Cyclosporin A and Glucocorticoids

Glucocorticoids (GC) produced endogenously in response to stress alter both innate and antigen-driven immunity. Cortisol (hydrocortisone) is the predominant GC in humans and most other species, whereas corticosterone is the most plentiful in mice and rats. Both natural and synthetic GC are used to reduce inflammation, manage autoimmune and hypersensitivity diseases, and treat certain neoplastic diseases. Certain inflammatory cytokines, including IL-1, IL-6 and TNFa stimulate (directly and indirectly) GC synthesis and release, a feedback mechanism to control inflammation. 

Both CsA and GC enter cells by diffusion and mediate immunosuppressive effects by binding to receptors cyclophilin in the case of CsA, and glucocorticoid receptor (GR) for GC. CsA prevents activation of lymphocytes. In contrast, GC prevent transcription of proinflammatory cytokines. 

In experimental mouse studies, TCDD exposure results in thymic atrophy and alterations in an array of adaptive immune responses including delayed-type hypersensitivity (DTH), cytotoxic T lymphocyte (CTL) activity, and T-cell-dependent antibody responses. In contrast, TCDD enhances neutrophil recruitment to the site of antigen challenge. Because both cell-mediated and humoral immunity are suppressed by TCDD and related HAHs, it is not surprising that administration of these compounds to mice results in increased susceptibility to challenge with viral, bacterial, or parasitic diseases, as well as syngeneic tumors. 

In adult mice the primary antibody response to sheep red blood cells (SRBC) is one of the most sensitive and reproducible immune endpoints that is affected by TCDD and related HAHs. For example, the TCDD dose that suppresses this response by 50% in mice is approximately 0.7 pg TCDD/kg. The antibody response to SRBCs is dependent on the collaborative interaction of antigen-presenting cells (dendritic cells) and T and B lymphocytes all of these cells appear to be targets for TCDD. 

Two areas of investigation provide evidence of a central role for the AhR in TCDD-induced immunosuppression. First, differences in susceptibility to TCDD- 

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