator (t-PA) [41] that converts plasminogen to plasmin that in turn is an activator of immunosuppressive TGF-(3 [42]. 

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