Differential Effects of 2,3,7,8-Tetrachlorodibenzo-P-Dioxin,bis(Tri-N-Butyltin)Oxide and Cyclosporine on Thymus Histophysiology

Abstract

Recent advances in the histophysiology of the normal thymus have revealed its complex architecture, showing distinct microenvironments at the light and electron microscopic level. The epithelium comprising the major component of the thymic stroma is not only involved in the positive selection of thymocytes, but also in their negative selection. Dendritic cells, however, are more efficient than epithelial cells in mediating negative selection. Thymocytes are dependent on the epithelium for normal development. Conversely, epithelial cells need the presence of thymocytes to maintain their integrity.The thymus rapidly responds to immunotoxic injury. Both the thymocytes and the nonlymphoid compartment of the organ can be targets of exposure. Disturbance of positive and negative thymocyte selection may have a major impact on the immunological function of the thymus. Suppression of peripheral T-cell-dependent immunity as a consequence of thymus toxicity is primarily seen after perinatal exposure when the thymus is most active. Autoimmunity may be another manifestation of chemically mediated thymus toxicity. Although the regenerative capacity of thymus structure is remarkable, it remains to be clarified whether this also applies to thymus function.In-depth mechanistic studies on chemical-induced dysfunction of the thymus have been conducted with the environmental contaminants 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) andbis(tri-n-butyltin)oxide (TBTO) as well as the pharmaceutical immunosuppressant cyclosporine (CsA). Each of these compounds exerts a differential effect on the morphology of the thymus, depending on the cellular targets for toxicity. TCDD and TBTO exposure results in cortical lymphodepletion, albeit by different mechanisms. An important feature of TCDD-mediated thymus toxicity is the disruption of epithelial cells in the cortex. TBTO primarily induces cortical thymocyte cell death. In contrast, CsA administration results in major alterations in the medulla, the cortex remaining largely intact. Medullary epithelial cells and dendritic cells are particularly sensitive to CsA. The differential effects of these three immunotoxicants suggest unique susceptibilities of the various cell types and regions that make up the thymus.