DIFFERENTIAL-EFFECTS OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN, BIS(TRI-N-BUTYLTIN)OXIDE AND CYCLOSPORINE ON THYMUS HISTOPHYSIOLOGY

Recent advances in the histophysiology of the normal thymus have revea led its complex architecture, showing distinct microenvironments at th e light and electron microscopic level. The epithelium comprising the major component of the thymic stroma is not only involved in the posit ive selection of thymocytes, but also in their negative selection. Den dritic cells, however, are more efficient than epithelial cells in med iating 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 respond s to immunotoxic injury. Both the thymocytes and the nonlymphoid compa rtment of the organ can be targets of exposure. Disturbance of positiv e and negative thymocyte selection may have a major impact on the immu nological function of the thymus. Suppression of peripheral T-cell-dep endent 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. A lthough the regenerative capacity of thymus structure is remarkable, i t 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) and bis(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 a nd TBTO exposure results in cortical lymphodepletion, albeit by differ ent mechanisms. An important feature of TCDD-mediated thymus toxicity is the disruption of epithelial cells in the cortex. TBTO primarily in duces cortical thymocyte cell death. In contrast, CsA administration r esults in major alterations in the medulla, the cortex remaining large ly intact. Medullary epithelial cells and dendritic cells are particul arly sensitive to CsA. The differential effects of these three immunot oxicants suggest unique susceptibilities of the various cell types and regions that make up the thymus.