Cyclosporin A-induced changes of the thymic microenvironment. A review of morphological studies.

Abstract

Cyclosporin A is an immunosuppressive drug, which disrupts the activation of peripheral T-lymphocyte pool and blocks the maturation of thymocytes within the thymus. Normally, thymic nonlymphoid cells provide the optimal inductive microenvironment for development of T-lymphocytes. After application of cyclosporin A the complex alterations of the thymic microenvironment occur, affecting all types of nonlymphoid cells. All subsets of thymic epithelial cells are thoroughly changed. The subcapsular epithelial cells show the prominent enlargement of cytokeratin contents. In electron microscopy, however, these cells present the morpho-functional aspect of resting cells. The epithelial cells in deeper cortex become enlarged and stockier, whereby their cell processes appear more ramified and thicker. Thus, the cytoreticulum they create seems much denser. These cells strongly express MHC antigens. Their subcellular organization is suggestive of increased synthetic and secretory activity. The number of medullary epithelial cells is decreased. The cells with the most mature phenotype are the most prominently depleted and the ones with phenotypically and morphologically immature appearance predominate. The number of Hassall's bodies is also decreased. The number of cortical macrophages does not increase. However, these cells become enlarged showing the prominent changes in enzyme capacity, histochemical features and ultrastructural organization. Thus, they become similar to macrophages located in the cortico-medullary zone of the normal rat thymus. Cortical macrophages increase the activity of hydrolytic enzymes, acid phosphatase and nonspecific esterase, develop the strong activity of chloroacetate esterase, the strong activity of respiratory enzyme succinic dehydrogenase and begin to show the marked presence of prostaglandin synthase. Moreover, the cytoplasmic inclusions, which are aldehyde fuchsin- and PAS-positive and show sudanophilia, appear within cortical macrophages. In electron microscopy these cells show an abundant cytoplasm a very active appearance and the variety of vacuolar cytoplasmic inclusions. The mitoses of neighboring thymocytes are often seen. The number of interdigitating cells is decreased due to reduced size of thymic medulla, but these cells do not show the substantial phenotype changes. The description and classification of all types of nonlymphoid cells, which constitute the normal thymic microenvironment, is also presented. The functional significance and possible mechanisms of CSA-induced changes of the thymic microenvironment are discussed.