Mechanisms of Immune Suppression

From the preceding brief description of the immune system, it is clear that toxic substances may potentially disrupt this system at many levels. This section provides a more detailed description of the different mechanisms that have been shown to account for immunotoxicity of representative compounds. 

---

Taylor A, Verhagen J, Blaser K, Akdis M, Akdis CA Mechanisms of immune suppression by interleukin-10 and transforming growth factor- the role of T regulatory cells. Immunology 2006 117 433-442. 

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... 

Grayson, T.H., L.F. Cooper, A.B. Wrathmell, J. Roper, A.J. Evenden and M.L. Gilpin. Host responses to Renibacterium salmoninarum and specific components of the pathogen reveal the mechanisms of immune suppression and activation. Immunology 106 273-283, 2002. 

DeFabo, E.C. and Noonan, F.P, Mechanism of immune suppression by ultraviolet radiation in vivo, I evidence for the existence of a unique photoreceptor in skin and its role in photoimmunology, J. Experimental Med., 157, 84-98, 1983. 

Experimental studies in laboratory rodents have demonstrated that a diverse array of chemical exposures suppress immune function (Table 19.2). In addition a limited number of clinical and epidemiologic studies have reported suppression of immune function and/or increased frequency of infectious and/or neoplastic disease following exposure of humans to some of these agents. From the description above it is clear there are a number of cellular and molecular targets for chemicals that act as immunosuppressants. Clearly, a chemical that disrupts cell proliferation would affect clonal expansion. Disruption of T cell maturation in the thymus is another potential mechanism for immune suppression. Chemicals may also interfere with receptor ligand binding at the cell... 

SEDGWICK, J. HOLT, P.G. (1985) Down-regulation of immune responses to inhaled antigen. Studies on the mechanism of induced suppression. Immunology, 56, 635-642. 

However, the increasing incidence over time of Thl-related disorders (diabetes mellitus type 1, Crohn disease, multiple sclerosis) has also been suggested to be more likely to be due to an alternative possible mechanism — reduced immune suppression and effect on regulatory T cells (Tedeschi Airaghi, 2001). 

The ability to induce immune tolerance to D-pen by pretreating BN rats with low dose D-pen prior to high dose D-pen has yielded additional evidence that cytokines might play a role in determining susceptibility to DIAI (Masson and Uetrecht 2004). Specifically, low dose tolerance to D-pen is associated with increased expression of the regulatory cytokines, IL-10 and TGF-p, in splenic CD4 and CD8 T cells (Donker et al. 1984 Masson and Uetrecht 2004). Both of these cytokines have been shown to suppress disease in other models of autoimmunity (Blenman et al. 2006 Rubtsov and Rudensky 2007). Thl cytokines also appear to be involved in the mechanism of immune tolerance to D-pen, as low dose pretreatment increased IFN-y expression in CD8 T cells (Masson and Uetrecht 2004). These observations indicate that regulatory and Thl cytokines might be at least partially responsible for the resistance to D-pen-induced autoimmunity. 

CCR4-expresssing regulatory T cells is also stimulated via glioma cell secretion of CCL2. This may be an important mechanism whereby gliomas suppress anti-tumor immune responses and evade immune detection (Jordan et al. 2008). 

Commensal or environmental fungi that are typically harmless can become invasive mycoses when the host immune defenses are impaired. Host immune suppression and risk for opportunistic mycoses can be broadly classified into three categories (1) quantitative or qualitative deficits in neutrophil function, (2) deficits in cell-mediated immunity, and (3) disruption of mechanical/and or microbiologic barriers. 

Atrophy of the thymus is a consistent finding in mammals poisoned by 2,3,7,8-TCDD, and suppression of thymus-dependent cellular immunity, particularly in young animals, may contribute to their death. Although the mechanisms of 2,3,7,8-TCDD toxicity are unclear, research areas include the role of thyroid hormones (Rozman et al. 1984) interference with plasma membrane functions (Matsumura 1983) alterations in ligand receptors (Vickers et al. 1985) the causes of hypophagia (reduced desire for food) and subsequent attempts to alter or reverse the pattern of weight loss (Courtney et al. 1978 Seefeld et al. 1984 Seefeld and Peterson 1984) and excretion kinetics of biotransformed metabolites (Koshakji et al. 1984). 

A variety of biochemical and molecular mechanisms have been described to explain how PUFAs can modulate immune cell fate and function. The primary mechanism of action of dietary n-3 PUFAs involves the replacement of AA in the lipid membrane of the cells with either EPA or DHA. This, in effect, competitively inhibits the oxygenation of AA by the COX enzymes. For example, the EPA-induced suppression in the production of AA-derived eicosanoids is followed by a subsequent increase in the production of those from EPA. Generally, the EPA-derived eicosanoids are considered to be much less potent than those from AA, thus explaining, at least partially, the anti-inflammatory effects of PUFAs. A similar mechanism of action can be demonstrated for DHA, either directly or by retroconversion to EPA. 

---